Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861
", "doi": "10.1038/s41467-025-60816-z", "pmcid": "PMC12219382", "issn": "2041-1723", "publisher": "Nature Publishing Group", "publication": "Nature Communications", "publication_date": "2025-07-01", "series_number": "1", "volume": "16", "issue": "1", "pages": "5599" }, { "id": "authors:d0d3p-bp464", "collection": "authors", "collection_id": "d0d3p-bp464", "cite_using_url": "https://authors.library.caltech.edu/records/d0d3p-bp464", "type": "article", "title": "Preface: Recognizing Implicit Bias in the Scientific & Legal Communities", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Tatel", "given_name": "David S." }, { "family_name": "Mazza", "given_name": "Anne-Marie" } ], "abstract": "[Introduction] Several years ago, in the Fall 2018 volume of Dædalus, we wrote “Bridging the Science-Law Divide,” an essay about the work of the National Academies of Sciences, Engineering, and Medicine's Committee on Science, Technology, and Law. In that essay, we discussed the importance of having the legal and scientific communities engage with each other on a host of issues, and highlighted work that the committee conducted on the courts' handling of scientific evidence and on society's governance of emerging technologies. We mentioned that, in the coming years, the committee hoped to focus on the issue of implicit bias (referred to as “unconscious bias” in our 2018 essay), as it was becoming increasingly evident that factors outside individual awareness were affecting personal and institutional decision-making that hindered the full participation of all our citizens.
", "doi": "10.1162/daed_e_02043", "issn": "0011-5266", "publisher": "MIT Press", "publication": "Daedalus", "publication_date": "2024-03-01", "series_number": "1", "volume": "153", "issue": "1", "pages": "6-7" }, { "id": "authors:s4pxh-pda93", "collection": "authors", "collection_id": "s4pxh-pda93", "cite_using_url": "https://authors.library.caltech.edu/records/s4pxh-pda93", "type": "article", "title": "Science, evidence, law, and justice", "author": [ { "family_name": "Albright", "given_name": "Thomas D.", "orcid": "0000-0003-0691-5992", "clpid": "Albright-Thomas-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Mazza", "given_name": "Anne-Marie", "clpid": "Mazza-Anne-Marie" }, { "family_name": "Mnookin", "given_name": "Jennifer L.", "clpid": "Mnookin-Jennifer-L" }, { "family_name": "Tatel", "given_name": "David S.", "clpid": "Tatel-David-S" } ], "abstract": "For nearly 25 y, the Committee on Science, Technology, and Law (CSTL), of the National Academies of Sciences, Engineering, and Medicine, has brought together distinguished members of the science and law communities to stimulate discussions that would lead to a better understanding of the role of science in legal decisions and government policies and to a better understanding of the legal and regulatory frameworks that govern the conduct of science. Under the leadership of recent CSTL co-chairs David Baltimore and David Tatel, and CSTL director Anne-Marie Mazza, the committee has overseen many interdisciplinary discussions and workshops, such as the international summits on human genome editing and the science of implicit bias, and has delivered advisory consensus reports focusing on topics of broad societal importance, such as dual use research in the life sciences, voting systems, and advances in neural science research using organoids and chimeras. One of the most influential CSTL activities concerns the use of forensic evidence by law enforcement and the courts, with emphasis on the scientific validity of forensic methods and the role of forensic testimony in bringing about justice. As coeditors of this Special Feature, CSTL alumni Tom Albright and Jennifer Mnookin have recruited articles at the intersection of science and law that reveal an emerging scientific revolution of forensic practice, which we hope will engage a broad community of scientists, legal scholars, and members of the public with interest in science-based legal policy and justice reform.", "doi": "10.1073/pnas.2312529120", "pmcid": "PMC10576109", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences", "publication_date": "2023-10-10", "series_number": "41", "volume": "120", "issue": "41", "pages": "e2312529120" }, { "id": "authors:3x1g7-ce439", "collection": "authors", "collection_id": "3x1g7-ce439", "cite_using_url": "https://authors.library.caltech.edu/records/3x1g7-ce439", "type": "article", "title": "Non-viral precision T\u2009cell receptor replacement for personalized cell therapy", "author": [ { "family_name": "Foy", "given_name": "Susan P." }, { "family_name": "Jacoby", "given_name": "Kyle" }, { "family_name": "Bota", "given_name": "Daniela A.", "orcid": "0000-0002-9680-9060" }, { "family_name": "Hunter", "given_name": "Theresa", "orcid": "0000-0002-6494-1294" }, { "family_name": "Pan", "given_name": "Zheng" }, { "family_name": "Stawiski", "given_name": "Eric" }, { "family_name": "Ma", "given_name": "Yan" }, { "family_name": "Lu", "given_name": "William" }, { "family_name": "Peng", "given_name": "Songming" }, { "family_name": "Wang", "given_name": "Clifford L." }, { "family_name": "Yuen", "given_name": "Benjamin" }, { "family_name": "Dalmas", "given_name": "Olivier" }, { "family_name": "Heeringa", "given_name": "Katharine" }, { "family_name": "Sennino", "given_name": "Barbara" }, { "family_name": "Conroy", "given_name": "Andy" }, { "family_name": "Bethune", "given_name": "Michael T." }, { "family_name": "Mende", "given_name": "Ines" }, { "family_name": "White", "given_name": "William" }, { "family_name": "Kukreja", "given_name": "Monica" }, { "family_name": "Gunturu", "given_name": "Swetha" }, { "family_name": "Humphrey", "given_name": "Emily" }, { "family_name": "Hussaini", "given_name": "Adeel" }, { "family_name": "An", "given_name": "Duo" }, { "family_name": "Litterman", "given_name": "Adam J." }, { "family_name": "Quach", "given_name": "Boi Bryant" }, { "family_name": "Ng", "given_name": "Alphonsus H. C.", "orcid": "0000-0003-0074-4598" }, { "family_name": "Lu", "given_name": "Yue", "orcid": "0000-0001-9036-2803" }, { "family_name": "Smith", "given_name": "Chad" }, { "family_name": "Campbell", "given_name": "Katie M.", "orcid": "0000-0001-6491-4432" }, { "family_name": "Anaya", "given_name": "Daniel" }, { "family_name": "Skrdlant", "given_name": "Lindsey" }, { "family_name": "Huang", "given_name": "Eva Yi-Hsuan" }, { "family_name": "Mendoza", "given_name": "Ventura" }, { "family_name": "Mathur", "given_name": "Jyoti" }, { "family_name": "Dengler", "given_name": "Luke" }, { "family_name": "Purandare", "given_name": "Bhamini" }, { "family_name": "Moot", "given_name": "Robert" }, { "family_name": "Yi", "given_name": "Michael C." }, { "family_name": "Funke", "given_name": "Roel" }, { "family_name": "Sibley", "given_name": "Alison" }, { "family_name": "Stallings-Schmitt", "given_name": "Todd" }, { "family_name": "Oh", "given_name": "David Y." }, { "family_name": "Chmielowski", "given_name": "Bartosz", "orcid": "0000-0002-2374-3320" }, { "family_name": "Abedi", "given_name": "Mehrdad", "orcid": "0000-0003-4640-0977" }, { "family_name": "Yuan", "given_name": "Yuan", "orcid": "0000-0001-7440-8939" }, { "family_name": "Sosman", "given_name": "Jeffrey A." }, { "family_name": "Lee", "given_name": "Sylvia M.", "orcid": "0000-0002-7425-2230" }, { "family_name": "Schoenfeld", "given_name": "Adam J.", "orcid": "0000-0002-2644-1416" }, { "family_name": "Baltimore", "given_name": "David L.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Franzusoff", "given_name": "Alex" }, { "family_name": "Ribas", "given_name": "Antoni", "orcid": "0000-0003-3669-8458" }, { "family_name": "Rao", "given_name": "Arati V." }, { "family_name": "Mandl", "given_name": "Stefanie J." } ], "abstract": "T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1,2,3. Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.
", "doi": "10.1038/s41586-022-05531-1", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2023-03-23", "series_number": "7953", "volume": "615", "issue": "7953", "pages": "687-696" }, { "id": "authors:gj12b-2a937", "collection": "authors", "collection_id": "gj12b-2a937", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230615-812763000.7", "type": "article", "title": "Paul Berg (1926\u20132023) Father of genetic engineering", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Paul Berg, the pioneering biochemist who invented recombinant DNA technology, died on 15 February at age 96. Paul, whose work made genetic engineering possible, was a bridge between the traditional world of biochemistry and metabolism and the modern world of molecular biology.", "doi": "10.1126/science.adh2943", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2023-03-17", "series_number": "6637", "volume": "379", "issue": "6637", "pages": "1095" }, { "id": "authors:w9mhk-1ha20", "collection": "authors", "collection_id": "w9mhk-1ha20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230425-250392700.4", "type": "article", "title": "1478\u2005A phase I study of personalized adoptive TCR T cell therapy in patients with solid tumors: safety, efficacy, and T cell trafficking to tumors of non-virally gene edited T cells", "author": [ { "family_name": "Foy", "given_name": "Susan", "clpid": "Foy-Susan" }, { "family_name": "Jacoby", "given_name": "Kyle" }, { "family_name": "Bota", "given_name": "Daniela" }, { "family_name": "Hunter", "given_name": "Theresa" }, { "family_name": "Schoenfeld", "given_name": "Adam" }, { "family_name": "Pan", "given_name": "Zheng" }, { "family_name": "Stawiski", "given_name": "Eric" }, { "family_name": "Ma", "given_name": "Yan" }, { "family_name": "Lu", "given_name": "William" }, { "family_name": "Peng", "given_name": "Songming" }, { "family_name": "Wang", "given_name": "Clifford" }, { "family_name": "Yuen", "given_name": "Benjamin" }, { "family_name": "Dalmas", "given_name": "Olivier" }, { "family_name": "Heeringa", "given_name": "Katharine" }, { "family_name": "Sennino", "given_name": "Barbara" }, { "family_name": "Conroy", "given_name": "Andy" }, { "family_name": "Bethune", "given_name": "Michael" }, { "family_name": "Mende", "given_name": "Ines" }, { "family_name": "White", "given_name": "William" }, { "family_name": "Kukreja", "given_name": "Monica" }, { "family_name": "Gunturu", "given_name": "Swetha" }, { "family_name": "Humphrey", "given_name": "Emily" }, { "family_name": "Hussaini", "given_name": "Adeel" }, { "family_name": "An", "given_name": "Duo" }, { "family_name": "Quach", "given_name": "Boi" }, { "family_name": "Ng", "given_name": "Alphonsus" }, { "family_name": "Lu", "given_name": "Yue" }, { "family_name": "Smith", "given_name": "Chad" }, { "family_name": "Campbell", "given_name": "Katie" }, { "family_name": "Anaya", "given_name": "Daniel" }, { "family_name": "Skrdlant", "given_name": "Lindsey" }, { "family_name": "Huang", "given_name": "Eva" }, { "family_name": "Mendoza", "given_name": "Ventura" }, { "family_name": "Mathur", "given_name": "Jyoti" }, { "family_name": "Dengler", "given_name": "Luke" }, { "family_name": "Purandare", "given_name": "Bhamini" }, { "family_name": "Moot", "given_name": "Robert" }, { "family_name": "Yi", "given_name": "Michael" }, { "family_name": "Funke", "given_name": "Roel" }, { "family_name": "Sibley", "given_name": "Alison" }, { "family_name": "Stallings-Schmitt", "given_name": "Todd" }, { "family_name": "Oh", "given_name": "David" }, { "family_name": "Chmielowski", "given_name": "Bartosz" }, { "family_name": "Abedi", "given_name": "Mehrdad" }, { "family_name": "Yuan", "given_name": "Yuan" }, { "family_name": "Sosman", "given_name": "Jeff" }, { "family_name": "Lee", "given_name": "Sylvia" }, { "family_name": "Williams", "given_name": "Claire" }, { "family_name": "Kim", "given_name": "Sean" }, { "family_name": "Keefe", "given_name": "Matthwe" }, { "family_name": "Leon", "given_name": "Michael" }, { "family_name": "Kim", "given_name": "Youngmi" }, { "family_name": "Reeves", "given_name": "Jason" }, { "family_name": "Goldman", "given_name": "Wes" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James" }, { "family_name": "Franzusoff", "given_name": "Alex" }, { "family_name": "Ribas", "given_name": "Antoni" }, { "family_name": "Rao", "given_name": "Arati" }, { "family_name": "Mandl", "given_name": "Stefanie" } ], "abstract": "Background: NeoTCR-P1 is a personalized autologous T cell therapy for treatment of patients with solid tumors. Neoantigen-specific T cell receptors (neoTCRs) were isolated from the patients' own circulating CD8 T cells using the imPACT Isolation Technology\u00ae, followed by non-viral precision genome engineering into an autologous apheresis product for infusion back into the patient. \n\nMethods: This phase 1 trial is a first-in-human, multi-center, dose-escalation study to evaluate the safety, tolerability, and manufacturing feasibility of NeoTCR-P1 alone or in combination with IL-2 in solid tumors. \n\nPatients with TCRs identified at screening and meeting eligibility criteria underwent apheresis to manufacture personalized NeoTCR-P1 cell product. Lymphodepleted patients received a single dose of up-to-three distinct NeoTCR cell products at dose levels of 0.4, 1.2, or 4\u00d710\u2079 NeoTCR-edited T cells. \n\nPre- and post-treatment blood and biopsy samples were collected to evaluate NeoTCR-P1 pharmacokinetics, tumor trafficking, signs of T cell engagement or potential mechanisms of resistance. \n\nResults: Sixteen patients were infused with NeoTCR-P1 T cells including patients with MSS-colorectal cancer (11), breast cancer (2), ovarian cancer (1), melanoma (1), or non-small cell lung cancer (1). Four of the sixteen patients were treated with NeoTCR-P1 + IL-2. \n\nTwo patients experienced toxicities associated with NeoTCR-P1 cell infusions: a grade 1 CRS and a grade 2 ICANS. Five patients had stable disease as their best response at their first tumor assessment (day 28). \n\nNeoTCR+ T cells detected in the peripheral blood had an average peak of 3.6% (range 0.9-7.3%) for DL1, 11.7% (7.7-20.8%) for DL2, and 19.8% (12.0-37.3%) for DL3. Increases in NeoTCR T cells were observed at higher dose levels, stronger lymphodepletion, or higher gene editing rates of the infused product. \n\nEight post-infusion biopsies were available for sequencing and imaging analysis; 17 of 22 neoTCR-T cells were detected in post-infusion biopsies with 12 neoTCRs among the top 4% of CDR3 sequences detected. The targeted neoantigens were detected in 7 of 8 post-treatment biopsies (15 of 22 targets), and personalized ctDNA confirmed targeting of a predicted sub-clonal mutation. An APOBEC signature and HLA-LOH were identified as potential mechanisms of resistance. By single-cell, spatial molecular imaging, neoTCR-T cells were visualized in post-treatment biopsies and found to differentially express potential markers of engagement. \n\nConclusions: This study demonstrates the feasibility of isolating and manufacturing NeoTCR-T cells using non-viral precision genome engineering, the safety of infusing up-to-three gene edited NeoTCR-T cell products, and T cell persistence and trafficking to a variety of solid tumors.", "doi": "10.1136/jitc-2022-sitc2022.1478", "issn": "2051-1426", "publisher": "BMJ Publishing Group Ltd", "publication": "Journal for ImmunoTherapy of Cancer", "publication_date": "2022-11", "series_number": "S2", "volume": "10", "issue": "S2", "pages": "A1536" }, { "id": "authors:0e6e7-5tx40", "collection": "authors", "collection_id": "0e6e7-5tx40", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220411-915265900", "type": "article", "title": "Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial", "author": [ { "family_name": "Casazza", "given_name": "Joseph P.", "orcid": "0000-0001-5648-4639", "clpid": "Casazza-Joseph-P" }, { "family_name": "Cale", "given_name": "Evan M." }, { "family_name": "Narpala", "given_name": "Sandeep" }, { "family_name": "Yamshchikov", "given_name": "Galina V." }, { "family_name": "Coates", "given_name": "Emily E." }, { "family_name": "Hendel", "given_name": "Cynthia S." }, { "family_name": "Novik", "given_name": "Laura" }, { "family_name": "Holman", "given_name": "LaSonji A." }, { "family_name": "Widge", "given_name": "Alicia T.", "orcid": "0000-0001-7615-8320" }, { "family_name": "Apte", "given_name": "Preeti" }, { "family_name": "Gordon", "given_name": "Ingelise" }, { "family_name": "Gaudinski", "given_name": "Martin R." }, { "family_name": "Conan-Cibotti", "given_name": "Michelle" }, { "family_name": "Lin", "given_name": "Bob C." }, { "family_name": "Nason", "given_name": "Martha C." }, { "family_name": "Trofymenko", "given_name": "Olga" }, { "family_name": "Telscher", "given_name": "Shinyi" }, { "family_name": "Plummer", "given_name": "Sarah H." }, { "family_name": "Wycuff", "given_name": "Diane" }, { "family_name": "Adams", "given_name": "William C." }, { "family_name": "Pandey", "given_name": "Janardan P." }, { "family_name": "McDermott", "given_name": "Adrian", "orcid": "0000-0003-0616-9117" }, { "family_name": "Roederer", "given_name": "Mario" }, { "family_name": "Sukienik", "given_name": "Avery N." }, { "family_name": "O'Dell", "given_name": "Sijy" }, { "family_name": "Gall", "given_name": "Jason G." }, { "family_name": "Flach", "given_name": "Britta" }, { "family_name": "Terry", "given_name": "Travis L." }, { "family_name": "Choe", "given_name": "Misook" }, { "family_name": "Shi", "given_name": "Wei" }, { "family_name": "Chen", "given_name": "Xuejun", "orcid": "0000-0001-9192-0440" }, { "family_name": "Kaltovich", "given_name": "Florence" }, { "family_name": "Saunders", "given_name": "Kevin O.", "orcid": "0000-0001-7399-7954" }, { "family_name": "Stein", "given_name": "Judy A." }, { "family_name": "Doria-Rose", "given_name": "Nicole A." }, { "family_name": "Schwartz", "given_name": "Richard M." }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Nabel", "given_name": "Gary J.", "orcid": "0000-0003-0619-4419" }, { "family_name": "Koup", "given_name": "Richard A." }, { "family_name": "Graham", "given_name": "Barney S." }, { "family_name": "Ledgerwood", "given_name": "Julie E." }, { "family_name": "Mascola", "given_name": "John R." }, { "family_name": "Andrews", "given_name": "Charla" }, { "family_name": "Arthur", "given_name": "Anita" }, { "family_name": "Awan", "given_name": "Seemal F." }, { "family_name": "Beck", "given_name": "Allison" }, { "family_name": "Burch", "given_name": "Eugeania" }, { "family_name": "Burgos Florez", "given_name": "Maria C." }, { "family_name": "Berkowitz", "given_name": "Nina M." }, { "family_name": "Boritz", "given_name": "Eli A." }, { "family_name": "Carlton", "given_name": "Kevin" }, { "family_name": "Cartagena", "given_name": "Cora T." }, { "family_name": "Carter", "given_name": "Christina" }, { "family_name": "Chen", "given_name": "Grace L." }, { "family_name": "Costner", "given_name": "Pamela" }, { "family_name": "Cunningham", "given_name": "Jennifer" }, { "family_name": "Douek", "given_name": "Daniel C." }, { "family_name": "Eshun", "given_name": "Aba M." }, { "family_name": "Evans", "given_name": "Catina" }, { "family_name": "Hicks", "given_name": "Renunda" }, { "family_name": "Houser", "given_name": "Katherine V." }, { "family_name": "Jones", "given_name": "Justine" }, { "family_name": "Larkin", "given_name": "Brenda" }, { "family_name": "Le", "given_name": "Lam" }, { "family_name": "Mendoza", "given_name": "Floreliz" }, { "family_name": "Migueles", "given_name": "Stephen" }, { "family_name": "Misasi", "given_name": "John" }, { "family_name": "Nguyen", "given_name": "Thuy A." }, { "family_name": "Ola", "given_name": "Abidemi" }, { "family_name": "Parker", "given_name": "Karen" }, { "family_name": "Pittman", "given_name": "Iris" }, { "family_name": "Requilman", "given_name": "La' Shawn" }, { "family_name": "Rothwell", "given_name": "Ro Shauna" }, { "family_name": "Schieber", "given_name": "Gretchen L." }, { "family_name": "Saunders", "given_name": "Jamie" }, { "family_name": "Sitar", "given_name": "Sandra" }, { "family_name": "Tran", "given_name": "Colin" }, { "family_name": "Trofymenko", "given_name": "Olga" }, { "family_name": "Vasilenko", "given_name": "Olga" }, { "family_name": "Waheed", "given_name": "Sana" }, { "family_name": "Wang", "given_name": "Lingshu" }, { "family_name": "Wang", "given_name": "Xiaolin" }, { "family_name": "Whalen", "given_name": "William" }, { "family_name": "Williams", "given_name": "Pernell" }, { "family_name": "Wu", "given_name": "Richard L." }, { "family_name": "Zephir", "given_name": "Kathy" }, { "literal": "VRC 603 Study Team" } ], "abstract": "Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial (NCT03374202). AAV8-VRC07 was given at doses of 5\u2009\u00d7\u200910\u00b9\u2070, 5\u2009\u00d7\u200910\u00b9\u00b9 and 2.5\u2009\u00d7\u200910\u00b9\u00b2 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1\u20133 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P\u2009=\u20090.008) and 52 weeks (P\u2009=\u20090.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1\u2009\u00b5g\u2009ml\u207b\u00b9 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.", "doi": "10.1038/s41591-022-01762-x", "issn": "1078-8956", "publisher": "Nature Publishing Group", "publication": "Nature Medicine", "publication_date": "2022-05", "series_number": "5", "volume": "28", "issue": "5", "pages": "1022-1030" }, { "id": "authors:ywykh-eje78", "collection": "authors", "collection_id": "ywykh-eje78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220104-185037609", "type": "article", "title": "T cell immunity independent HBV clearance and validation of a new HBV cure strategy in HBV infected uPA/SCID chimeric mice", "author": [ { "family_name": "Zhang", "given_name": "Bai-Hua", "clpid": "Zhang-Bai-Hua" }, { "family_name": "Zhou", "given_name": "Yuanping", "clpid": "Zhou-Yuanping" }, { "family_name": "Horrigan", "given_name": "Stephen", "clpid": "Horrigan-Stephen" }, { "family_name": "Zoulim", "given_name": "Fabien", "clpid": "Zoulim-Fabien" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Zhang", "given_name": "Yong-Yuan", "clpid": "Zhang-Yong-Yuan" } ], "abstract": "Background: Chronic HBV infection is maintained by HBV cccDNA. Evidence suggests that cccDNA persistence is maintained by cccDNA replenishment mainly through de novo infection. We aimed to test a new HBV cure strategy that constantly blocks new rounds of infection in HBV infected animal model with anti-HBs antibody. A prerequisite for establishing HBV cure with this new strategy is that infected livers must undergo spontaneous clearance. Methods: An optimized AAV vector was used to express sustained high level of anti-HBs. HBV infected uPA/SCID mice with null T and B cell immunity and viremia >1E8 HBV DNA copies/ml, were treated with AAV vector expressing malaria antibody or anti-HBs antibodies 7-week post inoculation. Serum HBV DNA and HBsAg level were monitored and liver HBV DNA including cccDNA level was determined through random sampling of each autopsied liver 20 times. Results: > 100ug/mL expressed antibodies were detected in week 3 after a single injection of 1E11 genome copies of each AAV vector and sustained for at least 250-day. There are two key findings: 1. T cell immunity independent clearance. Viremia in HBV infected animals can experience up to 10-fold drop for a few weeks, indicating a portion of infected cells spontaneously clear HBV infection. Viremia in animals treated with anti-HBs antibody was up to >100-fold lower than that with expressing malaria antibody, suggesting the presence of T cell immunity-independent clearance and de novo infection after all infectible liver cells infected. 2. Validation of new HBV cure strategy. Intervention with anti-HBs antibody reproduce two HBV cure courses resembling acute HBV infection, one group of animals (n=9) started progressive viremia reduction for up to 24-fold after reaching peak viremia (>3E10 copies/ml) and the other group (n=6) aborted peak infection with >100-fold lower viremia and 46-fold lower HBsAg level compared to animals with expressed malaria antibody. HBV DNA and HBsAg in one of 6 animals became undetectable for >3 months and cccDNA was only detected in 2 of 19 liver samplings (average 0.036 copies/cell and 0.008 copies/cell in two positive samplings), while cccDNA was detected in all 20 sampling with average 10.8 cccDNA copies/cell in an animal treated with malaria antibody. Conclusion: 1. T cell immunity-independent HBV clearance occurs, and it services a foundation for establishing HBV cure in HBV infected human livers of chimeric mice. 2. Constantly blocking de novo infection with engineered humoral immunity that remedies absent anti-HBs significantly lowers HBV infection and cccDNA level and reproduces two HBV cure courses resembling resolution courses in acute HBV infection.", "doi": "10.1002/hep.32187", "issn": "0270-9139", "publisher": "Wiley", "publication": "Hepatology", "publication_date": "2021-10", "series_number": "S1", "volume": "74", "issue": "S1", "pages": "64A" }, { "id": "authors:abag9-n6b48", "collection": "authors", "collection_id": "abag9-n6b48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210305-074231958", "type": "article", "title": "Systems biology for investigating drug resistance mechanism of melanoma", "author": [ { "family_name": "Su", "given_name": "Yapeng", "orcid": "0000-0002-6305-8467", "clpid": "Su-Yapeng" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Ko", "given_name": "Melissa", "clpid": "Ko-Melissa-E" }, { "family_name": "Cheng", "given_name": "Hanjun", "clpid": "Cheng-Hanjun" }, { "family_name": "Zhu", "given_name": "Ronghui", "orcid": "0000-0001-8171-482X", "clpid": "Zhu-Ronghui" }, { "family_name": "Xue", "given_name": "Min", "clpid": "Xue-Min" }, { "family_name": "Robert", "given_name": "Lidia", "clpid": "Robert-Lidia" }, { "family_name": "Levine", "given_name": "Raphael", "clpid": "Levine-Raphael-D" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Nolan", "given_name": "Garry", "clpid": "Nolan-Garry-P" }, { "family_name": "Wei", "given_name": "Wei", "orcid": "0000-0002-1018-7708", "clpid": "Wei-Wei" }, { "family_name": "Plevritis", "given_name": "Sylvia", "clpid": "Plevritis-Sylvia-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line.\n\nCancers commonly develop resistance against chemotherapeutics or targeted therapies through various types of genetic or non-genetic mechanisms. Non-genetic mechanisms have been shown to occur early on and can provide a latent reservoir of cells for the emergence of various different type of mechanisms, yet very limited understanding of process were resolve main from bulk analysis. Considering the heterogeneous nature of the tumor cells, a single-cell level characterization of the process worth detailed further investigation. Using MAPK inhibition of BRAF-mutant melanomas as a model system, we resolved that cells take different paths to go from drug-sensitive to drug-resistant state. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-na\u00efve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-na\u00efve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies.", "doi": "10.1158/1538-7445.am2020-6585", "issn": "0008-5472", "publisher": "American Association for Cancer Research", "publication": "Cancer Research", "publication_date": "2020-08", "series_number": "16", "volume": "80", "issue": "16", "pages": "Art. No. 6585" }, { "id": "authors:3v9sr-9f182", "collection": "authors", "collection_id": "3v9sr-9f182", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191007-074542895", "type": "article", "title": "Sequence-Dependent Dynamics of Synthetic and Endogenous RSSs in V(D)J Recombination", "author": [ { "family_name": "Hirokawa", "given_name": "Soichi", "orcid": "0000-0001-5584-2676", "clpid": "Hirokawa-Soichi" }, { "family_name": "Chure", "given_name": "Griffin", "orcid": "0000-0002-2216-2057", "clpid": "Chure-G" }, { "family_name": "Belliveau", "given_name": "Nathan M.", "orcid": "0000-0002-1536-1963", "clpid": "Belliveau-N-M" }, { "family_name": "Lovely", "given_name": "Geoffrey A.", "clpid": "Lovely-G-A" }, { "family_name": "Anaya", "given_name": "Michael", "orcid": "0000-0002-6944-3614", "clpid": "Anaya-Michael-A" }, { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Phillips", "given_name": "Rob", "orcid": "0000-0003-3082-2809", "clpid": "Phillips-R" } ], "abstract": "Developing lymphocytes of jawed vertebrates cleave and combine distinct gene segments to assemble antigen\u2013receptor genes. This process called V(D)J recombination that involves the RAG recombinase binding and cutting recombination signal sequences (RSSs) composed of conserved heptamer and nonamer sequences flanking less well-conserved 12- or 23-bp spacers. Little quantitative information is known about the contributions of individual RSS positions over the course of the RAG\u2013RSS interaction. We employ a single-molecule method known as tethered particle motion to track the formation, lifetime and cleavage of individual RAG\u201312RSS\u201323RSS paired complexes (PCs) for numerous synthetic and endogenous 12RSSs. We reveal that single-bp changes, including in the 12RSS spacer, can significantly and selectively alter PC formation or the probability of RAG-mediated cleavage in the PC. We find that some rarely used endogenous gene segments can be mapped directly to poor RAG binding on their adjacent 12RSSs. Finally, we find that while abrogating RSS nicking with Ca\u00b2\u207a leads to substantially shorter PC lifetimes, analysis of the complete lifetime distributions of any 12RSS even on this reduced system reveals that the process of exiting the PC involves unidentified molecular details whose involvement in RAG\u2013RSS dynamics are crucial to quantitatively capture kinetics in V(D)J recombination.", "doi": "10.1093/nar/gkaa418", "pmcid": "PMC7337519", "issn": "0305-1048", "publisher": "Oxford University Press", "publication": "Nucleic Acids Research", "publication_date": "2020-07-09", "series_number": "12", "volume": "48", "issue": "12", "pages": "6726-6739" }, { "id": "authors:gw605-vrz22", "collection": "authors", "collection_id": "gw605-vrz22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200511-122023000", "type": "article", "title": "Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line", "author": [ { "family_name": "Su", "given_name": "Yapeng", "orcid": "0000-0002-6305-8467", "clpid": "Su-Yapeng" }, { "family_name": "Ko", "given_name": "Melissa E.", "clpid": "Ko-Melissa-E" }, { "family_name": "Cheng", "given_name": "Hanjun", "clpid": "Cheng-Hanjun" }, { "family_name": "Zhu", "given_name": "Ronghui", "clpid": "Zhu-Ronghui" }, { "family_name": "Xue", "given_name": "Min", "clpid": "Xue-Min" }, { "family_name": "Wang", "given_name": "Jessica", "orcid": "0000-0003-1421-4969", "clpid": "Wang-Jessica-K" }, { "family_name": "Lee", "given_name": "Jihoon W.", "orcid": "0000-0002-6749-5111", "clpid": "Lee-Jihoon-W" }, { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-L-S" }, { "family_name": "Xu", "given_name": "Alexander", "orcid": "0000-0003-4877-4358", "clpid": "Xu-Alexander-M" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Robert", "given_name": "Lidia", "clpid": "Robert-L" }, { "family_name": "Takata", "given_name": "Kaitlyn", "orcid": "0000-0003-4864-9741", "clpid": "Takata-Kaitlyn-L" }, { "family_name": "Yuan", "given_name": "Dan", "clpid": "Yuan-Dan" }, { "family_name": "Lu", "given_name": "Yue", "orcid": "0000-0001-9036-2803", "clpid": "Lu-Yue" }, { "family_name": "Huang", "given_name": "Sui", "clpid": "Huang-Sui" }, { "family_name": "Ribas", "given_name": "Antoni", "orcid": "0000-0003-3669-8458", "clpid": "Ribas-A" }, { "family_name": "Levine", "given_name": "Raphael", "clpid": "Levine-R-D" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Wei", "given_name": "Wei", "orcid": "0000-0002-1018-7708", "clpid": "Wei-Wei" }, { "family_name": "Plevritis", "given_name": "Sylvia K.", "clpid": "Plevritis-S-K" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAF^(V600E) mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.", "doi": "10.1038/s41467-020-15956-9", "pmcid": "PMC7214418", "issn": "2041-1723", "publisher": "Nature Publishing Group", "publication": "Nature Communications", "publication_date": "2020-05-11", "volume": "11", "pages": "Art. No. 2345" }, { "id": "authors:d9zj8-8ze78", "collection": "authors", "collection_id": "d9zj8-8ze78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191125-134707503", "type": "article", "title": "Alternative Splicing Coupled with Transcript Degradation Modulates OAS1g Antiviral Activity", "author": [ { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-Luke-S" }, { "family_name": "Mann", "given_name": "Mati", "orcid": "0000-0002-1895-414X", "clpid": "Mann-Mati" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Joglekar", "given_name": "Alok V.", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-Alok-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "At the heart of an innate immune response lies a tightly regulated gene expression program. This precise regulation is crucial because small changes can shift the balance from protective to destructive immunity. Here we identify a frequently used alternative splice site in the gene oligoadenylate synthetase 1g (Oas1g), a key component of the 2-5A antiviral system. Usage of this splice site leads to the generation of a transcript subject to decay, and removal of the site leads to increased expression of Oas1g and an improved antiviral response. However, removal of the splice site also leads to an increase in apoptotic cell death, suggesting this splicing event exists as a compromise between the pathogen protective benefits and collateral damage associated with OAS1g activity. Across the innate immune response, we show a multitude of alternative splicing events predicted to lead to decay exist and thus, have the potential to play a significant role in the regulation of gene expression in innate immunity.", "doi": "10.1261/rna.073825.119", "pmcid": "PMC6961538", "issn": "1355-8382", "publisher": "RNA Society", "publication": "RNA", "publication_date": "2020-02", "series_number": "2", "volume": "26", "issue": "2", "pages": "126-136" }, { "id": "authors:7jeqx-tgn83", "collection": "authors", "collection_id": "7jeqx-tgn83", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191218-082734179", "type": "article", "title": "Myeloid Cell-Targeted miR-146a Mimic Inhibits NF-kB-Driven Inflammation and Leukemia Progression in Vivo", "author": [ { "family_name": "Su", "given_name": "Yu-Lin", "clpid": "Su-Yu-Lin" }, { "family_name": "Wang", "given_name": "Xiuli", "clpid": "Wang-Xiuli" }, { "family_name": "Mann", "given_name": "Mati", "clpid": "Mann-Mati" }, { "family_name": "Adamus", "given_name": "Tomasz", "clpid": "Adamus-T" }, { "family_name": "Wang", "given_name": "Dongfang", "clpid": "Wang-Dongfang" }, { "family_name": "Moreira", "given_name": "Dayson", "clpid": "Moreira-D" }, { "family_name": "Zhang", "given_name": "Zhuoran", "clpid": "Zhang-Zhuoran" }, { "family_name": "Ouyang", "given_name": "Ching", "clpid": "Ouyang-Ching" }, { "family_name": "He", "given_name": "Xin", "clpid": "He-Xin" }, { "family_name": "Zhang", "given_name": "Bin", "orcid": "0000-0002-3685-7503", "clpid": "Zhang-Bin" }, { "family_name": "Swiderski", "given_name": "Piotr", "clpid": "Swiderski-P" }, { "family_name": "Forman", "given_name": "Stephen", "clpid": "Forman-S-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Li", "given_name": "Ling", "clpid": "Li-Ling" }, { "family_name": "Marcucci", "given_name": "Guido", "clpid": "Marcucci-G" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Kortylewski", "given_name": "Marcin", "clpid": "Kortylewski-M" } ], "abstract": "NF-\u03baB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-\u03baB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell\u2013selective NF-\u03baB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-\u03baB in target cells. IV injections of C-miR146a mimic to miR-146a\u2013deficient mice prevented excessive NF-\u03baB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell\u2013induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-\u03baB\u2013related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-\u03baB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell\u2013targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.", "doi": "10.1182/blood.2019002045", "pmcid": "PMC6966933", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2020-01-16", "series_number": "3", "volume": "135", "issue": "3", "pages": "167-180" }, { "id": "authors:xt3ec-9r274", "collection": "authors", "collection_id": "xt3ec-9r274", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191205-103005796", "type": "article", "title": "Myeloid cell-targeted miR-146a mimic alleviates NF-\u03baB-driven cytokine storm without interfering with CD19-specific CAR T cell activity against B cell lymphoma", "author": [ { "family_name": "Kortylewski", "given_name": "Marcin", "clpid": "Kortylewski-M" }, { "family_name": "Su", "given_name": "Yu-Lin", "clpid": "Su-Yu-Lin" }, { "family_name": "Wang", "given_name": "Xiuli", "clpid": "Wang-Xiuli" }, { "family_name": "Mann", "given_name": "Mati", "clpid": "Mann-Mati" }, { "family_name": "Moreira", "given_name": "Dayson", "clpid": "Moreira-D" }, { "family_name": "Zhang", "given_name": "Zhuoran", "clpid": "Zhang-Zhuoran" }, { "family_name": "Ouyang", "given_name": "Ching", "clpid": "Ouyang-Ching" }, { "family_name": "Swiderski", "given_name": "Piotr", "clpid": "Swiderski-P" }, { "family_name": "Forman", "given_name": "Stephen", "clpid": "Forman-S-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Li", "given_name": "Ling", "clpid": "Li-Ling" }, { "family_name": "Marcucci", "given_name": "Guido", "clpid": "Marcucci-G" }, { "family_name": "Boldin", "given_name": "Mark", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" } ], "abstract": "Background: NF-\u03baB is a key regulator of inflammation, myeloproliferation and cancer progression, with an important role in leukemogenesis. Despite therapeutic potential, targeting NF-\u03baB proved challenging. However, in non-malignant myeloid cells NF-\u03baB activity is tightly regulated through many molecular mechanisms, including miRNA. \n\nMethods: Here, we describe an original approach to NF-\u03baB inhibition using miR146a, which targets upstream regulators of NF-\u03baB signaling. We generated a myeloid cell-targeted NF-\u03baB inhibitor by tethering a chemically-modified miR146a mimic oligonucleotide to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) ligand (C-miR146a). \n\nResults: Unlike an unconjugated miR-146a molecule, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells such as macrophages or myeloid leukemia cells. C-miR146a reduced protein levels of classic miR-146a targets, IRAK1 and TRAF6, thereby efficiently blocking NF-\u03baB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-\u03baB activation in myeloid cells, thereby alleviating myeloproliferation and exaggerated inflammatory responses to bacterial challenge. The NF-\u03baB-driven release of IL-1 and IL-6 from monocytes is known to be responsible for cytokine release syndrome (CRS), which can occur in response to bacterial infections, antibody-based therapies and relatively frequently as a serious adverse effect of chimeric antigen receptor (CAR) T-cell therapies. While low expression of miR146a has not yet been implicated in CRS, C-miR146a treatments did reduce pro-inflammatory activity of human monocytes, at the level of IL-1 and IL-6 production, induced by the CD19-specific but not by the naive CAR T cells in vitro. Repeated systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent CRS in xenotransplanted B-cell lymphoma model without impeding the on-target therapeutic effects of CAR T-cells against lymphoma cells. \n\nConclusions: Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory diseases and prevention of potential side effects of immunotherapies. The SR/TLR9-targeted miR-146a mimic design provides an outline for the development of miRNA therapeutics for a variety of myeloid cell-related diseases.", "doi": "10.1186/s40425-019-0764-0", "issn": "2051-1426", "publisher": "BioMed Central", "publication": "Journal for ImmunoTherapy of Cancer", "publication_date": "2019-11-06", "series_number": "S1", "volume": "7", "issue": "S1", "pages": "Art. No. O61" }, { "id": "authors:dvs8s-34p20", "collection": "authors", "collection_id": "dvs8s-34p20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190730-084832126", "type": "article", "title": "Alternative mRNA splicing in cancer immunotherapy", "author": [ { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-L-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" } ], "abstract": "Immunotherapies are yielding effective treatments for several previously untreatable cancers. Still, the identification of suitable antigens specific to the tumour that can be targets for cancer vaccines and T cell therapies is a challenge. Alternative processing of mRNA, a phenomenon that has been shown to alter the proteomic diversity of many cancers, may offer the potential of a broadened target space. Here, we discuss the promise of analysing mRNA processing events in cancer cells, with an emphasis on mRNA splicing, for the identification of potential new targets for cancer immunotherapy. Further, we highlight the challenges that must be overcome for this new avenue to have clinical applicability.", "doi": "10.1038/s41577-019-0195-7", "issn": "1474-1733", "publisher": "Nature Publishing Group", "publication": "Nature Reviews. Immunology", "publication_date": "2019-11", "series_number": "11", "volume": "19", "issue": "11", "pages": "675-687" }, { "id": "authors:8b757-acv48", "collection": "authors", "collection_id": "8b757-acv48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190718-140329246", "type": "article", "title": "MATE-Seq: Microfluidic Antigen-TCR Engagement Sequencing", "author": [ { "family_name": "Ng", "given_name": "Alphonsus H. C.", "orcid": "0000-0003-0074-4598", "clpid": "Ng-Alphonsus-H-C" }, { "family_name": "Peng", "given_name": "Songming", "orcid": "0000-0002-2742-6584", "clpid": "Peng-Songming" }, { "family_name": "Xu", "given_name": "Alexander M.", "orcid": "0000-0003-4877-4358", "clpid": "Xu-Alexander-M" }, { "family_name": "Noh", "given_name": "Won Jun", "clpid": "Noh-Won-Jun" }, { "family_name": "Guo", "given_name": "Katherine", "clpid": "Guo-Katherine" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-M-T" }, { "family_name": "Chour", "given_name": "William", "orcid": "0000-0003-1817-0123", "clpid": "Chour-William" }, { "family_name": "Choi", "given_name": "Jongchan", "clpid": "Choi-Jongchan" }, { "family_name": "Yang", "given_name": "Sung", "orcid": "0000-0002-6050-0993", "clpid": "Yang-Sung" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "Adaptive immunity is based on peptide antigen recognition. Our ability to harness the immune system for therapeutic gain relies on the discovery of the T cell receptor (TCR) genes that selectively target antigens from infections, mutated proteins, and foreign agents. Here we present a method that selectively labels peptide antigen-specific CD8+ T cells using magnetic nanoparticles functionalized with peptide\u2013MHC tetramers, isolates these specific cells within an integrated microfluidic device, and directly amplifies the TCR genes for sequencing. Critically, the identity of the peptide recognized by the TCR is preserved, providing the link between peptide and gene. The platform requires inputs on the order of just 100\u2006000 CD8+ T cells, can be multiplexed for simultaneous analysis of multiple peptides, and performs sorting and isolation on chip. We demonstrate 1000-fold sensitivity enhancement of detecting antigen-specific TCRs relative to bulk analysis and simultaneous capture of two virus antigen-specific TCRs from a population of T cells.", "doi": "10.1039/c9lc00538b", "issn": "1473-0197", "publisher": "Royal Society of Chemistry", "publication": "Lab on a Chip", "publication_date": "2019-09-21", "series_number": "18", "volume": "19", "issue": "18", "pages": "3011-3021" }, { "id": "authors:35565-f8k34", "collection": "authors", "collection_id": "35565-f8k34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190913-074926949", "type": "monograph", "title": "Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line", "author": [ { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Ko", "given_name": "Melissa E.", "clpid": "Ko-Melissa-E" }, { "family_name": "Cheng", "given_name": "Hanjun", "clpid": "Cheng-Hanjun" }, { "family_name": "Zhu", "given_name": "Ronghui", "clpid": "Zhu-Ronghui" }, { "family_name": "Xue", "given_name": "Min", "clpid": "Xue-Min" }, { "family_name": "Wang", "given_name": "Jessica", "orcid": "0000-0003-1421-4969", "clpid": "Wang-Jessica-K" }, { "family_name": "Lee", "given_name": "Jihoon W.", "clpid": "Lee-Jihoon-W" }, { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-L-S" }, { "family_name": "Xu", "given_name": "Alexander", "orcid": "0000-0003-4877-4358", "clpid": "Xu-Alexander-M" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Robert", "given_name": "Lidia", "clpid": "Robert-L" }, { "family_name": "Takata", "given_name": "Kaitlyn", "orcid": "0000-0003-4864-9741", "clpid": "Takata-Kaitlyn-L" }, { "family_name": "Huang", "given_name": "Sui", "clpid": "Huang-Sui" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-A" }, { "family_name": "Levine", "given_name": "Raphael", "clpid": "Levine-R-D" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Wei", "given_name": "Wei", "orcid": "0000-0002-1018-7708", "clpid": "Wei-Wei" }, { "family_name": "Plevritis", "given_name": "Sylvia K.", "clpid": "Plevritis-S-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge, with relevance towards understanding biological changes ranging from cellular differentiation to epigenetic (adaptive) responses of diseased cells to drugging. We report on a combined experimental and theoretic method for determining the trajectories that specific highly plastic BRAFV600E mutant patient-derived melanoma cancer cells take between drug-naive and drug-tolerant states. Recent studies have implicated non-genetic, fast-acting resistance mechanisms are activated in these cells following BRAF inhibition. While single-cell highly multiplex omics tools can yield snapshots of the cell state space landscape sampled at any given time point, individual cell trajectories must be inferred from a kinetic series of snapshots, and that inference can be confounded by stochastic cell state switching. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naive and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naive cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies.", "doi": "10.1101/767988", "publication_date": "2019-09-12" }, { "id": "authors:fqh62-czv13", "collection": "authors", "collection_id": "fqh62-czv13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190903-130240129", "type": "article", "title": "Sensitive Detection and Analysis of Neoantigen-Specific T Cell Populations from Tumors and Blood", "author": [ { "family_name": "Peng", "given_name": "Songming", "orcid": "0000-0002-2742-6584", "clpid": "Peng-Songming" }, { "family_name": "Zaretsky", "given_name": "Jesse M.", "clpid": "Zaretsky-Jesse-M" }, { "family_name": "Ng", "given_name": "Alphonsus H. C.", "orcid": "0000-0003-0074-4598", "clpid": "Ng-Alphonsus-H-C" }, { "family_name": "Chour", "given_name": "William", "orcid": "0000-0003-1817-0123", "clpid": "Chour-William" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Choi", "given_name": "Jongchan", "clpid": "Choi-Jongchan" }, { "family_name": "Hsu", "given_name": "Alice", "clpid": "Hsu-Alice" }, { "family_name": "Holman", "given_name": "Elizabeth", "orcid": "0000-0002-5158-4689", "clpid": "Holman-Elizabeth-A" }, { "family_name": "Ding", "given_name": "Xiaozhe", "clpid": "Ding-Xiaozhe-Z" }, { "family_name": "Guo", "given_name": "Katherine", "clpid": "Guo-Katherine" }, { "family_name": "Kim", "given_name": "Jungwoo", "orcid": "0000-0002-5215-2044", "clpid": "Kim-Jungwoo" }, { "family_name": "Xu", "given_name": "Alexander M.", "orcid": "0000-0003-4877-4358", "clpid": "Xu-Alexander-M" }, { "family_name": "Heath", "given_name": "John E.", "clpid": "Heath-John-E" }, { "family_name": "Noh", "given_name": "Won Jun", "clpid": "Noh-Won-Jun" }, { "family_name": "Zhou", "given_name": "Jing", "clpid": "Zhou-Jing" }, { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Lu", "given_name": "Yue", "orcid": "0000-0001-9036-2803", "clpid": "Lu-Yue" }, { "family_name": "McLaughlin", "given_name": "Jami", "clpid": "McLaughlin-J" }, { "family_name": "Cheng", "given_name": "Donghui", "clpid": "Cheng-Donghui" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-Owen-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines.", "doi": "10.1016/j.celrep.2019.07.106", "pmcid": "PMC6774618", "issn": "2211-1247", "publisher": "Cell Press", "publication": "Cell Reports", "publication_date": "2019-09-03", "series_number": "10", "volume": "28", "issue": "10", "pages": "2728-2738" }, { "id": "authors:fhc9f-zwt87", "collection": "authors", "collection_id": "fhc9f-zwt87", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190805-155608943", "type": "monograph", "title": "Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma", "author": [ { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Lee", "given_name": "Jihoon W.", "clpid": "Lee-Jihoon-W" }, { "family_name": "Ng", "given_name": "Rachel", "clpid": "Ng-Rachel" }, { "family_name": "Liu", "given_name": "Victoria", "orcid": "0000-0003-1845-2497", "clpid": "Liu-Victoria" }, { "family_name": "Peng", "given_name": "Songming", "orcid": "0000-0002-2742-6584", "clpid": "Peng-Songming" }, { "family_name": "Xue", "given_name": "Min", "clpid": "Xue-Min" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition of BRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of transcriptome and epigenome data, collected over two months of drug treatment and release, revealed changing levels of thousands of genes and extensive chromatin remodeling. However, a 3-step computational algorithm greatly simplified the interpretation of these changes, and revealed that the whole adaptive process was controlled by a gene module activated within just three days of treatment, with RelA driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. These findings were confirmed across several patient-derived cell lines and in melanoma patients under MAPK inhibitor treatment. Co-targeting BRAF and histone-modifying enzymes arrests adaptive transitions towards drug tolerance in epigenetically plastic melanoma cells and may be exploited therapeutically.", "doi": "10.1101/724740", "publication_date": "2019-08-05" }, { "id": "authors:f1xz9-7m743", "collection": "authors", "collection_id": "f1xz9-7m743", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190603-141218777", "type": "article", "title": "Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages", "author": [ { "family_name": "Jiang", "given_name": "Shuai", "clpid": "Jiang-Shuai" }, { "family_name": "Yan", "given_name": "Wei", "orcid": "0000-0001-9519-1812", "clpid": "Yan-Wei" }, { "family_name": "Wang", "given_name": "Shizhen Emily", "orcid": "0000-0002-5036-8175", "clpid": "Wang-Shizhen-Emily" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Tet methylcytosine dioxygenase 2 (Tet2) is an epigenetic regulator that removes methyl groups from deoxycytosine residues in DNA. Tet2-deficient murine macrophages show increased lipopolysaccharide (LPS)-induced and spontaneous inflammation at least partially because Tet2 acts to restrain interleukin (IL)-1\u03b2 and IL-6 expression in induced cells. MicroRNAs have emerged as critical regulatory noncoding RNAs that tune immune cell responses to physiological perturbations and play roles in pathological conditions in macrophages. To determine if a microRNA played any role in Tet2 activity, we examined the interrelationship of Tet2 action and the let-7 microRNA family, utilizing several let-7 microRNA engineered murine models. We first showed that Tet2, but not Tet3, is a direct target of the let-7a-1/let-7d/let-7f-1 (let-7adf) microRNAs in macrophages. We found that overexpression or deletion of the let-7adf gene cluster causes altered IL-6 induction both in tissue culture cells induced by LPS treatment in vitro as well as in a Salmonella infection mouse model in vivo. Mechanistically, let-7adf promotes IL-6 by directly repressing Tet2 levels and indirectly by enhancing a Tet2 suppressor, the key TCA cycle metabolite, succinate. We found that Let-7adf promotes succinate accumulation by regulating the Lin28a/Sdha axis. We thereby identify two pathways of let-7 control of Tet2 and, in turn, of the key inflammatory cytokine, IL-6, thus characterizing a regulatory pathway in which a microRNA acts as a feedback inhibitor of inflammatory processes.", "doi": "10.1073/pnas.1811040116", "pmcid": "PMC7056939", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2019-06-18", "series_number": "25", "volume": "116", "issue": "25", "pages": "12416-12421" }, { "id": "authors:2p0gt-x0q58", "collection": "authors", "collection_id": "2p0gt-x0q58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181105-091346689", "type": "article", "title": "Sixty Years of Discovery", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Each of us is a story. Mine is a story of doing science for 60 years, and I am honored to be asked to tell it. Even though this autobiography was written for the Annual Review of Immunology, I have chosen to describe my whole career in science because the segment that was immunology is so intertwined with all else I was doing. This article is an elongation and modification of a talk I gave at my 80th birthday celebration at Caltech on March 23, 2018.", "doi": "10.1146/annurev-immunol-042718-041210", "issn": "0732-0582", "publisher": "Annual Reviews", "publication": "Annual Review of Immunology", "publication_date": "2019-04", "volume": "37", "pages": "1-17" }, { "id": "authors:dj8gd-c1t96", "collection": "authors", "collection_id": "dj8gd-c1t96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190311-152538910", "type": "article", "title": "Cellular Immunotherapy Revolution: Arming the Immune System for Precision Therapy", "author": [ { "family_name": "Paucek", "given_name": "Richard D.", "orcid": "0000-0002-4105-2443", "clpid": "Paucek-R-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" } ], "abstract": "Immunotherapy treatments harnessing the patient's immune system herald a new era of personalized medicine, offering hope for curative responses in patients with serious illnesses. Cell-mediated immunity can eliminate cancer cells and provide durable remissions. This often relies on repurposing cytotoxic T cell activity through modified T cell receptors or chimeric antigen receptors. Furthermore, synthetic biology has expanded the cell engineering toolkit to provide immune cells with more functionality, including disease targeting, potency, and safety. We focus on T cell-based immunotherapy, highlighting discoveries of genetic engineering and therapeutic use. We also examine emerging paths that could be undertaken to improve this novel class of drugs, and discuss the challenges of toxicities as well as other limitations of cellular immunotherapy.", "doi": "10.1016/j.it.2019.02.002", "issn": "1471-4906", "publisher": "Elsevier", "publication": "Trends in Immunology", "publication_date": "2019-04", "series_number": "4", "volume": "40", "issue": "4", "pages": "292-309" }, { "id": "authors:sg60e-p1s82", "collection": "authors", "collection_id": "sg60e-p1s82", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190312-085351129", "type": "monograph", "title": "T Cell Receptor Immunotherapy Drives Human Immunodeficiency Virus Evolution in Humanized Mice", "author": [ { "family_name": "Joglekar", "given_name": "Alok V.", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-A-V" }, { "family_name": "Swift", "given_name": "Margaret", "clpid": "Swift-M" }, { "family_name": "Leonard", "given_name": "Michael T.", "orcid": "0000-0001-9084-2647", "clpid": "Leonard-M-T" }, { "family_name": "Jeppson", "given_name": "John D.", "clpid": "Jeppson-J-D" }, { "family_name": "Sandoval", "given_name": "Salemiz", "clpid": "Sandoval-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Effective CD8+ T cell responses targeted to the KK10 epitope of HIV presented by HLA-B*27:05, a protective HLA allele, correlate with the ability to control infection without antiretroviral therapy (ART). Here, we report an immunotherapy approach using two B*27:05-KK10-specific T Cell Receptors (TCRs) isolated from HIV controllers. Immunocompromised mice engrafted with human Hematopoietic Stem/Progenitor Cells (HSPCs) encoding for the TCRs showed differentiation into functionally active engineered T cells. Following infection with HIV, both TCRs showed sustained, albeit modest, viral suppression over 32 weeks, accompanied by a concomitant increase in CD4+ T cells. Sequencing of viral quasi-species from the plasma of infected mice demonstrated clear evidence for viral evolution under selection pressure from the TCRs. The most commonly observed mutation in the KK10 epitope was L6M, which preserved viral fitness but showed attenuated recognition by the TCRs. These studies show that TCR-immunotherapy was able to suppress HIV infection long-term while driving HIV evolution in humanized mice.", "doi": "10.1101/574608", "publication_date": "2019-03-12" }, { "id": "authors:kx4b3-k2683", "collection": "authors", "collection_id": "kx4b3-k2683", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181029-162149332", "type": "article", "title": "Bud13 Promotes a Type I Interferon Response By Countering Intron Retention in Irf7", "author": [ { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-L-S" }, { "family_name": "Majumdar", "given_name": "Devdoot", "clpid": "Majumdar-Devdoot-S" }, { "family_name": "Burns", "given_name": "Christian", "clpid": "Burns-C" }, { "family_name": "Vlach", "given_name": "Logan", "clpid": "Vlach-L" }, { "family_name": "Moradian", "given_name": "Annie", "orcid": "0000-0002-0407-2031", "clpid": "Moradian-A" }, { "family_name": "Sweredoski", "given_name": "Michael J.", "orcid": "0000-0003-0878-3831", "clpid": "Sweredoski-M-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Intron retention (IR) has emerged as an important mechanism of gene expression control, but the factors controlling IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified BUD13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in BUD13 was associated with increased IR, decreased mature Irf7 transcript and protein levels, and consequently a dampened type I interferon response, which compromised the ability of BUD13-deficient macrophages to withstand vesicular stomatitis virus (VSV) infection. Global analysis of BUD13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a BUD13-dependent manner. Deficiency of BUD13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, BUD13 facilitates the expression of genes at which IR occurs.", "doi": "10.1016/j.molcel.2018.11.038", "issn": "1097-2765", "publisher": "Elsevier", "publication": "Molecular Cell", "publication_date": "2019-02-21", "series_number": "4", "volume": "73", "issue": "4", "pages": "803-814" }, { "id": "authors:1e3tf-49212", "collection": "authors", "collection_id": "1e3tf-49212", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181130-094846557", "type": "article", "title": "T cell antigen discovery via signaling and antigen-presenting bifunctional receptors", "author": [ { "family_name": "Joglekar", "given_name": "Alok V.", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-A-V" }, { "family_name": "Leonard", "given_name": "Michael T.", "orcid": "0000-0001-9084-2647", "clpid": "Leonard-M-T" }, { "family_name": "Jeppson", "given_name": "John D.", "clpid": "Jeppson-J-D" }, { "family_name": "Swift", "given_name": "Margaret", "clpid": "Swift-M" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Peng", "given_name": "Songming", "orcid": "0000-0002-2742-6584", "clpid": "Peng-Songming" }, { "family_name": "Zaretsky", "given_name": "Jesse M.", "clpid": "Zaretsky-J-M" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-A" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-M-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "CD8^+ T cells recognize and eliminate tumors in an antigen-specific manner. Despite progress in characterizing the antitumor T cell repertoire and function, the identification of target antigens remains a challenge. Here we describe the use of chimeric receptors called signaling and antigen-presenting bifunctional receptors (SABRs) in a cell-based platform for T cell receptor (TCR) antigen discovery. SABRs present an extracellular complex comprising a peptide and major histocompatibility complex (MHC), and induce intracellular signaling via a TCR-like signal after binding with a cognate TCR. We devised a strategy for antigen discovery using SABR libraries to screen thousands of antigenic epitopes. We validated this platform by identifying the targets recognized by public TCRs of known specificities. Moreover, we extended this approach for personalized neoantigen discovery.", "doi": "10.1038/s41592-018-0304-8", "pmcid": "PMC6755906", "issn": "1548-7091", "publisher": "Nature Publishing Group", "publication": "Nature Methods", "publication_date": "2019-02", "series_number": "2", "volume": "16", "issue": "2", "pages": "191-198" }, { "id": "authors:hsx23-va522", "collection": "authors", "collection_id": "hsx23-va522", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181112-075749851", "type": "article", "title": "IND-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system", "author": [ { "family_name": "Puig-Saus", "given_name": "Cristina", "clpid": "Puig-Saus-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)\u2013engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application.\nExperimental Design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/K^b mice within a formal Good Laboratory Practice (GLP)\u2013compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)\u2013compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use.\nResults: TCR genetically modified and ex vivo\u2013cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality.\nConclusions: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.", "doi": "10.1158/1078-0432.CCR-18-0963", "pmcid": "PMC6359988", "issn": "1078-0432", "publisher": "American Association for Cancer Research", "publication": "Clinical Cancer Research", "publication_date": "2019-02", "series_number": "3", "volume": "25", "issue": "3", "pages": "1000-1011" }, { "id": "authors:ft9mw-15t57", "collection": "authors", "collection_id": "ft9mw-15t57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181106-104559775", "type": "article", "title": "Functional TCR T cell screening using single-cell droplet microfluidics", "author": [ { "family_name": "Segaliny", "given_name": "Aude I.", "orcid": "0000-0001-9670-8350", "clpid": "Segaliny-Aude-I" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Kong", "given_name": "Lingshun", "clpid": "Kong-Lingshun" }, { "family_name": "Ren", "given_name": "Ci", "clpid": "Ren-Ci" }, { "family_name": "Chen", "given_name": "Xiaoming", "clpid": "Chen-Xiaoming" }, { "family_name": "Wang", "given_name": "Jessica K.", "orcid": "0000-0003-1421-4969", "clpid": "Wang-Jessica-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wu", "given_name": "Guikai", "clpid": "Wu-Guikai" }, { "family_name": "Zhao", "given_name": "Weian", "orcid": "0000-0002-7794-9914", "clpid": "Zhao-Weian" } ], "abstract": "Adoptive T cell transfer, in particular TCR T cell therapy, holds great promise for cancer immunotherapy with encouraging clinical results. However, finding the right TCR T cell clone is a tedious, time-consuming, and costly process. Thus, there is a critical need for single cell technologies to conduct fast and multiplexed functional analyses followed by recovery of the clone of interest. Here, we use droplet microfluidics for functional screening and real-time monitoring of single TCR T cell activation upon recognition of target tumor cells. Notably, our platform includes a tracking system for each clone as well as a sorting procedure with 100% specificity validated by downstream single cell reverse-transcription PCR and sequencing of TCR chains. Our TCR screening prototype will facilitate immunotherapeutic screening and development of T cell therapies.", "doi": "10.1039/c8lc00818c", "pmcid": "PMC6279597", "issn": "1473-0197", "publisher": "Royal Society of Chemistry", "publication": "Lab on a Chip", "publication_date": "2018-12-21", "series_number": "24", "volume": "18", "issue": "24", "pages": "3733-3749" }, { "id": "authors:r3vdr-3en21", "collection": "authors", "collection_id": "r3vdr-3en21", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180122-131324532", "type": "article", "title": "Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age", "author": [ { "family_name": "Mann", "given_name": "Mati", "clpid": "Mann-Mati" }, { "family_name": "Mehta", "given_name": "Arnav", "clpid": "Mehta-Arnav" }, { "family_name": "de Boer", "given_name": "Carl G.", "clpid": "de-Boer-Carl-G" }, { "family_name": "Kowalczyk", "given_name": "Monika S.", "clpid": "Kowalczyk-Monika-S" }, { "family_name": "Lee", "given_name": "Kevin", "clpid": "Lee-Kevin-K" }, { "family_name": "Haldeman", "given_name": "Pearce", "clpid": "Haldeman-Pearce" }, { "family_name": "Rogel", "given_name": "Noga", "clpid": "Rogel-Noga" }, { "family_name": "Knecht", "given_name": "Abigail R.", "clpid": "Knecht-Abigail" }, { "family_name": "Farouq", "given_name": "Daneyal", "clpid": "Farouq-Daneyal" }, { "family_name": "Regev", "given_name": "Aviv", "orcid": "0000-0003-3293-3158", "clpid": "Regev-Aviv" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. However, with age, the balance is disrupted, and LT-HSCs produce a myeloid-biased output, resulting in poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA sequencing (scRNA-seq), we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is prevalent among aged LT-HSCs. We identify CD61 as a marker of mLT-HSCs and show that CD61-high LT-HSCs are uniquely primed to respond to acute inflammatory challenge. We predict that several transcription factors regulate the mLT-HSCs gene program and show that Klf5, Ikzf1, and Stat3 play an important role in age-related inflammatory myeloid bias. We have therefore identified and isolated an LT-HSC subset that regulates myeloid versus lymphoid balance under inflammatory challenge and with age.", "doi": "10.1016/j.celrep.2018.11.056", "pmcid": "PMC6424521", "issn": "2211-1247", "publisher": "Cell Press", "publication": "Cell Reports", "publication_date": "2018-12-11", "series_number": "11", "volume": "25", "issue": "11", "pages": "2992-3005" }, { "id": "authors:nkk6k-x1c59", "collection": "authors", "collection_id": "nkk6k-x1c59", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181023-133725439", "type": "article", "title": "Isolation and characterization of NY-ESO-1\u2013specific T cell receptors restricted on various MHC molecules", "author": [ { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Li", "given_name": "Xiao-Hua", "clpid": "Li-Xiao-Hua" }, { "family_name": "Yu", "given_name": "Jiaji", "clpid": "Yu-Jiaji" }, { "family_name": "McLaughlin", "given_name": "Jami", "clpid": "McLaughlin-Ja,i" }, { "family_name": "Cheng", "given_name": "Donghui", "clpid": "Cheng-Donghui" }, { "family_name": "Mathis", "given_name": "Colleen", "clpid": "Mathis-Colleen" }, { "family_name": "Homet Moreno", "given_name": "Blanca", "clpid": "Homet-Moreno-Blanca" }, { "family_name": "Woods", "given_name": "Katherine", "clpid": "Woods-Katherine" }, { "family_name": "Knights", "given_name": "Ashley J.", "clpid": "Knights-Ashley-J" }, { "family_name": "Garcia-Diaz", "given_name": "Angel", "clpid": "Garcia-Diaz-Angel" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Hu-Lieskovan", "given_name": "Siwen", "clpid": "Hu-Lieskovan-Siwen" }, { "family_name": "Puig-Saus", "given_name": "Cristina", "clpid": "Puig-Saus-Cristina" }, { "family_name": "Cebon", "given_name": "Jonathan", "clpid": "Cebon-Jonathan" }, { "family_name": "Ribas", "given_name": "Antoni", "orcid": "0000-0003-3669-8458", "clpid": "Ribas-Antoni" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-Owen-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. Due to the prevalence of the HLA-A2 MHC class I supertype in most human populations, the majority of TCR gene therapy trials targeting public antigens have employed HLA-A2\u2013restricted TCRs, limiting this approach to those patients expressing this allele. For these patients, TCR gene therapy trials have resulted in both tantalizing successes and lethal adverse events, underscoring the need for careful selection of antigenic targets. Broad and safe application of public antigen-targeted TCR gene therapies will require (i) selecting public antigens that are highly tumor-specific and (ii) targeting multiple epitopes derived from these antigens by obtaining an assortment of TCRs restricted by multiple common MHC alleles. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we pilot an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2.", "doi": "10.1073/pnas.1810653115", "pmcid": "PMC6233129", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2018-11-06", "series_number": "45", "volume": "115", "issue": "45", "pages": "E10702-E10711" }, { "id": "authors:vpry4-n7x96", "collection": "authors", "collection_id": "vpry4-n7x96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181030-074928774", "type": "monograph", "title": "Programmed Delayed Splicing: A Mechanism for Timed Inflammatory Gene Expression", "author": [ { "family_name": "Majumdar", "given_name": "Devdoot S.", "clpid": "Majumdar-D-S" }, { "family_name": "Frankiw", "given_name": "Luke", "clpid": "Frankiw-L-S" }, { "family_name": "Burns", "given_name": "Christian H.", "clpid": "Burns-C-H" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Inflammation involves timed gene expression, suggesting that the fine-tuned onset, amplitude, and termination of expression of hundreds of genes is of critical importance to organismal homeostasis. Recent study of post-transcriptional regulation of inflammatory gene expression led to the suggestion of a regulatory role for pre-mRNA splicing. Here, using a hybrid capture approach to purify incompletely spliced, chromatin-associated pre-mRNAs, we use deep sequencing to study pre-mRNA splicing of the NF-kB transcriptome. By freezing transcription and examining subsequent splicing of complete transcripts, we find many introns splice tens to hundreds of times slower than average. In many cases, this is attributable to poor splice donor sequences that are evolutionarily conserved. When these introns were altered by ~2 base pairs to yield stronger splice donors, gene expression levels increased markedly for several genes in the context of a reporter system. We propose that such splice sites represent a regulatory mechanism that determines the timing of production of the mRNAs from certain inflammatory genes and may also limit mRNA expression from these genes. Further work will be needed to understand the roles of this regulation in the inflammatory response. The suggestion of extensive temporal regulation of pre-mRNA splicing as a regulatory process in inflammation raises the question of where else in biology there may be timed processes with a similar underlying cause.", "doi": "10.1101/443796", "publication_date": "2018-10-15" }, { "id": "authors:k3saz-r6q61", "collection": "authors", "collection_id": "k3saz-r6q61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181024-150608861", "type": "article", "title": "Biotech leaders call for free press", "author": [ { "family_name": "Cohen", "given_name": "Ron", "orcid": "0000-0002-9152-8446", "clpid": "Cohen-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We, the undersigned, are biotechnology executives, entrepreneurs, academic leaders and investors. We are gravely concerned about trends in the United States that are undermining our news media, such that more than 300 news publications across the country recently found it necessary to run coordinated editorials in defense of the First Amendment's guarantee of freedom of the press.\n\nWhy do we, in particular, feel compelled to speak out? We dedicate our lives to discovering and developing new medicines. In recent years, we have witnessed astonishing advances in medicine, including treating diseases at the level of genes and cells. These modern miracles rely, more than anything else, on the free and public exchange of ideas. This encompasses the ability to collaborate, debate, and test one another's ideas and findings, and to publish data regardless of political, religious or other external pressures or considerations. This is foundational to the scientific method, without which we all might still be living in caves and have an average life expectancy of 30.", "doi": "10.1038/nbt.4271", "issn": "1087-0156", "publisher": "Nature Publishing Group", "publication": "Nature Biotechnology", "publication_date": "2018-10", "series_number": "10", "volume": "36", "issue": "10", "pages": "920-922" }, { "id": "authors:8pz1n-z8h47", "collection": "authors", "collection_id": "8pz1n-z8h47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190221-082729497", "type": "article", "title": "Bridging the Science-Law Divide", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Tatel", "given_name": "David S.", "clpid": "Tatel-David-S" }, { "family_name": "Mazza", "given_name": "Anne-Marie", "clpid": "Mazza-A-M" } ], "abstract": "Formal opportunities for members of the scientific and legal communities to engage in ongoing collegial consideration of issues at the interface of science and law are limited. In the late 1990s, the National Academies of Sciences, Engineering, and Medicine established the Committee on Science, Technology, and Law (CSTL)-composed of equal numbers of members from science, engineering, and law-to provide an ongoing forum that would build permanent links between these communities. The range of issues investigated by the CSTL and the influence of these explorations are discussed in this essay.", "doi": "10.1162/DAED_a_00528", "issn": "0011-5266", "publisher": "MIT Press", "publication": "Daedalus", "publication_date": "2018-09-24", "series_number": "4", "volume": "147", "issue": "4", "pages": "181-194" }, { "id": "authors:mfbbv-bbq20", "collection": "authors", "collection_id": "mfbbv-bbq20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181109-142044662", "type": "conference_item", "title": "Cyclic cell state transition is associated with the adaptive resistance to BRAF inhibition in melanomas", "author": [ { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Lu", "given_name": "Xiang", "clpid": "Lu-Xiang" }, { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "Robert", "given_name": "Lidia", "clpid": "Robert-L" }, { "family_name": "Ng", "given_name": "Alphonsus", "orcid": "0000-0003-0074-4598", "clpid": "Ng-Alphonsus-H-C" }, { "family_name": "Xue", "given_name": "Min", "clpid": "Xue-Min" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Levine", "given_name": "Raphael", "clpid": "Levine-R-D" }, { "family_name": "Wei", "given_name": "Wei", "orcid": "0000-0002-1018-7708", "clpid": "Wei-Wei" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "Cancers commonly develop resistance against chemotherapeutics or targeted therapies through either genetic mechanism or adaptive responses that commonly involve epigenetic reprogramming and activation of compensatory signaling pathways. Recent examples of such an adaptive response involve the treatment of BRAF mutant melanoma cancer patients with inhibitors of the BRAF/MAPK pathway. Several studies attribute it to a reversible cell state transition from a proliferative melanocytic state towards invasive neural crest-like and mesenchymal-like states. The capacity of certain BRAF mutant melanoma patient tumors, and the cell lines derived from them, to adapt to targeted therapies bears\nsome conceptual similarities to adaptive responses obsd. in other cancers. Further, the response of the cells that adapt to BRAF inhibition is highly variable depending on phenotypic plasticity of the cells, the length of drug exposure, and the dosing strategy. As such, general physiochem. approaches that provide quant., predictive models of such transitions may provide a common conceptual framework for understanding the large genome-scale gene expression level changes. Through analyzing the kinetic trajectory of the reversible, adaptive response of a highly plastic, patient-derived BRAF^(V600)\nmutant melanoma cell line to BRAFi, using genome-wide expression of these cells at 15 time points over a period that included 29 days of drug treatment, followed by either an addnl. 30 days of treatment, or 35 days of drug release, we found that the cells adapt to the drug treatment in two stages, terminating in a mesenchymal-like state after almost a month of treatment. At that stage, continued drug exposure induced no further changes in cell phenotype. Following drug release, the cells reverted back to the original, drug naive phenotype, but the reverse pathway took a different trajectory than the forward pathway. Thermodynamically-motivated Surprisal Anal. was utilized to identify two constraints\nof this cyclic cell state transition to construct a free energy surface. A kinetic ODE model of the two unbalanced processes revealed that the process assocd. with the long-term adaptive transition was driven the other process reflective of a short-term drug stress response. Such kinetic model further allowed identifying driving transcription factors and epigenetic regulations that prompt the cyclic cell state transition towards adaptive resistance.", "publisher": "Caltech Library", "publication_date": "2018-08" }, { "id": "authors:m0zyw-fqx04", "collection": "authors", "collection_id": "m0zyw-fqx04", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180227-091330026", "type": "article", "title": "Characterization of Postinfusion Phenotypic Differences in Fresh Versus Cryopreserved TCR Engineered Adoptive Cell Therapy Products", "author": [ { "family_name": "Nowicki", "given_name": "Theodore S.", "clpid": "Nowicki-T-S" }, { "family_name": "Escuin-Ordinas", "given_name": "Helena", "clpid": "Escuin-Ordinas-H" }, { "family_name": "Avramis", "given_name": "Earl", "clpid": "Avramis-Earl" }, { "family_name": "Chmielowski", "given_name": "Bartosz", "clpid": "Chmielowski-Bartosz" }, { "family_name": "Chodon", "given_name": "Thinle", "clpid": "Chodon-Thinle" }, { "family_name": "Berent-Maoz", "given_name": "Beata", "clpid": "Berent-Maoz-B" }, { "family_name": "Wang", "given_name": "Xiaoyan", "clpid": "Wang-Xiaoyan" }, { "family_name": "Kaplan-Lefko", "given_name": "Paula", "clpid": "Kaplan-Lefko-P" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Economou", "given_name": "James S.", "clpid": "Economou-James-S" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Comin-Anduix", "given_name": "Bego\u00f1a", "clpid": "Comin-Anduix-Bego\u00f1a" } ], "abstract": "Adoptive cell therapy (ACT) consisting of genetically engineered T cells expressing tumor antigen-specific T-cell receptors displays robust initial antitumor activity, followed by loss of T-cell activity/persistence and frequent disease relapse. We characterized baseline and longitudinal T-cell phenotype variations resulting from different manufacturing and administration protocols in patients who received ACT. Patients with melanoma who enrolled in the F5-MART-1 clinical trial (NCT00910650) received infusions of MART-1 T-cell receptors transgenic T cells with MART-1 peptide-pulsed dendritic cell vaccination. Patients were divided into cohorts based on several manufacturing changes in the generation and administration of the transgenic T cells: decreasing ex vivo stimulation/expansion time, increased cell dose, and receiving fresh instead of cryopreserved cells. T-cell phenotypes were analyzed by flow cytometry at baseline and longitudinally in peripheral blood. Transgenic T cells with shorter ex vivo culture/expansion periods displayed significantly increased expression of markers associated with less differentiated naive/memory populations, as well as significantly decreased expression of the inhibitory receptor programmed death 1 (PD1). Patients receiving fresh infusions of transgenic cells demonstrated expansion of central memory T cells and delayed acquisition of PD1 expression compared with patients who received cryopreserved products. Freshly infused transgenic T cells showed persistence and expansion of naive and memory T-cell populations and delayed acquisition of PD1 expression, which correlated with this cohort's superior persistence of transgenic cells and response to dendritic cell vaccines. These results may be useful in designing future ACT protocols.", "doi": "10.1097/CJI.0000000000000216", "pmcid": "PMC5959255", "issn": "1524-9557", "publisher": "Wolters Kluwer Health, Inc.", "publication": "Journal of Immunotherapy", "publication_date": "2018-06", "series_number": "5", "volume": "41", "issue": "5", "pages": "248-259" }, { "id": "authors:34ncw-jeb34", "collection": "authors", "collection_id": "34ncw-jeb34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190314-124617363", "type": "article", "title": "Hematopoietic stem/progenitor cells engineered with T cell receptors for immunotherapy for HIV infection", "author": [ { "family_name": "Joglekar", "given_name": "Alok", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-A-V" }, { "family_name": "Sandoval", "given_name": "Salemiz", "clpid": "Sandoval-S" }, { "family_name": "Jeppson", "given_name": "John", "clpid": "Jeppson-J-D" }, { "family_name": "Liu", "given_name": "Zhe", "clpid": "Liu-Zhe" }, { "family_name": "Leonard", "given_name": "Michael Troy", "orcid": "0000-0001-9084-2647", "clpid": "Leonard-M-T" }, { "family_name": "Swift", "given_name": "Margaret", "clpid": "Swift-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "HIV infection causes progressive depletion of CD4+ T cells and leads to severe immunodeficiency if left untreated. Current antiretroviral therapy can control infection, but does not cure it. The goal of this study was to develop a \"functional cure\" for HIV infection by providing a long-term, self-renewing source of antiviral immunity. To that end, we hypothesized that immunotherapy using engineered hematopoietic stem/progenitor cells (HSPCs) to express HIV-specific T cell receptors (TCRs) will be effective at controlling HIV. We first isolated six TCRs specific to the KK10 epitope from HLA-B27+ individuals and compared their function in vitro. Two TCRs, EC27 and EC5.5, were chosen for immunotherapy studies based on their superior function. To test HSPC-based immunotherapy, we transduced mobilized peripheral blood CD34+ HSPCs from HLA-B27+ healthy donors to express these TCRs and engrafted them in immunocompromised NOD/SCID/IL2R\u03b3c\u2212/\u2212 (NSG) mice. Transduced HSPCs were able to engraft mice and differentiate into T cells expressing the TCRs in peripheral blood and lymphoid tissues. Furthermore, engineered T cells isolated from engrafted mice showed KK10-driven expansion, cytotoxicity, and cytokine secretion. Expanded T cells were able to inhibit HIV-infection in vitro. Moreover, the functional activity of engineered T cells isolated from mice was comparable to modified primary T cells, highlighting their therapeutic potential. We are currently testing whether mice engrafted with transduced HSPCs can suppress HIV infection in vivo. If successful, these studies would demonstrate a \"functional cure\" of HIV infection, warranting further testing in clinical trials.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2018-05", "series_number": "S1", "volume": "200", "issue": "S1", "pages": "Art. No. 180.5" }, { "id": "authors:01wsv-9ae73", "collection": "authors", "collection_id": "01wsv-9ae73", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190314-125155136", "type": "article", "title": "T Cell Antigen Discovery using Signaling and Antigen-presenting Bifunctional Receptors (SABRs)", "author": [ { "family_name": "Joglekar", "given_name": "Alok", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-A-V" }, { "family_name": "Leonard", "given_name": "Michael Troy", "orcid": "0000-0001-9084-2647", "clpid": "Leonard-M-T" }, { "family_name": "Jeppson", "given_name": "John", "clpid": "Jeppson-J-D" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-M-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Checkpoint inhibitors, cancer vaccines, and adoptive cell therapy exploit T cell mediated immune responses to cancers. Discovering the exact antigens targeted by T cell responses is important for their efficacy. Antigen discovery for 'orphan' T cells or TCRs has been a challenging prospect due to high number of possible pMHC specificities. Several current approaches to decipher antigen specificities require prior knowledge of antigen sequences, are unable to scale up, or require production of soluble TCRs. To overcome these drawbacks, we have developed chimeric receptors called Signaling and Antigen-presenting Bifunctional Receptors (SABRs) that allow identification of antigen-presenting cells. SABRs present display pMHC on their extracellular domain, which is recognized by an orphan TCR. Upon recognition, SABRs initiate signaling in the presenting cell using a CD3zeta signaling domain. We transduced reporter cells with SABRs presenting HLA-A2-restricted epitopes from MelanA and NY-ESO-1, and co-incubated them with target cells expressing their cognate TCRs, which resulted in signal transduction only upon correct pMHC-TCR pairing, allowing the presenting cells to express GFP. Second, we showed that SABRs displaying independently expressed peptide and MHC could function similarly. These receptors could present pulsed peptides or endogenously expressed proteins, allowing the uncoupling of peptide and MHC, while retaining their signaling capability. We are currently testing the use of SABR-based antigen libraries to identify novel antigenic specificities targeted by T cells in cancers, infectious diseases, and autoimmune diseases.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2018-05", "series_number": "S1", "volume": "200", "issue": "S1", "pages": "Art. No. 181.9" }, { "id": "authors:5hx22-8pr02", "collection": "authors", "collection_id": "5hx22-8pr02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180327-150057315", "type": "article", "title": "Epigenetic silencing of miR-125b is required for normal B cell development", "author": [ { "family_name": "Li", "given_name": "Guideng", "orcid": "0000-0003-0840-7262", "clpid": "Li-Guideng" }, { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Sookram", "given_name": "Reeshelle", "clpid": "Sookram-Reeshelle" }, { "family_name": "Wong", "given_name": "Stephanie", "clpid": "Wong-Stephanie" }, { "family_name": "Wang", "given_name": "Jessica K.", "orcid": "0000-0003-1421-4969", "clpid": "Wang-Jessica-K" }, { "family_name": "Ouyang", "given_name": "Yong", "clpid": "Ouyang-Yong" }, { "family_name": "He", "given_name": "Peng", "clpid": "He-Peng" }, { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Casellas", "given_name": "Rafael", "clpid": "Casellas-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B-cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood. Such impairment appeared to be mediated primarily by inhibited expression of the sphingosine-1-phosphate receptor 1 (S1PR1). Enforced expression of S1PR1 or clustered regularly interspaced short palindromic repeats/Cas9\u2013mediated genome editing of the miR-125b targeting site in the S1PR1 3\u2032 untranslated region rescued the miR-125b\u2013mediated defect in B-cell egress. In addition to impaired B-cell egress, miR-125b dysregulation initially reduced pre\u2013B-cell output but later induced pre\u2013B-cell lymphoma/leukemia in mice. Genetic deletion of IRF4 was found in miR-125b\u2013induced B-cell cancer, but its role in oncogenic miR-125b\u2013induced B-cell transformation is still unknown. Here, we further demonstrated an interaction of the effects of miR-125b and IRF4 in cancer induction by showing that miR125b-induced B-cell leukemia was greatly accelerated in IRF4 homozygous mutant mice. Thus, we conclude that physiological silencing of miR-125b is required for normal B-cell development and also acts as a mechanism of cancer suppression.", "doi": "10.1182/blood-2018-01-824540", "pmcid": "PMC5921965", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2018-04-26", "series_number": "17", "volume": "131", "issue": "17", "pages": "1920-1930" }, { "id": "authors:7h9wy-zb431", "collection": "authors", "collection_id": "7h9wy-zb431", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180208-164208568", "type": "article", "title": "T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable", "author": [ { "family_name": "Joglekar", "given_name": "Alok V.", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-Alok-V" }, { "family_name": "Liu", "given_name": "Zhe", "clpid": "Liu-Zhe" }, { "family_name": "Weber", "given_name": "Jeffrey K.", "clpid": "Weber-Jeffrey-K" }, { "family_name": "Ouyang", "given_name": "Yong", "clpid": "Ouyang-Yong" }, { "family_name": "Jeppson", "given_name": "John D.", "orcid": "0000-0002-9669-0813", "clpid": "Jeppson-John-D" }, { "family_name": "Noh", "given_name": "Won Jun", "clpid": "Noh-Won-Jun" }, { "family_name": "Lamothe-Molina", "given_name": "Pedro A.", "clpid": "Lamothe-Molina-Pedro-A" }, { "family_name": "Chen", "given_name": "Huabiao", "clpid": "Chen-Huabiao" }, { "family_name": "Kang", "given_name": "Seung-gu", "clpid": "Kang-Seung-gu" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Zhou", "given_name": "Ruhong", "clpid": "Zhou-Ruhong" }, { "family_name": "Walker", "given_name": "Bruce D.", "clpid": "Walker-Bruce-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors.", "doi": "10.1073/pnas.1718659115", "pmcid": "PMC5828616", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2018-02-20", "series_number": "8", "volume": "115", "issue": "8", "pages": "1877-1882" }, { "id": "authors:rjzw1-y6295", "collection": "authors", "collection_id": "rjzw1-y6295", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180111-132021900", "type": "article", "title": "Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients", "author": [ { "family_name": "Jiang", "given_name": "Shuai", "clpid": "Jiang-Shuai" }, { "family_name": "Yan", "given_name": "Wei", "orcid": "0000-0001-9519-1812", "clpid": "Yan-Wei" }, { "family_name": "Wang", "given_name": "Shizhen Emily", "orcid": "0000-0002-5036-8175", "clpid": "Wang-Shizhen-Emily" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The control of uptake and utilization of necessary extracellular nutrients\u2014glucose and glutamine\u2014is an important aspect of B cell activation. Let-7 is a family of microRNAs known to be involved in metabolic control. Here, we employed several engineered mouse models, including B cell-specific overexpression of Lin28a or the let-7a-1/let-7d/let-7f-1 cluster (let-7adf) and knockout of individual let-7 clusters to show that let-7adf specifically inhibits T cell-independent (TI) antigen-induced immunoglobulin (Ig)M antibody production. Both overexpression and deletion of let-7 in this cluster leads to altered TI-IgM production. Mechanistically, let-7adf suppresses the acquisition and utilization of key nutrients, including glucose and glutamine, through directly targeting hexokinase 2 (Hk2) and by repressing a glutamine transporter Slc1a5 and a key degradation enzyme, glutaminase (Gls), a mechanism mediated by regulation of c-Myc. Our results suggest a novel role of let-7adf as a \"metabolic brake\" on B cell antibody production.", "doi": "10.1016/j.cmet.2017.12.007", "issn": "1550-4131", "publisher": "Elsevier", "publication": "Cell Metabolism", "publication_date": "2018-02-06", "series_number": "2", "volume": "27", "issue": "2", "pages": "393-403" }, { "id": "authors:b1jg4-4v262", "collection": "authors", "collection_id": "b1jg4-4v262", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180510-124207785", "type": "article", "title": "Skewing the Playing Field: A Single-Molecule Study on how RSS Sequence Influences Gene Segment Selection", "author": [ { "family_name": "Hirokawa", "given_name": "Soichi", "orcid": "0000-0001-5584-2676", "clpid": "Hirokawa-Soichi" }, { "family_name": "Belliveau", "given_name": "Nathan M.", "orcid": "0000-0002-1536-1963", "clpid": "Belliveau-N-M" }, { "family_name": "Lovely", "given_name": "Geoffrey A.", "clpid": "Lovely-G-A" }, { "family_name": "Anaya", "given_name": "Michael", "orcid": "0000-0002-6944-3614", "clpid": "Anaya-Michael-A" }, { "family_name": "Schatz", "given_name": "David G.", "clpid": "Schatz-David-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Phillips", "given_name": "Rob", "orcid": "0000-0003-3082-2809", "clpid": "Phillips-R" } ], "abstract": "V(D)J recombination, the cut-and-paste process that combines various antibody-encoding gene segments, provides jawed vertebrates with a combinatorically diverse arsenal of unique antibodies that allows the organism to identify virtually any invading bacterium or infected cell. To initiate this process, the RAG enzymatic complex binds two recognizable recombination signal sequences (RSSs) neighboring the gene segments and subsequently cleaves the DNA to expose the segments before additional enzymes join the two ends to create a continuous antibody-encoding gene. While the general process is well understood, the root causes for the non-uniform distribution of gene segment selection have not been clearly parsed out. In this project, we examine how the sequence diversity of RSSs affect RAG's affinity for forming paired complexes and its propensity for cleaving the DNA, the two key steps for passing two gene segments onward to generate an antibody-encoding gene. Using a single-molecule method known as tethered particle motion (TPM), we systemically study a range of RSS sequences, from single mutation deviations away from the consensus sequence to endogenous RSSs, to determine that RSS sequence is a significant determinant for whether a given gene segment in any antibody gene loci will be selected to produce an antibody. We expect that this work will set us on an initial path to better understanding how the dynamic nature of the genome influences the likelihood that a lymphocyte will produce a particular antibody.", "doi": "10.1016/j.bpj.2017.11.511", "issn": "0006-3495", "publisher": "Biophysical Society", "publication": "Biophysical Journal", "publication_date": "2018-02-02", "series_number": "3", "volume": "114", "issue": "3", "pages": "86a" }, { "id": "authors:fcb64-jpb47", "collection": "authors", "collection_id": "fcb64-jpb47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171221-152204867", "type": "article", "title": "Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes", "author": [ { "family_name": "Gee", "given_name": "Marvin H.", "clpid": "Gee-Marvin-H" }, { "family_name": "Han", "given_name": "Arnold", "clpid": "Han-Arnold" }, { "family_name": "Lofgren", "given_name": "Shane M.", "clpid": "Lofgren-Shane-M" }, { "family_name": "Beausang", "given_name": "John F.", "clpid": "Beausang-John-F" }, { "family_name": "Mendoza", "given_name": "Juan L.", "clpid": "Mendoza-Juan-L" }, { "family_name": "Birnbaum", "given_name": "Michael E.", "clpid": "Birnbaum-Michael-E" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Fischer", "given_name": "Suzanne", "orcid": "0000-0003-4110-6576", "clpid": "Fischer-Suzanne" }, { "family_name": "Yang", "given_name": "Xinbo", "clpid": "Yang-Xinbo" }, { "family_name": "Gomez-Eerland", "given_name": "Raquel", "clpid": "Gomez-Eerland-Raquel" }, { "family_name": "Bingham", "given_name": "David B.", "clpid": "Bingham-David-B" }, { "family_name": "Sibener", "given_name": "Leah V.", "clpid": "Sibener-Leah-V" }, { "family_name": "Fernandes", "given_name": "Ricardo A.", "clpid": "Fernandes-Ricardo-A" }, { "family_name": "Velasco", "given_name": "Andrew", "clpid": "Velasco-Andrew" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Schumacher", "given_name": "Ton N.", "clpid": "Schumacher-Ton-N" }, { "family_name": "Khatri", "given_name": "Purvesh", "clpid": "Khatri-Purvesh" }, { "family_name": "Quake", "given_name": "Stephen R.", "orcid": "0000-0002-1613-0809", "clpid": "Quake-S-R" }, { "family_name": "Davis", "given_name": "Mark M.", "clpid": "Davis-Mark-M" }, { "family_name": "Garcia", "given_name": "K. Christopher", "orcid": "0000-0001-9273-0278", "clpid": "Garcia-K-Christopher" } ], "abstract": "The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of \"orphan\" T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A\u221702:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile identification of tumor antigens through unbiased screening.", "doi": "10.1016/j.cell.2017.11.043", "pmcid": "PMC5786495", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2018-01-25", "series_number": "3", "volume": "172", "issue": "3", "pages": "549-563" }, { "id": "authors:wcgd0-5na41", "collection": "authors", "collection_id": "wcgd0-5na41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180129-092440324", "type": "article", "title": "A kinetic investigation of interacting, stimulated T cells identifies conditions for rapid functional enhancement, minimal phenotype differentiation, and improved adoptive cell transfer tumor eradication", "author": [ { "family_name": "Zhou", "given_name": "Jing", "clpid": "Zhou-Jing" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-M-T" }, { "family_name": "Malkova", "given_name": "Natalia", "clpid": "Malkova-N-V" }, { "family_name": "Sutherland", "given_name": "Alexander M.", "clpid": "Sutherland-A-M" }, { "family_name": "Comin-Anduix", "given_name": "Begonya", "clpid": "Comin-Anduix-B" }, { "family_name": "Su", "given_name": "Yapeng", "clpid": "Su-Yapeng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differentiation, and response to stimulation hinders the co-optimization of these factors. We report on a biophysical investigation of how the short-term kinetics of T cell functional activation, through molecular stimulation and cell-cell interactions, competes with phenotype differentiation. T cells receive molecular stimulation for a few minutes to a few hours in bulk culture. Following this priming period, the cells are then analyzed at the transcriptional level, or isolated as single cells, with continuing molecular stimulation, within microchambers for analysis via 11-plex secreted protein assays. We resolve a rapid feedback mechanism, promoted by T cell\u2014T cell contact interactions, which strongly amplifies T cell functional performance while yielding only minimal phenotype differentiation. When tested in mouse models of ACT, optimally primed T cells lead to complete tumor eradication. A similar kinetic process is identified in CD8^+ and CD4^+ T cells collected from a patient with metastatic melanoma.", "doi": "10.1371/journal.pone.0191634", "pmcid": "PMC5779691", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLOS ONE", "publication_date": "2018-01-23", "series_number": "1", "volume": "13", "issue": "1", "pages": "Art. No. e0191634" }, { "id": "authors:3ya2z-hkg22", "collection": "authors", "collection_id": "3ya2z-hkg22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171018-124112191", "type": "article", "title": "The Pathway to a Universal Influenza Vaccine", "author": [ { "family_name": "Paules", "given_name": "Catharine I.", "clpid": "Paules-Catharine-I" }, { "family_name": "Marston", "given_name": "Hilary D.", "clpid": "Marston-Hilary-D" }, { "family_name": "Eisinger", "given_name": "Robert W.", "clpid": "Eisinger-Robert-W" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Fauci", "given_name": "Anthony S.", "clpid": "Fauci-Anthony-S" } ], "abstract": "Development of a universal influenza vaccine is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. To facilitate this goal, we convened a workshop in Rockville, Maryland to identify knowledge gaps in influenza research and develop strategies to fill them.", "doi": "10.1016/j.immuni.2017.09.007", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2017-10-17", "series_number": "4", "volume": "47", "issue": "4", "pages": "599-603" }, { "id": "authors:e4mb2-pxv70", "collection": "authors", "collection_id": "e4mb2-pxv70", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171011-124140531", "type": "article", "title": "An NF-\u03baB-microRNA regulatory network tunes macrophage inflammatory responses", "author": [ { "family_name": "Mann", "given_name": "Mati", "orcid": "0000-0002-1895-414X", "clpid": "Mann-Mati" }, { "family_name": "Mehta", "given_name": "Arnav", "orcid": "0000-0002-0313-2848", "clpid": "Mehta-Arnav" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Lee", "given_name": "Kevin", "clpid": "Lee-Kevin-K" }, { "family_name": "Marinov", "given_name": "Georgi K.", "orcid": "0000-0003-1822-7273", "clpid": "Marinov-Georgi-K" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Lu", "given_name": "Li-Fan", "orcid": "0000-0002-9727-0036", "clpid": "Lu-Li-Fan" }, { "family_name": "Rudensky", "given_name": "Alexander Y.", "orcid": "0000-0003-1280-2898", "clpid": "Rudensky-Alexander-Y" } ], "abstract": "The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-\u03baB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-\u03baB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-\u03baB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-\u03baB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-\u03baB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity.", "doi": "10.1038/s41467-017-00972-z", "pmcid": "PMC5636846", "issn": "2041-1723", "publisher": "Nature Publishing Group", "publication": "Nature Communications", "publication_date": "2017-10-11", "volume": "8", "pages": "Art. No. 851" }, { "id": "authors:yg429-3cf41", "collection": "authors", "collection_id": "yg429-3cf41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20171016-153550997", "type": "article", "title": "Human Embryo Editing: Opportunities and Importance of Transnational Cooperation", "author": [ { "family_name": "Pei", "given_name": "Duanqing", "clpid": "Pei-Duanqing" }, { "family_name": "Beier", "given_name": "David W.", "clpid": "Beier-David-W" }, { "family_name": "Levy-Lahad", "given_name": "Ephrat", "clpid": "Levy-Lahad-Ephrat" }, { "family_name": "Marchant", "given_name": "Gary", "clpid": "Marchant-Gary" }, { "family_name": "Rossant", "given_name": "Janet", "clpid": "Rossant-Janet" }, { "family_name": "Belmonte", "given_name": "Juan Carlos Izpisua", "clpid": "Belmonte-Juan-Carlos-Izpisua" }, { "family_name": "Lovell-Badge", "given_name": "Robin", "clpid": "Lovell-Badge-Robin" }, { "family_name": "Jaenisch", "given_name": "Rudolf", "clpid": "Jaenisch-Rudolf" }, { "family_name": "Charo", "given_name": "Alta", "clpid": "Charo-Alta" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A recent National Academies report articulates a path forward for research, ethics, and governance of clinical applications involving genome editing. In light of recent human embryo editing developments, scientists and stakeholders from all nations should cooperate to take advantage of this historic opportunity for medicine and also basic human biology.", "doi": "10.1016/j.stem.2017.09.010", "issn": "1934-5909", "publisher": "Elsevier", "publication": "Cell Stem Cell", "publication_date": "2017-10-05", "series_number": "4", "volume": "21", "issue": "4", "pages": "423-426" }, { "id": "authors:etmd9-76c07", "collection": "authors", "collection_id": "etmd9-76c07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170724-124156529", "type": "article", "title": "Photon-induced near-field electron microscopy (PINEM) of eukaryotic cells", "author": [ { "family_name": "Kaplan", "given_name": "Mohammed", "orcid": "0000-0002-0759-0459", "clpid": "Kaplan-Mohammed" }, { "family_name": "Yoo", "given_name": "Byung-Kuk", "orcid": "0000-0002-2610-6685", "clpid": "Yoo-Byung-Kuk" }, { "family_name": "Tang", "given_name": "Jau", "orcid": "0000-0003-2078-1513", "clpid": "Tang-Jau" }, { "family_name": "Karam", "given_name": "Tony E.", "orcid": "0000-0002-1244-5141", "clpid": "Karam-T-E" }, { "family_name": "Liao", "given_name": "Bolin", "orcid": "0000-0002-0898-0803", "clpid": "Liao-Bolin" }, { "family_name": "Majumdar", "given_name": "Devdoot", "clpid": "Majumdar-Devdoot-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Jensen", "given_name": "Grant J.", "orcid": "0000-0003-1556-4864", "clpid": "Jensen-G-J" }, { "family_name": "Zewail", "given_name": "Ahmed H.", "clpid": "Zewail-A-H" } ], "abstract": "Photon-induced near-field electron microscopy (PINEM) is a technique to produce and then image evanescent electromagnetic fields on the surfaces of nanostructures. Most previous applications of PINEM have imaged surface plasmon-polariton waves on conducting nanomaterials. Here, the application of PINEM on whole human cancer cells and membrane vesicles isolated from them is reported. We show that photons induce time-, orientation-, and polarization-dependent evanescent fields on the surfaces of A431 cancer cells and isolated membrane vesicles. Furthermore, the addition of a ligand to the major surface receptor on these cells and vesicles (Epidermal Growth Factor Receptor, EGFR) reduces the intensity of these fields in both preparations. In the absence of plasmon waves in biological samples, we propose these evanescent fields reflect the changes of EGFR kinase domain polarization upon ligand binding.", "doi": "10.1002/anie.201706120", "issn": "1433-7851", "publisher": "Wiley", "publication": "Angewandte Chemie International Edition", "publication_date": "2017-09-11", "series_number": "38", "volume": "56", "issue": "38", "pages": "11498-11501" }, { "id": "authors:628pt-xez63", "collection": "authors", "collection_id": "628pt-xez63", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170124-111140333", "type": "article", "title": "Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids", "author": [ { "family_name": "Seet", "given_name": "Christopher S.", "clpid": "Seet-Christopher-S" }, { "family_name": "He", "given_name": "Chongbin", "clpid": "He-Chongbin" }, { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Li", "given_name": "Suwen", "clpid": "Li-Suwen" }, { "family_name": "Chick", "given_name": "Brent", "clpid": "Chick-Brent" }, { "family_name": "Gschweng", "given_name": "Eric H.", "clpid": "Gschweng-Eric-H" }, { "family_name": "Zhu", "given_name": "Yuhua", "clpid": "Zhu-Yuhua" }, { "family_name": "Kim", "given_name": "Kenneth", "clpid": "Kim-Kenneth" }, { "family_name": "Kohn", "given_name": "Donald B.", "clpid": "Kohn-Donald-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Crooks", "given_name": "Gay M.", "clpid": "Crooks-Gay-M" }, { "family_name": "Montel-Hagen", "given_name": "Am\u00e9lie", "clpid": "Montel-Hagen-Am\u00e9lie" } ], "abstract": "Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3^+TCR-\u03b1\u03b2^+ single-positive CD8^+ or CD4^+ cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR V\u03b2 expression, consistent with allelic exclusion of V\u03b2-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies.", "doi": "10.1038/nmeth.4237", "pmcid": "PMC5426913", "issn": "1548-7091", "publisher": "Nature Publishing Group", "publication": "Nature Methods", "publication_date": "2017-05", "series_number": "5", "volume": "14", "issue": "5", "pages": "521-530" }, { "id": "authors:1xdp5-x1566", "collection": "authors", "collection_id": "1xdp5-x1566", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180117-161110844", "type": "article", "title": "Technologies for personalizing cancer immunotherapies", "author": [ { "family_name": "Peng", "given_name": "Songming", "orcid": "0000-0002-2742-6584", "clpid": "Peng-Songming" }, { "family_name": "Zaretsky", "given_name": "Jesse", "clpid": "Zaretsky-J" }, { "family_name": "Bethune", "given_name": "Michael", "clpid": "Bethune-M-T" }, { "family_name": "Hsu", "given_name": "Alice", "clpid": "Hsu-Alice" }, { "family_name": "Heath", "given_name": "John E.", "clpid": "Heath-J-E" }, { "family_name": "Noh", "given_name": "Won Jun", "clpid": "Noh-Won-Jun" }, { "family_name": "Esswein", "given_name": "Shannon", "clpid": "Esswein-S" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "At the heart of most cancer immunotherapies are the specific interactions between tumor-infiltrating T cells, and the antigens that attract those T cells into the tumor. It has become increasingly apparent that (mutation containing) neoantigens likely play an important role in this regard. Putative neoantigens are identified by tumor exome analysis, but finding which of those candidates actually promote T cell tumor infiltration is challenging, as is pairing such antigens with the cognate T cell receptor (TCR) genes. Technologies that can address this challenge can help pave the way for personalized immunotherapies. For example, the active neoantigens can be engineered into personalized cell-based cancer vaccines, while the cognate TCRs represent engineered T cell therapy opportunities. I will discuss a nanotech/microchip tool that we have recently developed to address this challenge. The platform allows for the non-destructive enumeration of neoantigen specific T cell populations from either tumor infiltrating lymphocytes (TILs) or unexpanded peripheral blood mononuclear cells (PBMCs), beginning with as few as 10,000 CD8+ cells. I will discuss the application of the platform for kinetic studies of patient responses to checkpoint inhibitor therapy (via blood analysis), as well as applications for matching neoantigen-specificity with T cell receptor genes. I will also discuss how the resultant data can be used to guide the refinement of neoantigen prediction algorithms.", "doi": "10.1158/2326-6074.TUMIMM16-IA17", "issn": "2326-6066", "publisher": "American Association for Cancer Research", "publication": "Cancer Immunology Research", "publication_date": "2017-03", "series_number": "S3", "volume": "5", "issue": "S3", "pages": "IA17" }, { "id": "authors:mbw9r-y7483", "collection": "authors", "collection_id": "mbw9r-y7483", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170320-144628390", "type": "article", "title": "Preparation of peptide\u2013MHC and T-cell receptor dextramers by biotinylated dextran doping", "author": [ { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Comin-Anduix", "given_name": "Bego\u00f1a", "clpid": "Comin-Anduix-Bego\u00f1a" }, { "family_name": "Fu", "given_name": "Yu-Hsien Hwang", "clpid": "Fu-Yu-Hsien-Hwang" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Peptide\u2013major histocompatibility complex (pMHC) multimers enable the detection, characterization, and isolation of antigen-specific T-cell subsets at the single-cell level via flow cytometry and fluorescence microscopy. These labeling reagents exploit a multivalent scaffold to increase the avidity of individually weak T-cell receptor (TCR)-pMHC interactions. Dextramers are an improvement over the original streptavidin-based tetramer technology because they are more multivalent, improving sensitivity for rare, low-avidity T cells, including self/tumor-reactive clones. However, commercial pMHC dextramers are expensive, and in-house production is very involved for a typical biology research laboratory. Here, we present a simple, inexpensive protocol for preparing pMHC dextramers by doping in biotinylated dextran during conventional tetramer preparation. We use these pMHC dextramers to identify patient-derived, tumor-reactive T cells. We apply the same dextran doping technique to prepare TCR dextramers and use these novel reagents to yield new insight into MHC I\u2013mediated antigen presentation.", "doi": "10.2144/000114525", "issn": "0736-6205", "publisher": "Informa Healthcare", "publication": "BioTechniques", "publication_date": "2017-03", "series_number": "3", "volume": "62", "issue": "3", "pages": "123-130" }, { "id": "authors:ghq9j-8p751", "collection": "authors", "collection_id": "ghq9j-8p751", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-135937690", "type": "article", "title": "HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells", "author": [ { "family_name": "Wee", "given_name": "Edmund G.", "clpid": "Wee-Edmund-G" }, { "family_name": "Ondondo", "given_name": "Beatrice", "clpid": "Ondondo-Beatrice" }, { "family_name": "Berglund", "given_name": "Peter", "clpid": "Berglund-Peter" }, { "family_name": "Archer", "given_name": "Jacob", "clpid": "Archer-Jacob" }, { "family_name": "McMichael", "given_name": "Andrew J.", "clpid": "McMichael-Andrew-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "ter Meulen", "given_name": "Jan H.", "clpid": "ter-Meulen-Jan-H" }, { "family_name": "Hanke", "given_name": "Tomas", "clpid": "Hanke-Tomas" } ], "abstract": "To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/10^6splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.", "doi": "10.1016/j.ymthe.2016.12.004", "pmcid": "PMC5368423", "issn": "1525-0016", "publisher": "American Society of Gene & Cell Therapy", "publication": "Molecular Therapy", "publication_date": "2017-02-01", "series_number": "2", "volume": "25", "issue": "2", "pages": "494-503" }, { "id": "authors:750kw-7xf48", "collection": "authors", "collection_id": "750kw-7xf48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161212-110038485", "type": "article", "title": "Absence of miR-146a in podocytes increases risk of diabetic glomerulopathy via upregulation of erbb4 and notch-1", "author": [ { "family_name": "Lee", "given_name": "Ha Won", "clpid": "Lee-Ha-Won" }, { "family_name": "Khan", "given_name": "Samia Q.", "clpid": "Khan-Samia-Q" }, { "family_name": "Khaliqdina", "given_name": "Shehryar", "clpid": "Khaliqdina-Shehryar" }, { "family_name": "Altintas", "given_name": "Mehmet M.", "clpid": "Altintas-Mehmet-M" }, { "family_name": "Grahammer", "given_name": "Florian", "clpid": "Grahammer-Florian" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Koh", "given_name": "Kwihey", "clpid": "Koh-Kwihey" }, { "family_name": "Tardi", "given_name": "Nicholas J.", "clpid": "Tardi-Nicholas-J" }, { "family_name": "Faridi", "given_name": "Mohd Hafeez", "clpid": "Faridi-Mohd-Hafeez" }, { "family_name": "Geraghty", "given_name": "Terese", "clpid": "Geraghty-Terese" }, { "family_name": "Cimbaluk", "given_name": "David J.", "clpid": "Cimbaluk-David-J" }, { "family_name": "Susztak", "given_name": "Katalin", "clpid": "Susztak-Katalin" }, { "family_name": "Moita", "given_name": "Luis F.", "clpid": "Moita-Luis-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Tharaux", "given_name": "Pierre-Louis", "clpid": "Tharaux-Pierre-Louis" }, { "family_name": "Huber", "given_name": "Tobias B.", "clpid": "Huber-Tobias-B" }, { "family_name": "Kretzler", "given_name": "Matthias", "clpid": "Kretzler-Matthias" }, { "family_name": "Bitzer", "given_name": "Markus", "clpid": "Bitzer-Markus" }, { "family_name": "Reiser", "given_name": "Jochen", "clpid": "Reiser-Jochen" }, { "family_name": "Gupta", "given_name": "Vineet", "orcid": "0000-0001-6987-2550", "clpid": "Gupta-Vineet" } ], "abstract": "Podocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR-146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. MiR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a-/-) showed accelerated development of glomerulopathy and albuminuria upon streptozotocin (STZ)-induced hyperglycemia. The miR-146a targets, Notch-1 and ErbB4, were also significantly upregulated in the glomeruli of diabetic patients and mice, suggesting induction of the downstream TGF\u03b2-signaling. Treatment with a pan-ErbB kinase inhibitor erlotinib with nanomolar activity against ErbB4 significantly suppressed diabetic glomerular injury and albuminuria in both WT and miR-146a-/- animals. Treatment of podocytes in vitro with TGF-\u03b21 resulted in increased expression of Notch-1, ErbB4, pErbB4 and pEGFR, the heterodimerization partner of ErbB4, suggesting increased ErbB4/EGFR signaling. TGF-\u03b21 also increased levels of inflammatory cytokine MCP-1 and MCP-1 induced protein-1 (MCPIP1), a suppressor of miR-146a, suggesting an autocrine loop. Inhibition of ErbB4/EGFR with erlotinib co-treatment of podocytes suppressed this signaling. Our findings suggest a novel role for miR-146a in protecting against diabetic glomerulopathy and podocyte injury. They also point to Erbb4/EGFR as a novel, druggable target for therapeutic intervention, especially since several pan-ErbB inhibitors are clinically available.", "doi": "10.1074/jbc.M116.753822", "pmcid": "PMC5241746", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "2017-01-13", "series_number": "2", "volume": "292", "issue": "2", "pages": "732-747" }, { "id": "authors:ddssp-bat24", "collection": "authors", "collection_id": "ddssp-bat24", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170123-094833526", "type": "article", "title": "30 Years of NF-\u03baB: A Blossoming of Relevance to Human Pathobiology", "author": [ { "family_name": "Zhang", "given_name": "Qiang", "clpid": "Zhang-Qiang" }, { "family_name": "Lenardo", "given_name": "Michael J.", "clpid": "Lenardo-Michael-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB was discovered 30 years ago as a rapidly inducible transcription factor. Since that time, it has been found to have a broad role in gene induction in diverse cellular responses, particularly throughout the immune system. Here, we summarize elaborate regulatory pathways involving this transcription factor and use recent discoveries in human genetic diseases to place specific proteins within their relevant medical and biological contexts.", "doi": "10.1016/j.cell.2016.12.012", "pmcid": "PMC5268070", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2017-01-12", "series_number": "1-2", "volume": "168", "issue": "1-2", "pages": "37-57" }, { "id": "authors:q263r-gpn80", "collection": "authors", "collection_id": "q263r-gpn80", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-091735457", "type": "article", "title": "Antibody gene transfer with adeno-associated viral vectors as a method for HIV prevention", "author": [ { "family_name": "Brady", "given_name": "Jacqueline M.", "clpid": "Brady-Jacqueline-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" } ], "abstract": "Broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) show great promise in HIV prevention as they are capable of potently neutralizing a considerable breadth of genetically diverse strains. Passive transfer of monoclonal bNAb proteins can confer protection in animal models of HIV infection at modest concentrations, inspiring efforts to develop an HIV vaccine capable of eliciting bNAb responses. However, these antibodies demonstrate high degrees of somatic mutation and other unique characteristics that may hinder the ability of conventional approaches to consistently and effectively produce bNAb analogs. As an alternative strategy, we and others have proposed vector-mediated gene transfer to generate long-term, systemic production of bNAbs in the absence of immunization. Herein, we review the use of adeno-associated virus (AAV) vectors for delivery of HIV bNAbs and antibody-like proteins and summarize both the advantages and disadvantages of this strategy as a method for HIV prevention.", "doi": "10.1111/imr.12478", "pmcid": "PMC5300685", "issn": "0105-2896", "publisher": "John Wiley & Sons", "publication": "Immunological Reviews", "publication_date": "2017-01", "series_number": "1", "volume": "275", "issue": "1", "pages": "324-333" }, { "id": "authors:p803x-hc548", "collection": "authors", "collection_id": "p803x-hc548", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161104-095700365", "type": "article", "title": "Domain-swapped T cell receptors improve the safety of TCR gene therapy", "author": [ { "family_name": "Bethune", "given_name": "Michael T.", "clpid": "Bethune-Michael-T" }, { "family_name": "Gee", "given_name": "Marvin H.", "clpid": "Gee-Marvin-H" }, { "family_name": "Bunse", "given_name": "Mario", "clpid": "Bunse-Mario" }, { "family_name": "Lee", "given_name": "Mark S.", "clpid": "Lee-Mark-S" }, { "family_name": "Gschweng", "given_name": "Eric H.", "clpid": "Gschweng-Eric-H" }, { "family_name": "Pagadala", "given_name": "Meghana S.", "clpid": "Pagadala-Meghana-S" }, { "family_name": "Zhou", "given_name": "Jing", "clpid": "Zhou-Jing" }, { "family_name": "Cheng", "given_name": "Donghui", "clpid": "Cheng-Donghui" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Kohn", "given_name": "Donald B.", "clpid": "Kohn-Donald-B" }, { "family_name": "Kuhns", "given_name": "Michael S.", "clpid": "Kuhn-Michael-S" }, { "family_name": "Uckert", "given_name": "Wolfgang", "clpid": "Uckert-Wolfgang" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "T cells engineered to express a tumor-specific \u03b1\u03b2 T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic \u03b1\u03b2 chains with endogenous \u03b1\u03b2 chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the \u03b1 and \u03b2 chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of \u03b1\u03b2 TCR domains with corresponding \u03b3\u03b4 TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.", "doi": "10.7554/eLife.19095", "pmcid": "PMC5101000", "issn": "2050-084X", "publisher": "eLife Sciences Publications", "publication": "eLife", "publication_date": "2016-11-08", "volume": "5", "pages": "Art. No. e19095" }, { "id": "authors:qq6jf-pta93", "collection": "authors", "collection_id": "qq6jf-pta93", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161128-150950812", "type": "article", "title": "HIV-1 Conserved Mosaics Delivered by Regimens with Integration-deficient, DC-targeting Lentivirus Induce Robust T Cells", "author": [ { "family_name": "Ondondo", "given_name": "Beatrice", "clpid": "Ondondo-Beatrice" }, { "family_name": "Wee", "given_name": "Edmund", "clpid": "Wee-Edmund" }, { "family_name": "McMichael", "given_name": "Andrew", "clpid": "McMichael-Andrew-J" }, { "family_name": "Berglund", "given_name": "Peter", "clpid": "Berglund-Peter" }, { "family_name": "Archer", "given_name": "Jacob", "clpid": "Archer-Jacob" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ter Meulen", "given_name": "Jan", "clpid": "ter-Meulen-Jan-H" }, { "family_name": "Hanke", "given_name": "Tomas", "clpid": "Hanke-Tomas" } ], "abstract": "Background: To be effective against HIV-1, vaccine-induced\nT cells must selectively target functionally conserved and, at\nthe same time, protective epitopes present on the majority of\ncurrently circulating and reactivated HIV-1 strains, and rapidly\nreach protective frequencies upon exposure to the virus.\nHeterologous prime-boost regimens using virally vectored\nvaccines are currently the most promising strategy towards\nachieving this goal, nevertheless, induction of robust longterm\nmemory remains challenging. To this end, lentiviral\nvectors induce high frequencies of memory cells due to their\nlow-inflammatory nature, while typically inducing only low antivector\nimmune responses.\nMethods: We describe construction of novel candidate vaccines\nZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an\nintegration-deficient lentiviral vector platform with preferential\ntransduction of human dendritic cells and express bivalent\nmosaic of conserved-region T-cell immunogens with a high\nglobal HIV-1 match.\nResults: Each of the two mosaics was individually immunogenic\nand together in heterologous prime-boost regimens with nonreplicating\nsimian (chimpanzee) adenovirus or non-replicating\npoxvirus MVA vaccines induced very high frequencies of\nplurifunctional and broadly cross-reactive T cells in BALB/c and\noutbred CD1-SWISS mice.\nConclusions: These data support further development of this\nvaccine concept.", "issn": "0889-2229", "publisher": "Mary Ann Liebert", "publication": "AIDS Research and Human Retroviruses", "publication_date": "2016-10", "series_number": "Suppl. 1", "volume": "32", "issue": "Suppl. 1", "pages": "344" }, { "id": "authors:n5yyn-b8e30", "collection": "authors", "collection_id": "n5yyn-b8e30", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160829-080205246", "type": "article", "title": "A path toward understanding neurodegeneration", "author": [ { "family_name": "Kosik", "given_name": "K. S.", "clpid": "Kosik-Kenneth-S" }, { "family_name": "Sejnowski", "given_name": "T. J.", "orcid": "0000-0002-0622-7391", "clpid": "Sejnowski-Terrence-J" }, { "family_name": "Raichle", "given_name": "M. E.", "clpid": "Raichle-Marcus-E" }, { "family_name": "Ciechanover", "given_name": "A.", "clpid": "Ciechanover-Aaron" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The specter of neurodegenerative disease, particularly Alzheimer's disease, haunts the developed world and exacts a poorly documented toll on underdeveloped countries. With so little progress made toward finding a cure\u2014or, better, a prevention\u2014it is time to rethink the path to progress. This requires a change in perspective on the type of research that will make a difference. The lesson learned from cancer research is that a new commitment means rethinking the fundamental approach to the disease. Cancer research moved from taking potshots with, usually, cytotoxic drugs to a bottom-up, mechanism-based approach in which newly acquired genetic knowledge played the largest role. Today, that effort has produced a platform of knowledge from which academia and industry are drawing. For neurodegenerative disease, the genetic approach remains valid but the problem must concurrently be approached from a complementary, robust cell biological perspective, focusing on the cellular cascade of events that lead to neuronal cell death.", "doi": "10.1126/science.aai7622", "pmcid": "PMC6028188", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2016-08-26", "series_number": "6302", "volume": "353", "issue": "6302", "pages": "872-873" }, { "id": "authors:hrf71-wwv17", "collection": "authors", "collection_id": "hrf71-wwv17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160525-150035453", "type": "article", "title": "Deficiency of Nuclear Factor-\u03baB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice", "author": [ { "family_name": "Ramakrishnan", "given_name": "Parameswaran", "orcid": "0000-0002-1314-827X", "clpid": "Ramakrishnan-Parameswaran" }, { "family_name": "Yui", "given_name": "Mary A.", "orcid": "0000-0002-3136-2181", "clpid": "Yui-Mary-A" }, { "family_name": "Tomalka", "given_name": "Jeffrey A.", "clpid": "Tomalka-Jeffrey-A" }, { "family_name": "Majumdar", "given_name": "Devdoot", "clpid": "Majumdar-Devdoot-S" }, { "family_name": "Parameswaran", "given_name": "Reshmi", "clpid": "Parameswaran-Reshmi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The nuclear factor-\u03baB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel\u2013deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel\u2013deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4^+ and CD8^+ T cells from c-Rel\u2013deficient NOD mice showed significantly decreased T-cell receptor\u2013induced IL-2, IFN-\u03b3, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel\u2013competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel\u2013deficient NOD mice. The results suggest that c-Rel\u2013dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel\u2013dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell\u2013dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity.", "doi": "10.2337/db15-1607", "pmcid": "PMC4955991", "issn": "0012-1797", "publisher": "American Diabetes Association", "publication": "Diabetes", "publication_date": "2016-08", "series_number": "8", "volume": "65", "issue": "8", "pages": "2367-2379" }, { "id": "authors:khyg8-gvn36", "collection": "authors", "collection_id": "khyg8-gvn36", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160309-130909744", "type": "article", "title": "RNA-binding protein Lin28 in cancer and immunity", "author": [ { "family_name": "Jiang", "given_name": "Shuai", "clpid": "Jiang-Shuai" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The highly conserved RNA-binding protein, Lin28, is involved in many biological processes, including development, reprogramming, pluripotency, and metabolism. Importantly, Lin28 functions as an oncogene, promoting tumor progression and metastasis in various human cancers. Lin28 can regulate gene expression either by directly binding to mRNAs or by blocking microRNA biogenesis, and the underlying mechanisms include Let-7-dependent and Let-7-independent modes of action. Recent evidence shows that Lin28 also plays a fundamental role in immunity. The roles of Lin28 in disease are complex and require characterization of its physiological functions in cancer and immunological contexts. Here we review emerging information on the role of Lin28 in cancer and immunity and the molecular mechanisms it uses. We discuss our present knowledge of the system and highlight remaining mysteries related to the functions of this small RNA-binding protein. This knowledge may lead to Lin28 becoming a diagnostic marker for cancer or immune-related diseases and a possible therapeutic target.", "doi": "10.1016/j.canlet.2016.02.050", "issn": "0304-3835", "publisher": "Elsevier", "publication": "Cancer Letters", "publication_date": "2016-05-28", "series_number": "1", "volume": "375", "issue": "1", "pages": "108-113" }, { "id": "authors:dw92f-qdj54", "collection": "authors", "collection_id": "dw92f-qdj54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160826-094923399", "type": "article", "title": "The microRNA-212/132 cluster regulates B cell development by setting a threshold for Sox4 expression", "author": [ { "family_name": "Mehta", "given_name": "Arnav", "clpid": "Mehta-Arnav" }, { "family_name": "Mann", "given_name": "Mati", "clpid": "Mann-Mati" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs play unique roles as logic elements in B cell differentiation by allowing for fine-tuning of differentiation checkpoints. We have found that the miR-212/132 cluster is induced in B cells in response to anti-IgM stimulation and that it can regulate B cell differentiation by establishing a threshold of Sox4 expression necessary for progression of progenitor B cells. Over-expression of miR-132 blocks the transition of pre-pro-B cells to pro-B cells, in part by inducing apoptosis in primary bone marrow B cells. The deletion of miR-212/132 results in increased B cell output under conditions of inflammatory stress. We validate Sox4 as a novel target of miR-132, and show that co-expression of Sox4 with miR-132 can rescue the phenotype observed with over-expression of miR-132 alone. We further demonstrate that over-expression of miR-132 can inhibit the development of B cell leukemia in mice that have B cells expressing the c-myc oncogene. We have therefore described miR-212/132 as a novel regulator of B cell development through its regulation of Sox4 expression.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2016-05-01", "series_number": "S1", "volume": "196", "issue": "S1", "pages": "Art. No. 204.26" }, { "id": "authors:14m0c-9ns58", "collection": "authors", "collection_id": "14m0c-9ns58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160825-140558554", "type": "article", "title": "Role of T cell receptors in suppressing HIV infection in elite controllers", "author": [ { "family_name": "Joglekar", "given_name": "Alok", "orcid": "0000-0001-7554-7447", "clpid": "Joglekar-A-V" }, { "family_name": "Lamothe", "given_name": "Pedro A.", "clpid": "Lamothe-P-A" }, { "family_name": "Ouyang", "given_name": "Yong", "clpid": "Ouyang-Yong" }, { "family_name": "Liu", "given_name": "Zhe", "clpid": "Liu-Zhe" }, { "family_name": "Walker", "given_name": "Bruce D.", "clpid": "Walker-B-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Virtually all HIV-infected patients progress to AIDS if not treated. A group of patients, called Elite Controllers (ECs), can suppress HIV infection without treatment. This ability of ECs is, in part, due to potent CD8+ T cell (CTL) responses against HIV epitopes presented by human leukocyte antigen (HLA) molecules. In this study, we focused on CTL responses restricted to HLA-B27, an allele that is enriched in ECs, but is not sufficient for protective ability. In HLA-B27+ ECs or non-controllers (NCs), immunodominant CTL responses specific to the KK10 epitope in Gag are found. Previous studies have shown that unlike NCs, B27-KK10-specific CTLs from ECs are efficient at eliminating HIV-infected or KK10-peptide pulsed cells. As the potency of CTLs can be modulated by their T cell receptor (TCR), we hypothesized that B27-KK10-specific TCRs play a significant role in suppressing HIV in ECs. Therefore, we cloned B27-KK10-specific TCRs from ECs or NCs, expressed them in primary T cells, and tested their cytotoxicity. We incubated TCR-transduced T cells with either HIV-infected or KK10-peptide pulsed target cells and measured target cell lysis. Unexpectedly, EC-TCRs were not significantly different than NC-TCRs in their cytotoxicity. We then tested the ability of these cells to suppress HIV in humanized mice and found no significant difference between EC- and NC-TCRs. We are currently investigating various aspects of these TCRs such as cross-reactivity to variants of KK10. The result that TCRs from ECs and non-controllers do not recapitulate the phenotype of CTLs is intriguing and warrants further studies to uncover the mechanism of immunologic control of HIV. Our studies also have implications in immunotherapy and vaccine approaches for HIV.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2016-05-01", "series_number": "S1", "volume": "196", "issue": "S1", "pages": "Art. No. 79.10" }, { "id": "authors:4e8va-whx63", "collection": "authors", "collection_id": "4e8va-whx63", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160502-140420672", "type": "article", "title": "MicroRNAs as regulatory elements in immune system logic", "author": [ { "family_name": "Mehta", "given_name": "Arnav", "clpid": "Mehta-Arnav" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs.", "doi": "10.1038/nri.2016.40", "issn": "1474-1733", "publisher": "Nature Publishing Group", "publication": "Nature Reviews. Immunology", "publication_date": "2016-05", "series_number": "5", "volume": "16", "issue": "5", "pages": "279-294" }, { "id": "authors:rnr3a-mm489", "collection": "authors", "collection_id": "rnr3a-mm489", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161027-102948907", "type": "article", "title": "Why We Need a Summit on Human Gene Editing", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In 1981, Matthew Meselson pointed out that the puzzle brought to light by Darwin, of what constitutes heredity, was solved in two tranches. The first lasted from 1900, when\nMendel's work of the last half of the nineteenth century came into the consciousness of the scientific community. It lasted until 1950 or so, when the rules of genetic\ninheritance had been firmly established.", "issn": "0748-5492", "publisher": "University of Texas at Dallas", "publication": "Issues in Science and Technology", "publication_date": "2016-03", "series_number": "3", "volume": "32", "issue": "3", "pages": "35-38" }, { "id": "authors:y327x-c8w29", "collection": "authors", "collection_id": "y327x-c8w29", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150921-155613989", "type": "article", "title": "The microRNA-212/132 cluster regulates B cell development by targeting Sox4", "author": [ { "family_name": "Mehta", "given_name": "Arnav", "orcid": "0000-0002-0313-2848", "clpid": "Mehta-Arnav" }, { "family_name": "Mann", "given_name": "Mati", "orcid": "0000-0002-1895-414X", "clpid": "Mann-Mati" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Marinov", "given_name": "Georgi K.", "orcid": "0000-0003-1822-7273", "clpid": "Marinov-Georgi-K" }, { "family_name": "Majumdar", "given_name": "Devdoot", "orcid": "0000-0002-2541-3851", "clpid": "Majumdar-Devdoot-S" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Du", "given_name": "Xiaomi", "clpid": "Du-Xiaomi" }, { "family_name": "Erikci", "given_name": "Erdem", "orcid": "0000-0001-8665-2920", "clpid": "Erik\u00e7i-Erdem" }, { "family_name": "Chowdhury", "given_name": "Kamal", "clpid": "Chowdhury-Kamal" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs have emerged as key regulators of B cell fate decisions and immune function. Deregulation of several microRNAs in B cells leads to the development of autoimmune disease and cancer in mice. We demonstrate that the microRNA-212/132 cluster (miR-212/132) is induced in B cells in response to B cell receptor signaling. Enforced expression of miR-132 results in a block in early B cell development at the prepro\u2013B cell to pro\u2013B cell transition and induces apoptosis in primary bone marrow B cells. Importantly, loss of miR-212/132 results in accelerated B cell recovery after antibody-mediated B cell depletion. We find that Sox4 is a target of miR-132 in B cells. Co-expression of SOX4 with miR-132 rescues the defect in B cell development from overexpression of miR-132 alone, thus suggesting that miR-132 may regulate B lymphopoiesis through Sox4. In addition, we show that the expression of miR-132 can inhibit cancer development in cells that are prone to B cell cancers, such as B cells expressing the c-Myc oncogene. We have thus uncovered miR-132 as a novel contributor to B cell development.", "doi": "10.1084/jem.20150489", "pmcid": "PMC4577845", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2015-09-14", "series_number": "10", "volume": "212", "issue": "10", "pages": "1679-1692" }, { "id": "authors:cbqp5-2kb49", "collection": "authors", "collection_id": "cbqp5-2kb49", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150608-140349668", "type": "article", "title": "Broadly neutralizing human immunodeficiency virus type 1 antibody gene transfer protects nonhuman primates from mucosal simian-human immunodeficiency virus infection", "author": [ { "family_name": "Saunders", "given_name": "Kevin O.", "clpid": "Saunders-Kevin-O" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 \u03bcg/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled.", "doi": "10.1128/JVI.00908-15", "pmcid": "PMC4524228", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "2015-09", "series_number": "16", "volume": "89", "issue": "16", "pages": "8334-8345" }, { "id": "authors:kc6mm-b2p96", "collection": "authors", "collection_id": "kc6mm-b2p96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150720-140634045", "type": "article", "title": "The role of microRNA in nutritional control", "author": [ { "family_name": "Nolte-'t Hoen", "given_name": "E. N. M.", "clpid": "Nolte-'t-Hoen-E-N-M" }, { "family_name": "Van Rooij", "given_name": "E.", "clpid": "Van-Rooij-E" }, { "family_name": "Bushell", "given_name": "M.", "clpid": "Bushell-M" }, { "family_name": "Zhang", "given_name": "C.-Y.", "clpid": "Zhang-C-Y" }, { "family_name": "Dashwood", "given_name": "R. H.", "clpid": "Dashwood-R-H" }, { "family_name": "James", "given_name": "W. P. T.", "clpid": "James-W-P-T" }, { "family_name": "Harris", "given_name": "C.", "clpid": "Harris-C" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs (miRNAs) are one of a growing class of noncoding RNAs that are involved in the regulation of a wide range of metabolic processes including cellular differentiation, cell proliferation and apoptosis. The generation of miRNA is regulated in complex ways, for example by small interfering RNAs (small nucleolar and nuclear RNAs) and various other metabolites. This complexity of control is likely to explain how a relatively small part of the DNA that codes for proteins has enabled the evolution of such complex organisms as mammals. Non-protein-coding DNA is therefore thought to carry the memory of early evolutionary steps that led to progressively complex metabolic controls. Clinically, miRNAs are becoming increasingly important following the recognition that some congenital abnormalities can be traced to defects in miRNA processing. The potential for manipulating metabolism and affecting disease processes by the pharmaceutical or biological targeting of specific miRNA pathways is now being tested. miRNAs are also released into the extracellular milieu after packaging by cells into nano-sized extracellular vesicles. Such vesicles can be taken up by adjacent and possibly more distant cells, thereby allowing coordinated intercellular communication in specific tissues. Extracellular miRNAs found in the blood stream may also serve as novel biomarkers for both diagnosing specific forms of cancer and assessing the likelihood of metastasis, and as powerful prognostic indices for various cancers. Here, we discuss the role of intracellular and extracellular miRNAs in nutritional control of various (patho)physiological processes. In this review, we provide an update of the presentations from the 25th Marabou Symposium (Stockholm, 14\u201316 June 2013) entitled 'Role of miRNA in health and nutrition', attended by 50 international experts.", "doi": "10.1111/joim.12372", "issn": "0954-6820", "publisher": "Wiley", "publication": "Journal of Internal Medicine", "publication_date": "2015-08", "series_number": "2", "volume": "278", "issue": "2", "pages": "99-109" }, { "id": "authors:qdrnw-hkm90", "collection": "authors", "collection_id": "qdrnw-hkm90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160225-130253257", "type": "article", "title": "Regulation of stress-induced hematopoiesis", "author": [ { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Purpose of review: Hematopoietic stem cells can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the hematopoietic system can quickly adapt to demand by increasing output of innate immune cells many-fold, often at the expense of lymphopoiesis and erythropoiesis. We review recent advances in understanding the regulation of stress-induced hematopoiesis with a specific focus on the direct effects of inflammatory signaling on hematopoietic stem and progenitor cells (HSPCs).\n\nRecent findings: Recent studies have highlighted several areas of exciting new developments in the field, including the complex interaction and crosstalk within HSPCs and between bone marrow mesenchymal stem cells and endothelial cells needed to achieve regulated myelopoiesis, identification of increased number of inflammatory and infectious molecules with direct effects on HSPCs, the critical role of inflammatory signaling on embryonic specification of hematopoietic stem cells, and the ability of cytokines to instruct lineage choice at the HSPC level. \n\nSummary: These exciting new findings will shape our fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling.", "doi": "10.1097/MOH.0000000000000149", "pmcid": "PMC4573392", "issn": "1065-6251", "publisher": "Lippincott, Williams & Wilkins", "publication": "Current Opinion in Hematology", "publication_date": "2015-07", "series_number": "4", "volume": "22", "issue": "4", "pages": "286-292" }, { "id": "authors:8gb2c-me304", "collection": "authors", "collection_id": "8gb2c-me304", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150622-093830007", "type": "article", "title": "The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression", "author": [ { "family_name": "Mehta", "given_name": "Arnav", "orcid": "0000-0002-0313-2848", "clpid": "Mehta-Arnav" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Sinha", "given_name": "Nikita", "clpid": "Sinha-Nikita" }, { "family_name": "Marinov", "given_name": "Georgi K.", "orcid": "0000-0003-1822-7273", "clpid": "Marinov-Georgi-K" }, { "family_name": "Mann", "given_name": "Mati", "orcid": "0000-0002-1895-414X", "clpid": "Mann-Mati" }, { "family_name": "Kowalczyk", "given_name": "Monika S.", "clpid": "Kowalczyk-Monika-S" }, { "family_name": "Galimidi", "given_name": "Rachel P.", "clpid": "Galimidi-Rachel-P" }, { "family_name": "Du", "given_name": "Xiaomi", "clpid": "Du-Xiaomi" }, { "family_name": "Erikci", "given_name": "Erdem", "orcid": "0000-0001-8665-2920", "clpid": "Erik\u00e7i-Erdem" }, { "family_name": "Regev", "given_name": "Aviv", "orcid": "0000-0003-3293-3158", "clpid": "Regev-Aviv" }, { "family_name": "Chowdhury", "given_name": "Kamal", "clpid": "Chowdhury-Kamal" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.", "doi": "10.1016/j.immuni.2015.05.017", "pmcid": "PMC4471877", "issn": "1074-7613", "publisher": "Cell Press", "publication": "Immunity", "publication_date": "2015-06-16", "series_number": "6", "volume": "42", "issue": "6", "pages": "1021-1032" }, { "id": "authors:1jbdr-6e168", "collection": "authors", "collection_id": "1jbdr-6e168", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150324-125537305", "type": "article", "title": "Single-molecule analysis of RAG-mediated V(D)J DNA cleavage", "author": [ { "family_name": "Lovely", "given_name": "Geoffrey A.", "clpid": "Lovely-Geoffrey-A" }, { "family_name": "Brewster", "given_name": "Robert C.", "clpid": "Brewster-Robert-C" }, { "family_name": "Schatz", "given_name": "David G.", "clpid": "Schatz-David-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Phillips", "given_name": "Rob", "orcid": "0000-0003-3082-2809", "clpid": "Phillips-R" } ], "abstract": "The recombination-activating gene products, RAG1 and RAG2, initiate V(D)J recombination during lymphocyte development by cleaving DNA adjacent to conserved recombination signal sequences (RSSs). The reaction involves DNA binding, synapsis, and cleavage at two RSSs located on the same DNA molecule and results in the assembly of antigen receptor genes. We have developed single-molecule assays to examine RSS binding by RAG1/2 and their cofactor high-mobility group-box protein 1 (HMGB1) as they proceed through the steps of this reaction. These assays allowed us to observe in real time the individual molecular events of RAG-mediated cleavage. As a result, we are able to measure the binding statistics (dwell times) and binding energies of the initial RAG binding events and characterize synapse formation at the single-molecule level, yielding insights into the distribution of dwell times in the paired complex and the propensity for cleavage on forming the synapse. Interestingly, we find that the synaptic complex has a mean lifetime of roughly 400 s and that its formation is readily reversible, with only \u223c40% of observed synapses resulting in cleavage at consensus RSS binding sites.", "doi": "10.1073/pnas.1503477112", "pmcid": "PMC4394307", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2015-04-07", "series_number": "14", "volume": "112", "issue": "14", "pages": "E1715-E1723" }, { "id": "authors:8em0z-wmn71", "collection": "authors", "collection_id": "8em0z-wmn71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150319-185722928", "type": "article", "title": "A prudent path forward for genomic engineering and germline gene modification", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Berg", "given_name": "Paul", "clpid": "Berg-Paul" }, { "family_name": "Botchan", "given_name": "Michael", "clpid": "Botchan-Michael" }, { "family_name": "Carroll", "given_name": "Dana", "clpid": "Carroll-Dana" }, { "family_name": "Alto Charo", "given_name": "R.", "clpid": "Alta-Charo-R" }, { "family_name": "Church", "given_name": "George", "clpid": "Church-George-M" }, { "family_name": "Corn", "given_name": "Jacob E.", "clpid": "Corn-Jacob-E" }, { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Doudna", "given_name": "Jennifer A.", "clpid": "Doudna-Jennifer-A" }, { "family_name": "Fenner", "given_name": "Marsha", "clpid": "Fenner-Marsha" }, { "family_name": "Greely", "given_name": "Henry T.", "clpid": "Greely-Henry-T" }, { "family_name": "Jinek", "given_name": "Martin", "clpid": "Jinek-Martin" }, { "family_name": "Martin", "given_name": "G. Steven", "clpid": "Martin-G-Steven" }, { "family_name": "Penhoet", "given_name": "Edward", "clpid": "Penhoet-Edward" }, { "family_name": "Puck", "given_name": "Jennifer", "clpid": "Puck-Jennifer" }, { "family_name": "Sternberg", "given_name": "Samuel H.", "clpid": "Sternberg-Samuel-H" }, { "family_name": "Weissman", "given_name": "Jonathan S.", "orcid": "0000-0003-2445-670X", "clpid": "Weissman-Jonathan-S" }, { "family_name": "Yamamoto", "given_name": "Keith R.", "clpid": "Yamamoto-Keith-R" } ], "abstract": "A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed.", "doi": "10.1126/science.aab1028", "pmcid": "PMC4394183", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2015-04-03", "series_number": "6230", "volume": "348", "issue": "6230", "pages": "36-38" }, { "id": "authors:j2s55-nqh13", "collection": "authors", "collection_id": "j2s55-nqh13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150211-080735839", "type": "article", "title": "Durable Suppression of Established Transmitted Founder Replication in Infected BLT Humanized Mice by Vectored Immuno Therapy", "author": [ { "family_name": "Deal", "given_name": "Cailin", "clpid": "Deal-Cailin" }, { "family_name": "Ouyang", "given_name": "Yong", "clpid": "Ouyang-Yong" }, { "family_name": "Hong", "given_name": "Christin M.", "clpid": "Hong-Christin-M" }, { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" } ], "abstract": "Recent reports in humanized mice and monkeys have found that broadly neutralizing antibodies (bNAbs) can suppress the replication of laboratory strains of HIV and SHIV while bNAb concentration remains high. Vectored ImmunoProphylaxis\n(VIP) results in long-lived bNAb expression following a single intramuscular {IM) injection of a specialized viral vector, and this approach has been demonstrated as a means\nof durably suppressing viral load. However, previous reports of VIP-delivered bNAbs for HIV therapy required prior antiretroviral drug therapy to reduce viral load to prevent escape.\nMethods: Humanized BLT mice were infected IV with the\nREJO.c transmitted molecular founder strain of HIV. A low dose of combination antiretroviral therapy (ART) was administered to these animals for 5 weeks, followed by a single IM injection of VIP expressing VRC07 or luciferase. Mouse plasma was analyzed by ELISA to determine antibody concentration and by qPCR to determine viral load. Cellular fractions were analyzed by flow cytometry to quantify human CD4 cells over time. After sacrifice, plasma was subjected to a clinically validated ultrasensitive PCR-based viral load assay.\nResults: We detected viral loads of 10^5 copies/mL in infected mice prior to low-dose ART treatment, which resulted in a transient reduction and rebound to pre-therapy loads. Following VIP administration, we observed a rapid increase in the blood concentration of VRC07. Mice expressing VRC07 exhibited a sharp decline in viral load to undetectable levels and an increase in CD4 cells over four weeks and this effect was sustained for the\nremaining 8 weeks of the study. In contrast, mice expressing\nluciferase exhibited increasing viral loads with concomitant\ndecreases in CD4 cells throughout the study. \nConclusions: Our results demonstrate that VIP expressing VRC07 is sufficient to suppress actively replicating transmitted founder virus at high viral load and support efforts to move Vectored Immuno Therapy into clinical trials with infected patients.", "doi": "10.1089/aid.2014.5018.abstract", "issn": "0889-2229", "publisher": "Mary Ann Liebert", "publication": "AIDS Research and Human Retroviruses", "publication_date": "2014-10-30", "series_number": "S1", "volume": "30", "issue": "S1", "pages": "A16-A17" }, { "id": "authors:9ftwn-hqq97", "collection": "authors", "collection_id": "9ftwn-hqq97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141024-110607790", "type": "article", "title": "Broadly neutralizing antibodies abrogate established hepatitis C virus infection", "author": [ { "family_name": "de Jong", "given_name": "Ype P.", "clpid": "de-Jong-Ype-P" }, { "family_name": "Dorner", "given_name": "Marcus", "clpid": "Dorner-Marcus" }, { "family_name": "Mommersteeg", "given_name": "Michiel C.", "clpid": "Mommersteeg-M-C" }, { "family_name": "Xiao", "given_name": "Jing W.", "clpid": "Xiao-Jing-W" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Robbins", "given_name": "Justin B.", "clpid": "Robbins-Justin-B" }, { "family_name": "Winer", "given_name": "Benjamin Y.", "clpid": "Winer-Benjamin-Y" }, { "family_name": "Gerges", "given_name": "Sherif", "clpid": "Gerges-Sherif" }, { "family_name": "Vega", "given_name": "Kevin", "clpid": "Vega-Kevin" }, { "family_name": "Labitt", "given_name": "Rachael N.", "clpid": "Labitt-Rachael-N" }, { "family_name": "Donovan", "given_name": "Bridget M.", "clpid": "Donovan-Bridget-M" }, { "family_name": "Giang", "given_name": "Erick", "clpid": "Giang-Erick" }, { "family_name": "Krishnan", "given_name": "Anuradha", "clpid": "Krishnan-Anuradha" }, { "family_name": "Chiriboga", "given_name": "Luis", "clpid": "Chiriboga-Luis" }, { "family_name": "Charlton", "given_name": "Michael R.", "clpid": "Charlton-Michael-R" }, { "family_name": "Burton", "given_name": "Dennis R.", "clpid": "Burton-Dennis-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Law", "given_name": "Mansun", "clpid": "Law-Mansun" }, { "family_name": "Rice", "given_name": "Charles M.", "orcid": "0000-0003-3087-8079", "clpid": "Rice-C-M" }, { "family_name": "Ploss", "given_name": "Alexander", "clpid": "Ploss-Alexander" } ], "abstract": "In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs\u2014AR3A, AR3B, and AR4A\u2014delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.", "doi": "10.1126/scitranslmed.3009512", "pmcid": "PMC4312107", "issn": "1946-6234", "publisher": "American Association for the Advancement of Science", "publication": "Science Translational Medicine", "publication_date": "2014-09-17", "series_number": "254", "volume": "6", "issue": "254", "pages": "Art. No. 254ra129" }, { "id": "authors:j65v2-75561", "collection": "authors", "collection_id": "j65v2-75561", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141024-094315621", "type": "article", "title": "MicroRNA-125b Represses IRF4 to Induce Acute Myeloid Leukemia", "author": [ { "family_name": "Chaudhuri", "given_name": "A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "So", "given_name": "A. Y.", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Sookram", "given_name": "R.", "clpid": "Sookram-Reeshelle" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNA-125b (miR-125b) is upregulated in a variety of neoplastic blood disorders. We previously showed that miR-125b expression is enriched in hematopoietic stem and progenitor cells (HSPCs), and that upregulation of miR-125b in the mouse hematopoietic system causes an aggressive acute myeloid leukemia. Here we elucidate the molecular mechanism by which miR-125b causes acute myeloid leukemia.", "doi": "10.1016/j.ijrobp.2014.05.2230", "issn": "0360-3016", "publisher": "Elsevier", "publication": "International Journal of Radiation Oncology Biology Physics", "publication_date": "2014-09-01", "series_number": "S1", "volume": "90", "issue": "S1", "pages": "S770-S771" }, { "id": "authors:hgcy7-bwz48", "collection": "authors", "collection_id": "hgcy7-bwz48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141008-074936325", "type": "article", "title": "T-Cell Immunotherapy: Looking Forward", "author": [ { "family_name": "Corrigan-Curay", "given_name": "Jacqueline", "clpid": "Corrigan-Curay-Jacqueline" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The rapidly expanding field of T-cell immunotherapy has experienced clinical successes along with some serious toxicities. \"T Cell Immunotherapy: Optimizing Trial Design,\" a workshop sponsored by the National Institutes of Health's (NIH's) Office of Biotechnology Activities (OBA), brought together researchers to discuss the scientific advances and share new data on key trial design issues, including the selection of new targets, optimizing the T-cell population, preconditioning regimens, strategies to promote persistence of cells, and analysis and management of acute reactions to T-cell infusions with the goal of identifying best practices and a research agenda that will facilitate further development and maximize the safety of this promising approach.", "doi": "10.1038/mt.2014.148", "pmcid": "PMC4435492", "issn": "1525-0016", "publisher": "American Society of Gene & Cell Therapy", "publication": "Molecular Therapy", "publication_date": "2014-09", "series_number": "9", "volume": "22", "issue": "9", "pages": "1564-1574" }, { "id": "authors:sew2a-y4c70", "collection": "authors", "collection_id": "sew2a-y4c70", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140820-085536231", "type": "article", "title": "Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice", "author": [ { "family_name": "Deal", "given_name": "Cailin", "clpid": "Deal-Cailin" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Espinosa", "given_name": "Diego A.", "clpid": "Espinosa-Diego-A" }, { "family_name": "Zavala", "given_name": "Fidel", "clpid": "Zavala-Fidel" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ketner", "given_name": "Gary", "clpid": "Ketner-Gary" } ], "abstract": "Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 \u00b5g/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.", "doi": "10.1073/pnas.1407362111", "pmcid": "PMC4151717", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2014-08-26", "series_number": "34", "volume": "111", "issue": "34", "pages": "12528-12532" }, { "id": "authors:2srxy-6ap37", "collection": "authors", "collection_id": "2srxy-6ap37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140721-090655047", "type": "article", "title": "Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity", "author": [ { "family_name": "Okoye", "given_name": "Isobel S.", "clpid": "Okoye-Isobel-S" }, { "family_name": "Czieso", "given_name": "Stephanie", "clpid": "Czieso-Stephanie" }, { "family_name": "Ktistaki", "given_name": "Eleni", "clpid": "Ktistaki-Eleni" }, { "family_name": "Roderick", "given_name": "Kathleen", "clpid": "Roderick-Kathleen" }, { "family_name": "Coomes", "given_name": "Stephanie M.", "clpid": "Coomes-Stephanie-M" }, { "family_name": "Pelly", "given_name": "Victoria S.", "clpid": "Pelly-Victoria-S" }, { "family_name": "Kannan", "given_name": "Yashaswini", "clpid": "Kannan-Yashaswini" }, { "family_name": "Lloret-Perez", "given_name": "Jimena", "clpid": "Lloret-Perez-Jimena" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Langhorne", "given_name": "Jean", "clpid": "Langhorne-Jean" }, { "family_name": "Wilson", "given_name": "Mark S.", "clpid": "Wilson-Mark-S" } ], "abstract": "Allergic diseases, orchestrated by hyperactive CD4^(+) Th2 cells, are some of the most common global chronic diseases. Therapeutic intervention relies upon broad-scale corticosteroids with indiscriminate impact. To identify targets in pathogenic Th2 cells, we took a comprehensive approach to identify the microRNA (miRNA) and mRNA transcriptome of highly purified cytokine-expressing Th1,\nTh2, Th9, Th17, and Treg cells both generated in vitro and isolated ex vivo from allergy, infection, and autoimmune disease models. We report here that distinct regulatory miRNA networks operate to regulate Th2 cells in house dust mite-allergic or helminth-infected animals and in vitro Th2 cells, which are distinguishable from other T cells. We validated several miRNA (miR) candidates (miR-15a,\nmiR-20b, miR-146a, miR-155, and miR-200c), which targeted a suite of dynamically regulated genes in Th2 cells. Through in-depth studies using miR-155^(\u2212/\u2212) or miR-146a^(\u2212/\u2212) T cells, we identified that T-cell\u2013intrinsic miR-155 was required for type-2 immunity, in part through regulation of S1pr1, whereas T-cell\u2013intrinsic miR-146a was required to prevent overt Th1/Th17 skewing. These data identify miR-155, but not miR-146a, as a potential therapeutic target to alleviate Th2-medited inflammation and allergy.", "doi": "10.1073/pnas.1406322111", "pmcid": "PMC4121777", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2014-07-29", "series_number": "30", "volume": "111", "issue": "30", "pages": "E3081-E3090" }, { "id": "authors:tr5vn-8sb88", "collection": "authors", "collection_id": "tr5vn-8sb88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140731-083448424", "type": "article", "title": "MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi", "author": [ { "family_name": "Lochhead", "given_name": "Robert B.", "clpid": "Lochhead-Robert-B" }, { "family_name": "Ma", "given_name": "Ying", "clpid": "Ma-Ying" }, { "family_name": "Zachary", "given_name": "James F.", "clpid": "Zachary-James-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Weis", "given_name": "John H.", "clpid": "Weis-John-H" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Weis", "given_name": "Janis J.", "clpid": "Weis-Janis-J" } ], "abstract": "MicroRNAs have been shown to be important regulators of inflammatory and immune responses and are implicated in several immune disorders including systemic lupus erythematosus and rheumatoid arthritis, but their role in Lyme borreliosis remains unknown. We performed a microarray screen for expression of miRNAs in joint tissue from three mouse strains infected with Borrelia burgdorferi. This screen identified upregulation of miR-146a, a key negative regulator of NF-\u03baB signaling, in all three strains, suggesting it plays an important role in the in vivo response to B. burgdorferi. Infection of B6 miR-146a^(\u2212/\u2212) mice with B. burgdorferi revealed a critical nonredundant role of miR-146a in modulating Lyme arthritis without compromising host immune response or heart inflammation. The impact of miR-146a was specifically localized to the joint, and did not impact lesion development or inflammation in the heart. Furthermore, B6 miR-146a^(\u2212/\u2212) mice had elevated levels of NF-\u03baB-regulated products in joint tissue and serum late in infection. Flow cytometry analysis of various lineages isolated from infected joint tissue of mice showed that myeloid cell infiltration was significantly greater in B6 miR-146a^(\u2212/\u2212) mice, compared to B6, during B. burgdorferi infection. Using bone marrow-derived macrophages, we found that TRAF6, a known target of miR-146a involved in NF-\u03baB activation, was dysregulated in resting and B. burgdorferi-stimulated B6 miR-146a^(\u2212/\u2212) macrophages, and corresponded to elevated IL-1\u03b2, IL-6 and CXCL1 production. This dysregulated protein production was also observed in macrophages treated with IL-10 prior to B. burgdorferi stimulation. Peritoneal macrophages from B6 miR-146a^(\u2212/\u2212) mice also showed enhanced phagocytosis of B. burgdorferi. Together, these data show that miR-146a-mediated regulation of TRAF6 and NF-\u03baB, and downstream targets such as IL-1\u03b2, IL-6 and CXCL1, are critical for modulation of Lyme arthritis during chronic infection with B. burgdorferi.", "doi": "10.1371/journal.ppat.1004212", "pmcid": "PMC4072785", "issn": "1553-7366", "publisher": "Public Library of Science", "publication": "PLoS Pathogens", "publication_date": "2014-06", "series_number": "6", "volume": "10", "issue": "6", "pages": "Art. No. e1004212" }, { "id": "authors:7vxns-71676", "collection": "authors", "collection_id": "7vxns-71676", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140613-144829921", "type": "article", "title": "Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma", "author": [ { "family_name": "Chodon", "given_name": "Thinle", "clpid": "Chodon-Thinle" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. \n\nExperimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. \n\nResults: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1\u2013specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1\u2013specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. \n\nConclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.", "doi": "10.1158/1078-0432.CCR-13-3017", "pmcid": "PMC4070853", "issn": "1078-0432", "publisher": "American Association for Cancer Research", "publication": "Clinical Cancer Research", "publication_date": "2014-05-01", "series_number": "9", "volume": "20", "issue": "9", "pages": "2457-2465" }, { "id": "authors:xz27e-wy233", "collection": "authors", "collection_id": "xz27e-wy233", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140227-222713478", "type": "article", "title": "Conversion of Danger Signals into Cytokine Signals by Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis", "author": [ { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Ma", "given_name": "Chao", "clpid": "Ma-Chao" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Mehta", "given_name": "Arnav", "clpid": "Mehta-Arnav" }, { "family_name": "DiLoreto", "given_name": "Race", "clpid": "DiLoreto-Race" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "During an infection, the body increases the output of mature immune cells to fight off the \npathogen. Despite convincing evidence that hematopoietic stem and progenitor cells (HSPCs) \ncan sense pathogens directly, how this contributes to hematopoietic cell output remains unknown. \nHere we have combined mouse models with a single cell proteomics platform to show that in \nresponse to toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells \nproduce copious amount of diverse cytokines through the NF-\u03baB signaling. Interestingly, the \ncytokine production ability of HSPCs trumps mature immune cells in both magnitude and \nbreadth. Among cytokines produced by HSPCs, IL-6 is a particularly important regulator of \nmyeloid differentiation and HSPC proliferation in a paracrine manner and in mediating rapid \nmyeloid cell recovery during neutropenia. This study has uncovered a novel property of HSPCs \nthat enables them to convert danger signals into versatile cytokine signals for regulation of stress \nhematopoiesis.", "doi": "10.1016/j.stem.2014.01.007", "pmcid": "PMC4119790", "issn": "1934-5909", "publisher": "Elsevier", "publication": "Cell Stem Cell", "publication_date": "2014-04-03", "series_number": "4", "volume": "14", "issue": "4", "pages": "445-459" }, { "id": "authors:tffqt-nrw96", "collection": "authors", "collection_id": "tffqt-nrw96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140515-081047373", "type": "article", "title": "Emerging Themes in Biology: Hints for the Future", "author": [ { "family_name": "Nurse", "given_name": "Paul", "clpid": "Nurse-Paul" }, { "family_name": "Goldstein", "given_name": "Joseph L.", "clpid": "Goldstein-Joseph-L" }, { "family_name": "Brown", "given_name": "Michael S.", "clpid": "Brown-Michael-S" }, { "family_name": "Greider", "given_name": "Carol", "clpid": "Greider-Carol" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "For future understanding of biology, we have to get to grips with complexity. Most biological processes are based on complex networks involving many components. Because they have been generated by natural selection, redundancies and add-on functions abound, and some parts may only be relevant in specific circumstances. Occam's razor rarely applies. So how can sense be made of this complexity?", "doi": "10.1016/j.cell.2014.03.013", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2014-03-27", "series_number": "1", "volume": "157", "issue": "1", "pages": "272-273" }, { "id": "authors:2v2mb-fq471", "collection": "authors", "collection_id": "2v2mb-fq471", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140418-092054237", "type": "article", "title": "Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages", "author": [ { "family_name": "Haldar", "given_name": "Malay", "clpid": "Haldar-Malay" }, { "family_name": "Kohyama", "given_name": "Masako", "clpid": "Kohyama-Masako" }, { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Wumesh", "given_name": "K. C.", "clpid": "Wumesh-K-C" }, { "family_name": "Wu", "given_name": "Xiaodi", "clpid": "Wu-Xiaodi" }, { "family_name": "Brise\u00f1o", "given_name": "Carlos G.", "clpid": "Brise\u00f1o-Carlos-G" }, { "family_name": "Satpathy", "given_name": "Ansuman T.", "clpid": "Satpathy-Ansuman-T" }, { "family_name": "Kretzer", "given_name": "Nicole M.", "clpid": "Kretzer-Nicole-M" }, { "family_name": "Arase", "given_name": "Hisashi", "clpid": "Arase-Hisashi" }, { "family_name": "Rajasekaran", "given_name": "Namakkal S.", "clpid": "Rajasekaran-Namakkal-S" }, { "family_name": "Wang", "given_name": "Li", "clpid": "Wang-Li" }, { "family_name": "Egawa", "given_name": "Takeshi", "clpid": "Egawa-Takeshi" }, { "family_name": "Igarashi", "given_name": "Kazuhiko", "clpid": "Igarashi-Kazuhiko" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Murphy", "given_name": "Theresa L.", "clpid": "Murphy-Theresa-L" }, { "family_name": "Murphy", "given_name": "Kenneth M.", "clpid": "Murphy-Kenneth-M" } ], "abstract": "Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80^+VCAM1^+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis.", "doi": "10.1016/j.cell.2014.01.069", "pmcid": "PMC4010949", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2014-03-13", "series_number": "6", "volume": "156", "issue": "6", "pages": "1223-1234" }, { "id": "authors:b3dqa-v3h20", "collection": "authors", "collection_id": "b3dqa-v3h20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140218-133808799", "type": "article", "title": "Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission", "author": [ { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Ouyang", "given_name": "Yong", "clpid": "Ouyang-Yong" }, { "family_name": "Hong", "given_name": "Christin M.", "clpid": "Hong-Christin-M" }, { "family_name": "Chen", "given_name": "Joyce", "clpid": "Chen-Joyce" }, { "family_name": "Nguyen", "given_name": "Steven M.", "clpid": "Nguyen-Steven-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.", "doi": "10.1038/nm.3471", "pmcid": "PMC3990417", "issn": "1078-8956", "publisher": "Nature Publishing Group", "publication": "Nature Medicine", "publication_date": "2014-03", "series_number": "3", "volume": "20", "issue": "3", "pages": "296-300" }, { "id": "authors:nj0xj-bsc91", "collection": "authors", "collection_id": "nj0xj-bsc91", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140710-102048609", "type": "article", "title": "Single Molecule Dynamics Governing the Initiation of V(D)J Recombination", "author": [ { "family_name": "Lovely", "given_name": "Geoffrey", "clpid": "Lovely-Geoffrey-A" }, { "family_name": "Lind\u00e9n", "given_name": "Martin", "clpid": "Lind\u00e9n-Martin" }, { "family_name": "Ramesh", "given_name": "Pradeep", "clpid": "Ramesh-P" }, { "family_name": "Schatz", "given_name": "David", "clpid": "Schatz-David-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Phillips", "given_name": "Rob", "orcid": "0000-0003-3082-2809", "clpid": "Phillips-R" } ], "abstract": "The recombination activating genes (RAG)1 and RAG2 perform V(D)J recombination by rearranging conserved recombination signal sequences (RSSs) to generate antigen-receptors during lymphopoiesis. However the orchestration of V(D)J recombination on biologically relevant (long) length scales has resisted experimental investigation. Here we develop single-molecule assays to watch in real time as RAG1/2 and its co-factor HMGB1 carry out V(D)J recombination from start (RSS binding) to finish (hairpin formation) on long DNA molecules. We capture various intermediate states preceding hairpin formation, show how RAG1/2 and HMGB1 form bends on the DNA, demonstrate how the identity of the recombination signal sequence modulates bending with single bp resolution and show HMGB1 must compact DNA flanking RSSs to form hairpins. Our results provide single-molecule mechanistic insight into the orchestration of V(D)J recombination.", "doi": "10.1016/j.bpj.2013.11.3826", "issn": "0006-3495", "publisher": "Biophysical Society", "publication": "Biophysical Journal", "publication_date": "2014-01-28", "series_number": "2", "volume": "106", "issue": "2", "pages": "692A" }, { "id": "authors:0rv4p-ybh17", "collection": "authors", "collection_id": "0rv4p-ybh17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140203-085822605", "type": "article", "title": "A MicroRNA-mediated feedback loop controls vascular inflammatory signaling", "author": [ { "family_name": "Cheng", "given_name": "Henry S.", "clpid": "Cheng-Henry-S" }, { "family_name": "Sivachandran", "given_name": "Nirojini", "clpid": "Sivachandran-Nirojini" }, { "family_name": "Lau", "given_name": "Andrew", "clpid": "Lau-Andrew" }, { "family_name": "Boudreau", "given_name": "Emilie", "clpid": "Boudreau-Emilie" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Delgado-Olguin", "given_name": "Paul", "clpid": "Delgado-Olguin-Paul" }, { "family_name": "Cybulsky", "given_name": "Myron I.", "clpid": "Cybulsky-Myron-I" }, { "family_name": "Fish", "given_name": "Jason E.", "clpid": "Fish-Jason-E" } ], "abstract": "Activation of inflammatory signaling pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We find that a microRNA family (miR-146a and miR-J46b) is induced in endothelial cells upon exposure to pro-inflammatory cytokinc. Although transcription of the miR-146alb loci is rapidly induced, induction of mature miR-146a/b is delayed and sustained\ncompared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression.", "doi": "10.1007/s10456-013-9412-3", "issn": "0969-6970", "publisher": "Springer", "publication": "Angiogenesis", "publication_date": "2014-01", "series_number": "1", "volume": "17", "issue": "1", "pages": "281" }, { "id": "authors:f3z8g-phk23", "collection": "authors", "collection_id": "f3z8g-phk23", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140203-092411494", "type": "article", "title": "MicroRNA-146 targets novel signaling pathway in endothelial\n activation", "author": [ { "family_name": "Cheng", "given_name": "Henry", "clpid": "Cheng-Henry-S" }, { "family_name": "Sivachandran", "given_name": "Nirojini", "clpid": "Sivachandran-Nirojini" }, { "family_name": "Lau", "given_name": "Andrew", "clpid": "Lau-Andrew" }, { "family_name": "Boudreau", "given_name": "Emilie", "clpid": "Boudreau-Emilie" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Delgado-Olguin", "given_name": "Paul", "clpid": "Delgado-Olguin-Paul" }, { "family_name": "Cybulsky", "given_name": "Myron I.", "clpid": "Cybulsky-Myron-I" }, { "family_name": "Fish", "given_name": "Jason E.", "clpid": "Fish-Jason-E" } ], "abstract": "Prolonged activation of inflammatory pathways in the endothelium leads to vascular diseases, including sepsis and atherosclerosis. During this process, activated endothelial cells recruit circulating leukocytes by expressing adhesion molecules and chemoattractants,\nsuch as vascular cellular adhesion molcculc-1 (VCAM-1) and\nmonocyte chemoattractant protein-1 (MCP-1).", "doi": "10.1007/s10456-013-9412-3", "issn": "0969-6970", "publisher": "Springer", "publication": "Angiogenesis", "publication_date": "2014-01", "series_number": "1", "volume": "17", "issue": "1", "pages": "299" }, { "id": "authors:p20hv-8vy31", "collection": "authors", "collection_id": "p20hv-8vy31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140306-114228881", "type": "article", "title": "Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis", "author": [ { "family_name": "Figueiredo", "given_name": "Nuno", "clpid": "Figuereido-Nuno" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.", "doi": "10.1016/j.immuni.2013.08.039", "pmcid": "PMC3968948", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2013-11-14", "series_number": "5", "volume": "39", "issue": "5", "pages": "874-884" }, { "id": "authors:qjdbp-0cw71", "collection": "authors", "collection_id": "qjdbp-0cw71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131122-082540756", "type": "article", "title": "Vectored ImmunoProphylaxis with VRC07 Protects BLT Humanized Mice from Vaginal Transmission of Founder HIV", "author": [ { "family_name": "Balazs", "given_name": "A. B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Yong", "given_name": "O.", "clpid": "Yong-O" }, { "family_name": "Hong", "given_name": "C. M.", "clpid": "Hong-Christin-M" }, { "family_name": "Chen", "given_name": "J.", "clpid": "Chen-Joyce" }, { "family_name": "Rao", "given_name": "D. S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "An", "given_name": "D.", "clpid": "An-Dong-Sung" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Recently, a number of antibodies capable of broadly\nneutralizing HIV have been isolated from HIV infected patients,\nstimulating efforts to elicit their production in naive individuals.\nAs an alternative to vaccination, we recently described vectored\nimmunoprophylaxis (VIP) as an approach capable of generating\nhigh serum concentrations of a desired monoclonal antibody in\nmice following a single intramuscular injection of a specialized\nadeno associated viral vector (AAV). Mice that received VIP encoding\nb12, VRC01 or VRC07 antibodies demonstrated long-term\ncirculating antibody expression in serum, and VIP-treated humanized\nmice exhibited remarkable protection against high dose,\nintravenous challenge with CXCR4-tropic HIV. However, most\nhuman infections are initiated by transmission of CCR5-tropic\nstrains through mucosal tissues.", "doi": "10.1089/aid.2013.1500", "issn": "0889-2229", "publisher": "Mary Ann Liebert", "publication": "AIDS Research and Human Retroviruses", "publication_date": "2013-11-01", "series_number": "11", "volume": "29", "issue": "11", "pages": "A161" }, { "id": "authors:92hfy-8gd39", "collection": "authors", "collection_id": "92hfy-8gd39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130919-142521151", "type": "article", "title": "Activation of the Transcriptional Function of the NF-\u03baB Protein c-Rel by O-GlcNAc Glycosylation", "author": [ { "family_name": "Ramakrishnan", "given_name": "Parameswaran", "orcid": "0000-0002-1314-827X", "clpid": "Ramakrishnan-Parameswaran" }, { "family_name": "Clark", "given_name": "Peter M.", "clpid": "Clark-Peter-M" }, { "family_name": "Mason", "given_name": "Daniel E.", "clpid": "Mason-Daniel-E" }, { "family_name": "Peters", "given_name": "Eric C.", "clpid": "Peters-Eric-C" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The transcription factor nuclear factor \u03baB (NF-\u03baB) rapidly reprograms gene expression in response to\nvarious stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation,\nmethylation, and acetylation. The addition of O-linked b-N-acetylglucosamine (a process\nknown as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions\nsuch as hyperglycemia and cellular stress. We report that the NF-\u03baB subunit c-Rel is modified and activated\nby O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for\nthe DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated\nc-Rel\u2013mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T\ncell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins\nenhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)\u2013induced expression of other\nNF-\u03baB target genes, such as NFKBIA (which encodes IkBa) and TNFAIP3 (which encodes A20),\noccurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role\nfor hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell\u2013mediated autoimmunity in\nconditions such as type 1 diabetes by enhancing the production of T helper cell cytokines.", "doi": "10.1126/scisignal.2004097", "pmcid": "PMC4066889", "issn": "1937-9145", "publisher": "American Association for the Advancement of Science", "publication": "Science Signaling", "publication_date": "2013-08-27", "series_number": "290", "volume": "6", "issue": "290", "pages": "Art. No. ra75" }, { "id": "authors:b28m2-n9a31", "collection": "authors", "collection_id": "b28m2-n9a31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130906-140108923", "type": "article", "title": "miR-146a regulates hematopoietic stem cell maintenance and cell cycle entry", "author": [ { "family_name": "Woltosz", "given_name": "Joanna Wegrzyn", "clpid": "Woltosz-Joanna-Wegrzyn" }, { "family_name": "Knapp", "given_name": "David", "clpid": "Knapp-David" }, { "family_name": "Copley", "given_name": "Michael", "clpid": "Copley-Michael" }, { "family_name": "Ibrahim", "given_name": "Rawa", "clpid": "Ibrahim-Rawa" }, { "family_name": "Umlandt", "given_name": "Patricia", "clpid": "Umlandt-Patricia" }, { "family_name": "Fuller", "given_name": "Megan", "clpid": "Fuller-Megan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Boldin", "given_name": "Mark", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Eaves", "given_name": "Connie", "clpid": "Eaves-Connie" }, { "family_name": "Karsan", "given_name": "Aly", "clpid": "Karsan-Aly" } ], "abstract": "Maintenance of blood homeostasis depends on the balance between self-renewal of hematopoietic stem cells (HSCs) and their differentiation into blood cell progenitors. A variety of different intrinsic or extrinsic regulators, including multiple microRNA (miRNA) species, have been described to play a role in the regulation of these processes. Disruption of any of these regulators could lead to stem cell exhaustion or increased risk of leukemogenesis. Given recent reports of the role of miR-146a in malignant hematopoiesis, we evaluated its role in hematopoietic stem progenitor cell (HSPC) function. We show that miR-146a is highly expressed in HSCs and its expression decreases in committed progenitors. miR-146a- deficient HSCs had dramatically reduced self-renewal capacity as measured by serial competitive bone marrow transplantation assays. The lower self-renewal capacity was accompanied by decreased quiescence in miR-146a-deficient cells, as revealed by decreased proportion of miR-146a-/- HSPCs (Lin- Sca-1+ c-kit-, LSK) in G0 of the cell cycle (Ki-67- negative), and their increased proliferation, measured by BrdU incorporation. We further showed that increased proliferation of HSPCs is cell intrinsic. By sorting EPCR+ CD48- CD150+ (ESLAM) HSCs and examining cell division kinetics at the single cell level, we found that miR-146a-/- HSC undergo cell division earlier and differentiate more rapidly than wild-type HSCs, thereby producing larger colonies containing more differentiated (Lin+) cells. Our data provide evidence that miR-146a loss attenuates HSC quiescence and impairs their self-renewal ability, leading to hyperproliferation of progenitor cells. The phenotype seen is cell autonomous and the findings suggest that miR-146a plays a critical role in maintaining long term HSC function.", "issn": "0301-472X", "publisher": "Elsevier", "publication": "Experimental Hematology", "publication_date": "2013-08", "series_number": "8", "volume": "41", "issue": "8", "pages": "S17" }, { "id": "authors:85e7n-90956", "collection": "authors", "collection_id": "85e7n-90956", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130830-101903782", "type": "article", "title": "RNA splicing regulates the temporal order of TNF-induced gene expression", "author": [ { "family_name": "Hao", "given_name": "Shengli", "clpid": "Hao-Shengli" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "When cells are induced to express inflammatory genes by treatment\nwith TNF, the mRNAs for the induced genes appear in three distinct\nwaves, defining gene groups I, II, and III, or early, intermediate, and\nlate genes. To examine the basis for these different kinetic classes,\nwe have developed a PCR-based procedure to distinguish pre-mRNAs\nfrom mRNAs. It shows that the three groups initiate transcription\nvirtually simultaneously but that delays in splicing characterize\ngroups II and III. We also examined the elongation times, concluding\nthat pre-mRNA synthesis is coordinate but splicing differences\ndirectly regulate the timing of mRNA production.", "doi": "10.1073/pnas.1309990110", "pmcid": "PMC3718113", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2013-07-16", "series_number": "29", "volume": "110", "issue": "29", "pages": "11934-11939" }, { "id": "authors:04p0r-mfd97", "collection": "authors", "collection_id": "04p0r-mfd97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130812-135356477", "type": "article", "title": "Broad protection against influenza infection by vectored immunoprophylaxis in mice", "author": [ { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Bloom", "given_name": "Jesse D.", "orcid": "0000-0003-1267-3408", "clpid": "Bloom-J-D" }, { "family_name": "Hong", "given_name": "Christin M.", "clpid": "Hong-Christin-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines.", "doi": "10.1038/nbt.2618", "pmcid": "PMC4030719", "issn": "1087-0156", "publisher": "Nature Publishing Group", "publication": "Nature Biotechnology", "publication_date": "2013-07", "series_number": "7", "volume": "31", "issue": "7", "pages": "647-652" }, { "id": "authors:2f19m-xa056", "collection": "authors", "collection_id": "2f19m-xa056", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131203-132959481", "type": "article", "title": "MicroRNA\u2010146 represses endothelial activation by inhibiting pro\u2010inflammatory pathways", "author": [ { "family_name": "Cheng", "given_name": "Henry S.", "clpid": "Cheng-Henry-S" }, { "family_name": "Sivachandran", "given_name": "Nirojini", "clpid": "Sivachandran-Nirojini" }, { "family_name": "Lau", "given_name": "Andrew", "clpid": "Lau-Andrew" }, { "family_name": "Boudreau", "given_name": "Emilie", "clpid": "Boudreau-Emilie" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Delgado-Olguin", "given_name": "Paul", "clpid": "Delgado-Olguin-Paul" }, { "family_name": "Cybulsky", "given_name": "Myron I.", "clpid": "Cybulsky-Myron-I" }, { "family_name": "Fish", "given_name": "Jason E.", "clpid": "Fish-Jason-E" } ], "abstract": "Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-\u03baB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.", "doi": "10.1002/emmm.201202318", "pmcid": "PMC3721471", "issn": "1757-4676", "publisher": "Wiley Open Access", "publication": "EMBO Molecular Medicine", "publication_date": "2013-07", "series_number": "7", "volume": "5", "issue": "7", "pages": "1017-1034" }, { "id": "authors:qncyh-5q187", "collection": "authors", "collection_id": "qncyh-5q187", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130521-130754509", "type": "article", "title": "MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic\n stem cells in mice", "author": [ { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "During inflammation and infection, hematopoietic stem and progenitor cells are\nstimulated to proliferate and differentiate into mature immune cells, especially of the myeloid\nlineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation. Deletion of\nmiR-146a produces effects that appear as dysregulated inflammatory hematopoiesis, leading to a\ndecline in the number and quality of hematopoietic stem cells (HSCs), excessive myeloproliferation,\nand, ultimately, to HSC exhaustion and hematopoietic neoplasms. At the cellular level, the defects\nare attributable to both an intrinsic problem in the miR-146a\u2013deficient HSCs and extrinsic effects of\nlymphocytes and nonhematopoietic cells. At the molecular level, this involves a molecular axis\nconsisting of miR-146a, signaling protein TRAF6, transcriptional factor NF-\u03baB, and cytokine IL-6.\nThis study has identified miR-146a to be a critical regulator of HSC homeostasis during chronic\ninflammation in mice and provided a molecular connection between chronic inflammation and the\ndevelopment of bone marrow failure and myeloproliferative neoplasms.", "doi": "10.7554/eLife.00537", "pmcid": "PMC3660742", "issn": "2050-084X", "publisher": "eLife Sciences Publications", "publication": "eLife", "publication_date": "2013-05-21", "series_number": "2", "volume": "2013", "issue": "2", "pages": "Art. No. e00537" }, { "id": "authors:tng3h-2q797", "collection": "authors", "collection_id": "tng3h-2q797", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130912-103249016", "type": "article", "title": "MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells", "author": [ { "family_name": "Zhao", "given_name": "Jimmy", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Rao", "given_name": "Dinesh", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "O'Connell", "given_name": "Ryan", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "During inflammation and infection, hematopoietic stem and progenitor cells (HSPCs) are\nstimulated to proliferate and differentiate into mature immune cells, especially of the\nmyeloid lineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation.\nDeletion of miR-146a produces effects that appear as dysregulated inflammatory\nhematopoiesis, leading to a decline in the number and quality of hematopoietic stem cells\n(HSCs), excessive myeloproliferation, and, ultimately, to exhaustion of the HSCs and\nhematopoietic neoplasms. In the absence of miR-146a, LPS-mediated serial inflammatory\nstimulation accelerates the effects of aging. The chronic inflammatory stress on HSCs in\ndeleted mice involves a molecular axis consisting of upregulation of TRAF6 leading to\nexcessive activity of NF-\u03baB and overproduction of the cytokine IL-6. At the cellular level, we\nshow that the defects are attributable to both an intrinsic problem in the miR-146a-deficient\nHSCs and extrinsic effects of miR-146a-deficient lymphocytes and non-hematopoietic cells.\nThis study has identified a microRNA, miR-146a, to be a critical regulator of HSC\nhomeostasis during chronic inflammatory challenge in mice and has provided a molecular\nconnection between chronic inflammation and the development of bone marrow failure and\nmyeloid malignancies. This may have implications for human hematopoietic malignancies,\nsuch as myelodysplastic syndrome, which frequently displays downregulated miR-146a\nexpression.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2013-05-01", "volume": "190", "pages": "52.1" }, { "id": "authors:5gtrc-t2c43", "collection": "authors", "collection_id": "5gtrc-t2c43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130507-082500976", "type": "article", "title": "The Yin and Yang of microRNAs: leukemia and immunity", "author": [ { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Yin and Yang are two complementary forces that together describe the nature of real-world elements. Yin is the dark side; Yang is the light side. We describe microRNAs having both Yin and Yang characteristics because they can contribute to normal function (Yang) but also to autoimmunity, myeloproliferation, and cancer (Yin). We have been working on a number of microRNAs that have these dual characteristics and here we focus on two, miR-125b and miR-146a. We have concentrated on these two RNAs because we have very extensive knowledge of them, much of it from our laboratory, and also because they provide a strong contrast: the effects of overexpression of miR-125b are rapid, suggesting that it acts directly, whereas the effects of miR-146a are slow to develop, suggesting that they arise from chronic alterations in cellular behavior.", "doi": "10.1111/imr.12043", "pmcid": "PMC3620843", "issn": "0105-2896", "publisher": "Wiley-Blackwell", "publication": "Immunological Reviews", "publication_date": "2013-05", "series_number": "1", "volume": "253", "issue": "1", "pages": "129-145" }, { "id": "authors:mptdd-0ap21", "collection": "authors", "collection_id": "mptdd-0ap21", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130702-113609364", "type": "article", "title": "Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells", "author": [ { "family_name": "Giannoni", "given_name": "Francesca", "clpid": "Giannoni-Francesca" }, { "family_name": "Hardee", "given_name": "Cinnamon L.", "clpid": "Hardee-Cinnamon-L" }, { "family_name": "Wherley", "given_name": "Jennifer", "clpid": "Wherley-Jennifer" }, { "family_name": "Gschweng", "given_name": "Eric", "clpid": "Gschweng-Eric" }, { "family_name": "Senadheera", "given_name": "Shantha", "clpid": "Senadheera-Shantha" }, { "family_name": "Kaufman", "given_name": "Michael L.", "clpid": "Kaufman-Michael-L" }, { "family_name": "Chan", "given_name": "Rebecca", "clpid": "Chan-Rebecca" }, { "family_name": "Bahner", "given_name": "Ingrid", "clpid": "Bahner-Ingrid" }, { "family_name": "Gersuk", "given_name": "Vivian", "clpid": "Gersuk-Vivian" }, { "family_name": "Wang", "given_name": "Xiaoyan", "clpid": "Wang-Xiaoyan" }, { "family_name": "Gjertson", "given_name": "David", "clpid": "Gjertson-David" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Economou", "given_name": "James S.", "clpid": "Economou-James-S" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Kohn", "given_name": "Donald B.", "clpid": "Kohn-Donald-B" } ], "abstract": "Transduction and transplantation of human hematopoietic stem/progenitor cells (HSPC) with the genes for a T-cell receptor (TCR) that recognizes a tumor-associated antigen may lead to sustained long-term production of T cells expressing the TCR and confer specific antitumor activity. We evaluated this using a lentiviral vector (CCLc-MND-F5) carrying cDNA for a human TCR specific for an HLA-A*0201-restricted peptide of Melanoma Antigen Recognized by T cells (MART-1). CD34+ HSPC were transduced with the F5 TCR lentiviral vector or mock transduced and transplanted into neonatal NSG mice or NSG mice transgenic for human HLA-A*0201 (NSG-A2). Human CD8+ and CD4+ T cells expressing the human F5 TCR were present in the thymus, spleen, and peripheral blood after 4\u20135 months. Expression of human HLA-A*0201 in NSG-A2 recipient mice led to significantly increased numbers of human CD8+ and CD4+ T cells expressing the F5 TCR, compared with control NSG recipients. Transduction of the human CD34+ HSPC by the F5 TCR transgene caused a high degree of allelic exclusion, potently suppressing rearrangement of endogenous human TCR-\u03b2 genes during thymopoiesis. In summary, we demonstrated the feasibility of engineering human HSPC to express a tumor-specific TCR to serve as a long-term source of tumor-targeted mature T cells for immunotherapy of melanoma.", "doi": "10.1038/mt.2013.8", "pmcid": "PMC3666644", "issn": "1525-0016", "publisher": "American Society of Gene & Cell Therapy", "publication": "Molecular Therapy", "publication_date": "2013-05", "series_number": "5", "volume": "21", "issue": "5", "pages": "1044-1054" }, { "id": "authors:s542y-17038", "collection": "authors", "collection_id": "s542y-17038", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130612-134853720", "type": "article", "title": "Elucidating the temporal dynamics of NF-\u03baB activation by TNF-\u03b1 in melanoma", "author": [ { "family_name": "Kulkarni", "given_name": "R. P.", "clpid": "Kulkarni-R-P" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Melanoma is a heterogeneous disease resulting from dysregulation of molecular pathways, leading\nto poorly controlled tumor growth and metastasis if the cancer is not surgically excised in time. NF-\n\u03baB is a critical transcription factor which underlies several key pathways of cellular growth, though\nits contribution in melanoma is not well elucidated. TNF-\u03b1 is a cytokine which activates NF-\u03baB by\ntargeting the I\u03baB inhibitor to the proteasome for degradation. Recent work has suggested that the\nmelanoma stem-like state is directly dependent on TNF-\u03b1 activity, further stressing the importance\nof this pathway in melanoma. We have found that TNF-\u03b1 activation of NF-\u03baB causes transcription\nof several genes, including A20, NFKBIA, and NFKBIE, which is regulated in a temporal fashion\nand is concentration dependent. Furthermore, this activation can be modulated through pharmacologic\nagents including bortezomib, which blocks proteasome degradation of I\u03baB, thereby delaying\nor preventing TNF-\u03b1 activity. We have also generated a fluorescent lentiviral-based reporter system\nfor directly observing NF-\u03baB protein expression and localization (through a p65-fluorescent\nprotein fusion) in the cytoplasm and nucleus in order to better elucidate the dynamics of NF-\u03baB\nactivity in melanoma and are concurrently working to model these dynamics. The NF-\u03baB pathway\nrepresents an important aspect in melanoma pathogenesis and our work serves to elucidate the\nmechanism of this activation which may be useful in developing novel strategies to block growth.", "doi": "10.1038/jid.2013.105", "issn": "0022-202X", "publisher": "Nature Publishing Group", "publication": "Journal of Investigative Dermatology", "publication_date": "2013-05", "series_number": "S1", "volume": "133", "issue": "S1", "pages": "S227" }, { "id": "authors:v82fs-8mm50", "collection": "authors", "collection_id": "v82fs-8mm50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130627-100022739", "type": "article", "title": "Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy", "author": [ { "family_name": "Ma", "given_name": "Chao", "clpid": "Ma-Chao" }, { "family_name": "Cheung", "given_name": "Ann F.", "clpid": "Cheung-Ann-F" }, { "family_name": "Chodon", "given_name": "Thinle", "clpid": "Chodon-Thinle" }, { "family_name": "Koya", "given_name": "Richard C.", "clpid": "Koya-Richard-C" }, { "family_name": "Wu", "given_name": "Zhongqi", "clpid": "Wu-Zhongqi" }, { "family_name": "Ng", "given_name": "Charles", "clpid": "Ng-Charles" }, { "family_name": "Avramis", "given_name": "Earl", "clpid": "Avramis-Earl" }, { "family_name": "Cochran", "given_name": "Alistair J.", "clpid": "Cochran-Alistair-J" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Chmielowski", "given_name": "Bartosz", "clpid": "Chmielowski-Bartosz" }, { "family_name": "Economou", "given_name": "James S.", "clpid": "Economou-James-S" }, { "family_name": "Comin-Anduix", "given_name": "Begonya", "clpid": "Comin-Anduix-Begonya" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Heath", "given_name": "James R.", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" } ], "abstract": "Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.\n\nSignificance: A longitudinal functional study of adoptively transferred TCR\u2013engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.", "doi": "10.1158/2159-8290.CD-12-0383", "pmcid": "PMC3716460", "issn": "2159-8274", "publisher": "American Association for Cancer Research", "publication": "Cancer Discovery", "publication_date": "2013-04", "series_number": "4", "volume": "3", "issue": "4", "pages": "418-429" }, { "id": "authors:sf9ts-15h69", "collection": "authors", "collection_id": "sf9ts-15h69", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130916-154115267", "type": "article", "title": "The Effects of Broadly Neutralizing Antibodies in Experimental HCV Infection", "author": [ { "family_name": "de Jong", "given_name": "Y. P.", "clpid": "de-Jong-Ype-P" }, { "family_name": "Dorner", "given_name": "M.", "clpid": "Dorner-Marcus" }, { "family_name": "Balazs", "given_name": "A. B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Robbins", "given_name": "J. B.", "clpid": "Robbins-Justin-B" }, { "family_name": "Labitt", "given_name": "R. N.", "clpid": "Labitt-Rachael-N" }, { "family_name": "Donovan", "given_name": "B. M.", "clpid": "Donovan-Bridget-M" }, { "family_name": "Krishnan", "given_name": "A.", "clpid": "Krishnan-Anuradha" }, { "family_name": "Charlton", "given_name": "M.", "clpid": "Charlton-Michael-R" }, { "family_name": "Chiriboga", "given_name": "L.", "clpid": "Chiriboga-Luis" }, { "family_name": "Burton", "given_name": "D. R.", "clpid": "Burton-Dennis-R" }, { "family_name": "Rice", "given_name": "C. M.", "clpid": "Rice-C-M" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Law", "given_name": "M.", "clpid": "Law-Mansun" }, { "family_name": "Ploss", "given_name": "A.", "clpid": "Ploss-Alexander" } ], "abstract": "Hepatitis C virus (HCV) infection is the leading indication for\nliver transplantation in the US. The graft is universally infected\nafter transplantation, and this typically results in accelerated\nfibrosis progression. Current HCV therapies have poor efficacy and\ntolerability in the challenging pre- and posttransplant populations.\nAlternative pre- and post-transplantation measures are needed to\nprevent graft infection. One potential strategy to prevent such\ninfection is the administration of potent broadly neutralizing\nantibodies (bnAbs).", "issn": "0168-8278", "publisher": "Elsevier", "publication": "Journal of Hepatology", "publication_date": "2013-04", "volume": "58", "pages": "S466-S467" }, { "id": "authors:cvfre-6qm39", "collection": "authors", "collection_id": "cvfre-6qm39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130326-075457311", "type": "article", "title": "Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity", "author": [ { "family_name": "Huffaker", "given_name": "Thomas B.", "clpid": "Huffaker-Thomas-B" }, { "family_name": "Hu", "given_name": "Ruozhen", "clpid": "Hu-Ruozhen" }, { "family_name": "Runtsch", "given_name": "Marah C.", "clpid": "Runtsch-Marah-C" }, { "family_name": "Bake", "given_name": "Erin", "clpid": "Bake-Erin" }, { "family_name": "Chen", "given_name": "Xinjian", "clpid": "Chen-Xinjian" }, { "family_name": "Zhao", "given_name": "Jimmy", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Round", "given_name": "June L.", "clpid": "Round-June-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" } ], "abstract": "An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon \u03b3 (IFN\u03b3) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155^(\u2212/\u2212) mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFN\u03b3 expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4^+ and CD8^+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.", "doi": "10.1016/j.celrep.2012.10.025", "pmcid": "PMC3628775", "issn": "2211-1247", "publisher": "Elsevier", "publication": "Cell Reports", "publication_date": "2012-12-27", "series_number": "6", "volume": "2", "issue": "6", "pages": "1697-1709" }, { "id": "authors:rcem9-yhn50", "collection": "authors", "collection_id": "rcem9-yhn50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130206-144107544", "type": "article", "title": "Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice", "author": [ { "family_name": "Hur", "given_name": "Eun Mi", "clpid": "Hur-Eun-Mi" }, { "family_name": "Patel", "given_name": "Sonal N.", "clpid": "Patel-Sonal-N" }, { "family_name": "Shimizu", "given_name": "Saki", "clpid": "Shimizu-Saki" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Gnanapragasam", "given_name": "Priyanthi N. P.", "clpid": "Gnanapragasam-Priyanthi-N-P" }, { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "HIV-1 infections are generally initiated at mucosal sites. Thus, IgA antibody, which plays pivotal roles in mucosal immunity, might efficiently prevent HIV infection. However, mounting a highly effective HIV-specific mucosal IgA response by conventional immunization has been challenging and the potency of HIV-specific IgA against infection needs to be addressed in vivo. Here we show that the polymeric IgA form of anti-HIV antibody inhibits HIV mucosal transmission more effectively than the monomeric IgA or IgG1 form in a comparable range of concentrations in humanized mice. To deliver anti-HIV IgA in a continual manner, we devised a hematopoietic stem/progenitor cell (HSPC)\u2013based genetic approach using an IgA gene. We transplanted human HSPCs transduced with a lentiviral construct encoding a class-switched anti-HIV IgA (b12-IgA) into the humanized bone marrow-liver-thymus (BLT) mice. The transgene was expressed specifically in B cells and plasma cells in lymphoid organs and mucosal sites. After vaginal HIV-1 challenge, mucosal CD4^+ T cells in the b12-IgA\u2013producing mice were protected from virus-mediated depletion. Similar results were also obtained in a second humanized model, \"human immune system mice.\" Our study demonstrates the potential of anti-HIV IgA in immunoprophylaxis in vivo, emphasizing the importance of the mucosal IgA response in defense against HIV/AIDS.", "doi": "10.1182/blood-2012-04-422303", "pmcid": "PMC3512234", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2012-11-29", "series_number": "23", "volume": "120", "issue": "23", "pages": "4571-4582" }, { "id": "authors:wta8q-xhf21", "collection": "authors", "collection_id": "wta8q-xhf21", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130117-154355776", "type": "article", "title": "Use of Mutated Self-Cleaving 2A Peptides as a Molecular Rheostat to Direct Simultaneous Formation of Membrane and Secreted Anti-HIV Immunoglobulins", "author": [ { "family_name": "Yu", "given_name": "Kenneth K.", "clpid": "Yu-Kenneth-K" }, { "family_name": "Aguilar", "given_name": "Kiefer", "clpid": "Aguilar-Kiefer" }, { "family_name": "Tsai", "given_name": "Jonathan", "clpid": "Tsai-Jonathan" }, { "family_name": "Galimidi", "given_name": "Rachel", "clpid": "Galimidi-Rachel-P" }, { "family_name": "Gnanapragasam", "given_name": "Priyanthi", "clpid": "Gnanapragasam-Priyanthi-N-P" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In nature, B cells produce surface immunoglobulin and secreted antibody from the same immunoglobulin gene via alternative splicing of the pre-messenger RNA. Here we present a novel system for genetically programming B cells to direct the simultaneous formation of membrane-bound and secreted immunoglobulins that we term a \"Molecular Rheostat\", based on the use of mutated \"self-cleaving\" 2A peptides. The Molecular Rheostat is designed so that the ratio of secreted to membrane-bound immunoglobulins can be controlled by selecting appropriate mutations in the 2A peptide. Lentiviral transgenesis of Molecular Rheostat constructs into B cell lines enables the simultaneous expression of functional b12-based IgM-like BCRs that signal to the cells and mediate the secretion of b12 IgG broadly neutralizing antibodies that can bind and neutralize HIV-1 pseudovirus. We show that these b12-based Molecular Rheostat constructs promote the maturation of EU12 B cells in an in vitro model of B lymphopoiesis. The Molecular Rheostat offers a novel tool for genetically manipulating B cell specificity for B-cell based gene therapy.", "doi": "10.1371/journal.pone.0050438", "pmcid": "PMC3508920", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2012-11-28", "series_number": "11", "volume": "7", "issue": "11", "pages": "Art. No. e50438" }, { "id": "authors:vajfa-bba31", "collection": "authors", "collection_id": "vajfa-bba31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130325-093910426", "type": "article", "title": "Single Cell Proteomics Reveals Novel Cytokine-Producing Function of Hematopoietic Stem and Progenitor Cells", "author": [ { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Ma", "given_name": "Chao", "clpid": "Ma-Chao" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Heath", "given_name": "James", "orcid": "0000-0001-5356-4385", "clpid": "Heath-J-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "During infection, hematopoietic stem and progenitor cells (HSPCs) are called upon to proliferate and differentiate to produce\nmore innate and adaptive immune cells to combat infection. Traditionally, HSPCs are thought to respond to depletion of\ndownstream hematopoietic cells during infection. More recent evidence suggests that HSPCs may respond directly to\ninfection and pro-inflammatory cytokines. However, little is known about the direct immune response of HSPCs and the\nmolecular signaling regulating this response upon sensing an infection. In this study, we have combined transgenic and\ngenetic knockout mouse models with a novel single cell barcode proteomics microchip technology to tackle these questions.\nWe show that although long-term hematopoietic stem cells (HSCs) (defined by Lineage-cKit+Sca1+CD150+CD48-) do not\nsecrete cytokines upon toll-like receptor (TLR) stimulation, short-term HSCs and multipotent progenitor cells (MPPs)\n(defined by Lineage-cKit+Sca1+, referred to as LKS thereafter) can produce copious amounts of cytokines upon direct\nTLR-4 and TLR-2 stimulation, indicating that LKS cells can directly participate in an immune response by producing a myriad\nof cytokines, upon a bacterial infection. Within the population of LKS cells we detect multiple functional subsets of cells,\nspecialized in producing myeloid-like, lymphoid-like or both types of cytokines. Moreover, we show that the cytokine\nproduction by LKS cells is regulated by the NF-\u03baB activity, as p50-deficient LKS cells show reduced cytokine production\nwhile microRNA-146a (miR-146a)-deficient LKS cells show significantly increased cytokine production.", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2012-11-16", "series_number": "21", "volume": "120", "issue": "21", "pages": "26" }, { "id": "authors:9mhxj-gnt04", "collection": "authors", "collection_id": "9mhxj-gnt04", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121107-154121628", "type": "article", "title": "Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice", "author": [ { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Minisandram", "given_name": "Aarathi", "clpid": "Minisandram-Arathi" }, { "family_name": "Martin", "given_name": "Ayana", "clpid": "Martin-Ayana" }, { "family_name": "Taganov", "given_name": "Konstantin", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Boldin", "given_name": "Mark", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "APCs are essential for innate and adaptive\nimmunity as well as self-immune\ntolerance. Here, we show that the\nCap'n'collar member Bach1 regulates the\ngeneration of APCs, specifically macrophages\nand dendritic cells, in mice. The\nimpaired APC development in Bach1^(-/-)\nmice was accompanied by defects in\ndownstream T-cell responses and partial\nprotection from experimental autoimmune\nencephalomyelitis. Genomewide\nanalyses identified a panel of Bach1 target\ngenes and ablation of the direct Bach1\ntarget gene HO-1 exacerbated the impaired\nAPC development observed in\nBach1^(-/-) mice. This was attributed to the\nimpaired ability of HO-1^(-/-)Bach1^(-/-)\ndouble mutants to produce upstreamAPC\nprogenitor cells, including common myeloid\nprogenitor (CMP)\u2013Flk2^+. By contrast,\nwe observed an increase in hematopoietic\nstem-progenitor cells (HSPCs) in\nthese mice, suggesting a developmental\nblock in the progression of HSPCs to\nCMP-Flk2^+ and subsequently APCs.", "doi": "10.1182/blood-2012-04-426247", "pmcid": "PMC3448256", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2012-09-20", "series_number": "12", "volume": "120", "issue": "12", "pages": "2428-2437" }, { "id": "authors:nssck-3r269", "collection": "authors", "collection_id": "nssck-3r269", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121116-083505667", "type": "article", "title": "Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission", "author": [ { "family_name": "Balazs", "given_name": "A. B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Chen", "given_name": "J.", "clpid": "Chen-Joyce" }, { "family_name": "Hong", "given_name": "C.", "clpid": "Hong-Christin-M" }, { "family_name": "Ouyang", "given_name": "S.", "clpid": "Ouyang-S" }, { "family_name": "An", "given_name": "D.", "clpid": "An-Dong-Sung" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Background:\nRecently, a number of antibodies capable of broadly neutralizing\nHIV have been isolated from HIV infected\npatients, stimulating efforts to develop vaccines capable of\neliciting their production in naive individuals. As an alternative\nto vaccination, we recently described vectored\nimmunoprophylaxis (VIP) as an approach capable of generating\nhigh serum concentrations of a desired monoclonal\nantibody in mice following a single intramuscular\ninjection of a specialized adeno associated viral vector\n(AAV). Mice that received VIP encoding b12 and VRC01\nantibodies demonstrated long-term circulating antibody\nexpression in serum, and VIP-treated humanized mice\nexhibited remarkable protection against high dose, intravenous\nchallenge with CXCR4-tropic HIV. However, most\nhuman infections are initiated by transmission of CCR5-\ntropic strains through mucosal tissues.\nMethods:\nTo measure the efficacy of VIP against clinically relevant\nstrains, we humanized VIP-treated mice by adoptive transfer\nof peripheral blood mononuclear cells (PBMC) and\nchallenged these animals with CCR5-tropic HIV strains\nincluding JR-CSF, as well as REJO.c, a transmitted molecular\nfounder. To determine the ability of VIP to prevent\nmucosal transmission of HIV, we developed a repetitive\nintravaginal challenge model in VIP-treated BLT humanized\nmice that were challenged weekly with JR-CSF and\nmonitored for infection.\nResults:\nPBMC humanized mice expressing either b12 or VRC01\nwere protected from intravenous challenge with JR-CSF.\nIn contrast, the b12-resistant REJO.c strain readily infected\nPBMC humanized mice expressing b12 antibody, while\nmice expressing VRC01 demonstrated nearly complete\nprotection following challenge. Intravaginally challenged\nBLT animals expressing a luciferase negative control protein\nall became infected over the study period while a\nmajority of animals expressing VRC01 had no detectable\nHIV infection despite fourteen intravaginal challenges\nwith JR-CSF.\nConclusion:\nVIP is capable of protecting humanized mice from challenge\nby diverse HIV strains and can substantially inhibit\nmucosal transmission. These findings warrant continued\ndevelopment of VIP as a novel approach for HIV prevention\nin humans.", "doi": "10.1186/1742-4690-9-S2-P42", "pmcid": "PMC3442095", "issn": "1742-4690", "publisher": "BioMed Central", "publication": "Retrovirology", "publication_date": "2012-09-13", "series_number": "S2", "volume": "9", "issue": "S2", "pages": "Art. No. P42" }, { "id": "authors:vn3w1-4bk15", "collection": "authors", "collection_id": "vn3w1-4bk15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130108-120955180", "type": "article", "title": "Reconstruction of the 1918 Influenza Virus: Unexpected Rewards from the Past", "author": [ { "family_name": "Taubenberger", "given_name": "Jeffery K.", "clpid": "Taubenberger-Jeffery-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Doherty", "given_name": "Peter C.", "clpid": "Doherty-Peter-C" }, { "family_name": "Markel", "given_name": "Howard", "clpid": "Markel-Howard" }, { "family_name": "Morens", "given_name": "David M.", "clpid": "Morens-David-M" }, { "family_name": "Webster", "given_name": "Robert G.", "clpid": "Webster-Robert-G" }, { "family_name": "Wilson", "given_name": "Ian A.", "clpid": "Wilson-Ian-A" } ], "abstract": "The influenza pandemic of 1918\u20131919 killed approximately 50 million people. The unusually severe morbidity and mortality associated with the pandemic spurred physicians and scientists to isolate the etiologic agent, but the virus was not isolated in 1918. In 1996, it became possible to recover and sequence highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims. These viral RNA sequences eventually permitted reconstruction of the complete 1918 virus, which has yielded, almost a century after the deaths of its victims, novel insights into influenza virus biology and pathogenesis and has provided important information about how to prevent and control future pandemics.", "doi": "10.1128/mBio.00201-12", "pmcid": "PMC3448162", "issn": "2150-7511", "publisher": "American Society for Microbiology", "publication": "mBio", "publication_date": "2012-09-11", "series_number": "5", "volume": "3", "issue": "5", "pages": "Art. No. e00201-12" }, { "id": "authors:p7z1z-g9069", "collection": "authors", "collection_id": "p7z1z-g9069", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121108-105355641", "type": "article", "title": "EHMT1 Protein Binds to Nuclear Factor-\u03baB p50 and Represses Gene Expression", "author": [ { "family_name": "Ea", "given_name": "Chee-Kwee", "clpid": "Ea-Chee-Kwee" }, { "family_name": "Hao", "given_name": "Shengli", "clpid": "Hao-Shengli" }, { "family_name": "Yeo", "given_name": "Kok Siong", "clpid": "Yeo-Kok-Siong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Transcriptional homeostasis relies on the balance between positive and negative regulation of gene transcription. Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. Here, we report that a euchromatic H3K9 methyltransferase, EHMT1, functions as a negative regulator in both the NF-\u03baB- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-\u03baB target genes. Moreover, EHMT1 interacts with p50, and, surprisingly, p50 appears to repress the expression of type I interferon genes and genes activated by type I interferons by recruiting EHMT1 to catalyze H3K9 methylation at their promoter regions. Silencing the expression of EHMT1 by RNA interference enhances expression of a subset NF-\u03baB-regulated genes, augments interferon production, and augments antiviral immunity.", "doi": "10.1074/jbc.M112.365601", "pmcid": "PMC3438952", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "2012-09-07", "series_number": "37", "volume": "287", "issue": "37", "pages": "31207-31217" }, { "id": "authors:hrxy9-x8j61", "collection": "authors", "collection_id": "hrxy9-x8j61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120910-071639316", "type": "article", "title": "miR-146a controls the resolution of T cell responses in mice", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Yu", "given_name": "Yang", "clpid": "Yu-Yang" }, { "family_name": "Liu", "given_name": "Claret Siyuan", "clpid": "Liu-Claret-Siyuan" }, { "family_name": "Ea", "given_name": "Chee-Kwee", "clpid": "Ea-Chee-Kwee" }, { "family_name": "Ramakrishnan", "given_name": "Parameswaran", "orcid": "0000-0002-1314-827X", "clpid": "Ramakrishnan-Parameswaran" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-\u03baB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-\u03baB is associated with T cell\u2013mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-\u03baB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-\u03baB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-\u03baB activity, at least partly through repressing the NF-\u03baB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-\u03baB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.", "doi": "10.1084/jem.20112218", "pmcid": "PMC3428948", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2012-08-27", "series_number": "9", "volume": "209", "issue": "9", "pages": "1655-1670" }, { "id": "authors:bdra2-v1596", "collection": "authors", "collection_id": "bdra2-v1596", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120927-115842334", "type": "article", "title": "As Good As It Gets? The Problem of HIV Persistence despite Antiretroviral Drugs", "author": [ { "family_name": "Sigal", "given_name": "Alex", "orcid": "0000-0001-8571-2004", "clpid": "Sigal-Alex" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Human immunodeficienty virus (HIV) infection is suppressed but not eliminated by antiretroviral drugs. Viral persistence in the face of therapy has been explained by viral latency, lowered effectiveness of drugs in some anatomical sites and cell types, and cell-to-cell spread. These mechanisms allow for drug-sensitive virus to persist despite treatment. Understanding the persistence mechanism at work at different times after infection, including the time of initial infection immediately following transmission\nwhen reservoirs are first formed, will reveal if we are at the limit of what can be achieved with the current therapy paradigm of suppressing ongoing virus replication with drugs. We discuss some of the possible reasons why HIV persists at different points on the infection timeline, focusing on the role ongoing replication may have in maintaining the infection despite drugs at early times postexposure.", "doi": "10.1016/j.chom.2012.07.005", "issn": "1931-3128", "publisher": "Elsevier", "publication": "Cell Host & Microbe", "publication_date": "2012-08-16", "series_number": "2", "volume": "12", "issue": "2", "pages": "132-138" }, { "id": "authors:p3mpr-4rn84", "collection": "authors", "collection_id": "p3mpr-4rn84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120831-084546249", "type": "article", "title": "Regulation of the LY-6CHI Monocyte Response by MIR-146A", "author": [ { "family_name": "Etzrodt", "given_name": "Martin", "clpid": "Etzrodt-M" }, { "family_name": "Cortez-Retamozo", "given_name": "Virna", "clpid": "Cortez-Retamozo-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Weissleder", "given_name": "Ralph", "clpid": "Weissleder-R" }, { "family_name": "Pittet", "given_name": "Mikael", "clpid": "Pittet-M" } ], "abstract": "Monocytes exist in at least two distinct phenotypically and functionally committed subsets ('inflammatory' Ly-6Chi and 'resident' Ly-6Clo in mice). During the innate immune response the balance between monocyte subsets needs to be tightly regulated; however, which cell endogenous factors are involved in this process remain largely unknown. Here we identified miR-146a as a selective regulator of the inflammatory Ly-6Chi monocyte response. miR-146a is differentially expressed in Ly-6Chi and Ly-6Clo monocyte subsets in steady-state and can be selectively induced in Ly-6Chi cells upon inflammatory challenge. In competitive bone marrow chimera experiments miR-146a-/- Ly-6Chi monocytes outcompeted their wild-type counterparts accumulating at the site of inflammation. We found that miR-146a-/- mice displayed both elevated proliferation of monocytic precursors as well as increased recruitment of mature monocytes through higher expression of the chemokine receptor CCR2. Competitive co-adoptive transfer studies of granulocyte and macrophage progenitors (GMP) derived from wild-type and miR-146a-/- mice demonstrated that the phenotype selectively affected Ly-6Chi monocytes, but neither Ly-6Clo cells nor the granulocyte progeny and thus was cell intrinsic. We also identified Relb, a member of the non-canonical NF-\u03baB/Rel family as a direct miR-146a target in Ly-6Chi monocytes. In conclusion miR-146a selectively regulates the amplitude of Ly-6Chi monocytes while it spares Ly-6Clo monocyte responses.", "issn": "0301-472X", "publisher": "Elsevier", "publication": "Experimental Hematology", "publication_date": "2012-08", "series_number": "8", "volume": "40", "issue": "8", "pages": "S75" }, { "id": "authors:vjhtv-c6786", "collection": "authors", "collection_id": "vjhtv-c6786", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120619-150910546", "type": "article", "title": "microRNA Regulation of Inflammatory Responses", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.", "doi": "10.1146/annurev-immunol-020711-075013", "issn": "0732-0582", "publisher": "Annual Reviews", "publication": "Annual Review of Immunology", "publication_date": "2012-04", "volume": "30", "pages": "295-312" }, { "id": "authors:es99z-8ac75", "collection": "authors", "collection_id": "es99z-8ac75", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121116-144353588", "type": "article", "title": "Regulation of Monocyte Functional Heterogeneity by miR-146a and Relb", "author": [ { "family_name": "Etzrodt", "given_name": "Martin", "clpid": "Etzrodt-M" }, { "family_name": "Cortez-Retamozo", "given_name": "Virna", "clpid": "Cortez-Retamozo-V" }, { "family_name": "Newton", "given_name": "Andita", "clpid": "Newton-A" }, { "family_name": "Zhao", "given_name": "Jimmy", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Ng", "given_name": "Aylwin", "clpid": "Ng-Aylwin" }, { "family_name": "Wildgruber", "given_name": "Moritz", "clpid": "Wildgruber-M" }, { "family_name": "Romero", "given_name": "Pedro", "clpid": "Romero-Pedro" }, { "family_name": "Wurdinger", "given_name": "Thomas", "clpid": "Wurdinger-T" }, { "family_name": "Xavier", "given_name": "Ramnik", "clpid": "Xavier-R" }, { "family_name": "Geissmann", "given_name": "Frederic", "clpid": "Geissmann-F" }, { "family_name": "Meylan", "given_name": "Etienne", "clpid": "Meylan-E" }, { "family_name": "Nahrendorf", "given_name": "Matthias", "clpid": "Nahrendorf-M" }, { "family_name": "Swirski", "given_name": "Filip K.", "clpid": "Swirski-F-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Weissleder", "given_name": "Ralph", "clpid": "Weissleder-R" }, { "family_name": "Pittet", "given_name": "Mikael J.", "clpid": "Pittet-M-J" } ], "abstract": "Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6C^(hi)/Ly-6C^(lo)) and human (CD14^(hi)/CD14^(lo)CD16^+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6C^(hi) monocyte response during inflammatory challenge whereas it did not affect Ly-6C^(lo) cells. miR-146a-mediated regulation was cell-intrinsic and depended on Relb, a member of the noncanonical NF-\u03baB/Rel family, which we identified as a direct miR-146a target. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6C^(hi) monocyte responses while sparing Ly-6C^(lo) monocyte activity.", "doi": "10.1016/j.celrep.2012.02.009", "pmcid": "PMC3334310", "issn": "2211-1247", "publisher": "Elsevier", "publication": "Cell Reports", "publication_date": "2012-04", "series_number": "4", "volume": "1", "issue": "4", "pages": "317-324" }, { "id": "authors:pjj94-2ze33", "collection": "authors", "collection_id": "pjj94-2ze33", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120406-101100886", "type": "article", "title": "Renato Dulbecco (1914\u20132012)", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "When a gentle superman passes from our midst, we must bow our heads in recognition of his powers. Renato Dulbecco was both gentle and remarkable. He died on 19 February at his home in La Jolla, California. I got to know Renato when he invited me in 1965 to set up my first laboratory within his space at the then-nascent Salk Institute. He was moving from a professorship at the California Institute of Technology (Caltech), where he already had a notable career in virology. We were to share a Nobel Prize, with Howard Temin, just 10 years later.", "doi": "10.1126/science.1221692", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2012-03-30", "series_number": "6076", "volume": "335", "issue": "6076", "pages": "1587-1587" }, { "id": "authors:05hdh-50937", "collection": "authors", "collection_id": "05hdh-50937", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200427-120954920", "type": "article", "title": "Renato Dulbecco (1914-2012)", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "When a gentle superman passes from our midst, we must bow our heads in recognition of his powers. Renato Dulbecco was both gentle and remarkable. He died on 19 February at his home in La Jolla, California. I got to know Renato when he invited me in 1965 to set up my first laboratory within his space at the then-nascent Salk Institute. He was moving from a professorship at the California Institute of Technology (Caltech), where he already had a notable career in virology. We were to share a Nobel Prize, with Howard Temin, just 10 years later.\n\nRenato was born in 1914 in Catanzaro, Italy. He was a student in the memorable pre\u2013World War II laboratory of Giuseppe Levi at the University of Turin, along with two other Italians who, like him, came to America and won Nobel Prizes\u2014Rita Levi-Montalcini and Salvador Luria. He became a physician, was conscripted into the Italian army to serve on the Russian front, defected, and became a partisan. Luria meanwhile had gone to France and then the United States. While at Indiana University he asked Renato to join him in Bloomington. In 1947, Renato went to Indiana as a research associate and began his great career in life science research.", "doi": "10.1126/science.1221692", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2012-03-30", "series_number": "6076", "volume": "335", "issue": "6076", "pages": "1587-1587" }, { "id": "authors:9hqeh-skn78", "collection": "authors", "collection_id": "9hqeh-skn78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120402-074825961", "type": "article", "title": "Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A", "author": [ { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Mehta", "given_name": "Arnav", "clpid": "Mehta-Arnav" }, { "family_name": "Minisandram", "given_name": "Aarathi", "clpid": "Minisandram-Arathi" }, { "family_name": "Sinha", "given_name": "Nikita", "clpid": "Sinha-Nikita" }, { "family_name": "Jonsson", "given_name": "Vanessa D.", "clpid": "Jonsson-Vanessa-D" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.", "doi": "10.1073/pnas.1200677109", "pmcid": "PMC3306721", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2012-03-13", "series_number": "11", "volume": "109", "issue": "11", "pages": "4233-4238" }, { "id": "authors:xdah9-3c698", "collection": "authors", "collection_id": "xdah9-3c698", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120430-085843753", "type": "article", "title": "MicroRNAs, new effectors and regulators of NF-\u03baB", "author": [ { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Since its discovery 25 years ago, nuclear factor-\u03baB (NF-\u03baB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF-\u03baB initiates an elaborate genetic program. Some of the NF-\u03baB-driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non-coding RNA genes. We also include a personal discussion of how NF-\u03baB was first discovered.", "doi": "10.1111/j.1600-065X.2011.01089.x", "issn": "0105-2896", "publisher": "Wiley", "publication": "Immunological Reviews", "publication_date": "2012-03", "series_number": "S1", "volume": "246", "issue": "S1", "pages": "205-220" }, { "id": "authors:3g8et-0tk73", "collection": "authors", "collection_id": "3g8et-0tk73", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120120-114254226", "type": "article", "title": "Antibody-based protection against HIV infection by vectored immunoprophylaxis", "author": [ { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Chen", "given_name": "Joyce", "clpid": "Chen-Joyce" }, { "family_name": "Hong", "given_name": "Christin M.", "clpid": "Hong-Christin-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.", "doi": "10.1038/nature10660", "pmcid": "PMC3253190", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2012-01-05", "series_number": "7379", "volume": "481", "issue": "7379", "pages": "81-84" }, { "id": "authors:phyet-39772", "collection": "authors", "collection_id": "phyet-39772", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121127-135839836", "type": "book_section", "title": "MicroRNAs and Hematopoietic Cell Development", "book_title": "MicroRNAs in Development", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "contributor": [ { "family_name": "Hornstein", "given_name": "Eran", "clpid": "Hornstein-E" } ], "abstract": "Hematopoiesis is a dynamic and highly complex developmental process that gives rise to a multitude of the cell types that circulate in the blood of multicellular organisms. These cells provide tissues with oxygen, guard against infection, prevent bleeding by clotting, and mediate inflammatory reactions. Because the hematopoietic system plays such a central role in human diseases such as infections, cancer, autoimmunity, and anemia, it has been intensely studied for more than a century. This scrutiny has helped to shape many of the developmental paradigms that exist today and has identified specific protein factors that serve as master regulators of blood cell lineage specification. Despite this progress, many aspects of blood cell development remain obscure, suggesting that novel layers of regulation must exist. Consequently, the emergence of regulatory noncoding RNAs, such as the microRNAs (miRNAs), is beginning to provide new insights into the molecular control networks underlying hematopoiesis and diseases that stem from aberrations in this process. This review will discuss how miRNAs fit into our current understanding of hematopoietic development in mammals and how breakdowns in these pathways can trigger disease.", "doi": "10.1016/B978-0-12-387038-4.00006-9", "isbn": "978-0-12-387038-4", "publisher": "Elsevier", "place_of_publication": "Amsterdam", "publication_date": "2012", "pages": "145-174" }, { "id": "authors:wvdc7-z3360", "collection": "authors", "collection_id": "wvdc7-z3360", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120113-153637328", "type": "article", "title": "Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells", "author": [ { "family_name": "Vatakis", "given_name": "Dimitrios N.", "clpid": "Vatakis-Dimitrios-N" }, { "family_name": "Koya", "given_name": "Richard C.", "clpid": "Koya-Richard-C" }, { "family_name": "Nixon", "given_name": "Christopher C.", "clpid": "Nixon-Christopher-C" }, { "family_name": "Wei", "given_name": "Liu", "clpid": "Wei-Liu" }, { "family_name": "Kim", "given_name": "Sohn G.", "clpid": "Kim-Sohn-G" }, { "family_name": "Avancena", "given_name": "Patricia", "clpid": "Avancena-Patricia" }, { "family_name": "Bristol", "given_name": "Gregory", "clpid": "Bristol-Gregory" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Kohn", "given_name": "Donald B.", "clpid": "Kohn-Donald-B" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Radu", "given_name": "Caius G.", "clpid": "Radu-Caius-G" }, { "family_name": "Galic", "given_name": "Zoran", "clpid": "Galic-Zoran" }, { "family_name": "Zack", "given_name": "Jerome A.", "clpid": "Zack-Jerome-A" } ], "abstract": "The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201\u2013restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific na\u00efve CD8^+ T-cell population. Following tumor challenge, these transgenic CD8^+ T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non\u2013HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.", "doi": "10.1073/pnas.1115050108", "pmcid": "PMC3251070", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2011-12-20", "series_number": "51", "volume": "108", "issue": "51", "pages": "E1408-E1416" }, { "id": "authors:6bdsg-tp844", "collection": "authors", "collection_id": "6bdsg-tp844", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111206-080652724", "type": "article", "title": "MicroRNA-125b Potentiates Macrophage Activation", "author": [ { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "So", "given_name": "Alex Yick-Lun", "clpid": "So-Alex-Yick-Lun" }, { "family_name": "Sinha", "given_name": "Nikita", "clpid": "Sinha-Nikita" }, { "family_name": "Gibson", "given_name": "William S. J.", "clpid": "Gibson-William-S-J" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNA (miR)-125b expression is modulated in macrophages in response to stimulatory cues. In this study, we report a functional role of miR-125b in macrophages. We found that miR-125b is enriched in macrophages compared with lymphoid cells and whole immune tissues. Enforced expression of miR-125b drives macrophages to adapt an activated morphology that is accompanied by increased costimulatory factor expression and elevated responsiveness to IFN-y, whereas anti\u2013miR-125b treatment decreases CD80 surface expression. To determine whether these alterations in cell signaling, gene expression, and morphology have functional\nconsequences, we examined the ability of macrophages with enhanced miR-125b expression to present Ags and found that they better stimulate T cell activation than control macrophages. Further indicating increased function, these macrophages were more effective at killing EL4 tumor cells in vitro and in vivo. Moreover, miR-125b repressed IFN regulatory factor 4 (IRF4), and IRF4 knockdown in macrophages mimicked the miR-125b overexpression phenotype. In summary, our evidence suggests that miR-125b is at least partly responsible for generating the activated nature of macrophages, at least partially by reducing IRF4 levels, and\npotentiates the functional role of macrophages in inducing immune responses.", "doi": "10.4049/jimmunol.1102001", "pmcid": "PMC3208133", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2011-11-15", "series_number": "10", "volume": "187", "issue": "10", "pages": "5062-5068" }, { "id": "authors:wv1c2-0qe71", "collection": "authors", "collection_id": "wv1c2-0qe71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111003-111714898", "type": "article", "title": "Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T-cell reservoirs in mice", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Yu", "given_name": "Yang", "clpid": "Yu-Yang" }, { "family_name": "Kalwani", "given_name": "Manorama", "clpid": "Kalwani-Manorama" }, { "family_name": "Tseng", "given_name": "Tai-Wei Joy", "clpid": "Tseng-Tai-Wei-Joy" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Memory T cells (T_Ms) have been detected in many tissues but their quantitative distribution remains largely undefined. We show that in mice there is a remarkably biased accumulation of long-term CD4 T_Ms into mucosal sites (mainly gut, especially Peyer patches), and CD8 T_Ms into lymph nodes and spleen (in particular, peripheral lymph nodes [PLNs]). This distinction correlates with their differentiated expression of PLN- and gut-homing markers. CD8 and CD4 T_Ms selectively require the expression of PLN-homing marker CCR7 or gut-homing marker \u03b14\u03b27 for maintenance. PLNs and gut supply CD8 and CD4 T_Ms with their individually favored homeostatic cytokine, IL-15, or IL-7. Cytokine stimulation in turn regulates the different gut-homing marker expression on CD4 and CD8 T_Ms. IL-15 plays a major role in vivo regulating CD8 TMs homing to PLNs. Thus, the reservoir segregation of CD4 and CD8 T_Ms meets their individual needs for homeostatic cytokines and is under feedback control of cytokine stimulation.", "doi": "10.1182/blood-2011-04-349746", "pmcid": "PMC3175781", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2011-09-15", "series_number": "11", "volume": "118", "issue": "11", "pages": "3039-3050" }, { "id": "authors:7g0sc-fjd81", "collection": "authors", "collection_id": "7g0sc-fjd81", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111021-132323980", "type": "article", "title": "Lennart Philipson (1929-2011): A Warrior Has Passed Obituary", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Lennart Philipson died on June 26,\n2011. His passing is a great loss to the\nworldwide biomedical research community.\nHe was a big man\u2014physically, emotionally\nand operationally, dominating\nrooms, psyches and institutions. He was\nmy wonderful friend, and when Lennart\nbecame your friend, it filled a big need in\nyour life.", "doi": "10.1371/journal.pbio.1001153", "pmcid": "PMC3176751", "issn": "1544-9173", "publisher": "Public Library of Science", "publication": "PLoS Biology", "publication_date": "2011-09", "series_number": "9", "volume": "9", "issue": "9", "pages": "Art. No. e1001153" }, { "id": "authors:p67y1-1wn74", "collection": "authors", "collection_id": "p67y1-1wn74", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110802-105536854", "type": "article", "title": "NF-\u03baB is 25", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB-mediated inflammatory biology can be formulated as the following five states: latency, induction, response,\nresolution and pathology. The first four involve carefully tuned molecular processes; pathology is the loss of control.", "doi": "10.1038/ni.2072", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2011-08", "series_number": "8", "volume": "12", "issue": "8", "pages": "683-685" }, { "id": "authors:vknvx-0s921", "collection": "authors", "collection_id": "vknvx-0s921", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110815-134453493", "type": "article", "title": "Sam68 Is Required for Both NF-\u03baB Activation and Apoptosis Signaling by the TNF Receptor", "author": [ { "family_name": "Ramakrishnan", "given_name": "Parameswaran", "orcid": "0000-0002-1314-827X", "clpid": "Ramakrishnan-Parameswaran" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The RNA-binding protein Sam68 is implicated in various cellular processes including RNA metabolism, apoptosis, and signal transduction. Here we identify a role of Sam68 in TNF-induced NF-\u03baB activation and apoptosis. We found that Sam68 is recruited to the TNF receptor, and its deficiency dramatically reduces RIP recruitment and ubiquitylation. It also impairs cIAP1 recruitment and maintenance of recruited TRAF2 at the TNF receptor. In its absence, activation of the TAK1-IKK kinase complex is defective, greatly reducing signal transduction. Sam68 is also found as a part of the TNF-induced cytoplasmic caspase-8-FADD complex. RIP is not recruited to this complex in Sam68 knockout cells, and caspase activation is virtually absent. These findings delineate previously unknown functions for Sam68 in the TNF signaling pathway, where it acts as a signaling adaptor both in the membrane-associated complex I and in the cytoplasmic complex II, regulating both NF-\u03baB activation and apoptosis.", "doi": "10.1016/j.molcel.2011.05.007", "pmcid": "PMC3142289", "issn": "1097-2765", "publisher": "Elsevier", "publication": "Molecular Cell", "publication_date": "2011-07-22", "series_number": "2", "volume": "43", "issue": "2", "pages": "167-179" }, { "id": "authors:h3ymm-mwb54", "collection": "authors", "collection_id": "h3ymm-mwb54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110812-085604415", "type": "article", "title": "A Computational-Experimental Approach Identifies Mutations That Enhance Surface Expression of an Oseltamivir-Resistant Influenza Neuraminidase", "author": [ { "family_name": "Bloom", "given_name": "Jesse D.", "orcid": "0000-0003-1267-3408", "clpid": "Bloom-J-D" }, { "family_name": "Nayak", "given_name": "Jagannath S.", "clpid": "Nayak-Jagannath-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The His274 \u2192 Tyr (H274Y) oseltamivir (Tamiflu) resistance mutation causes a substantial decrease in the total levels of surface-expressed neuraminidase protein and activity in early isolates of human seasonal H1N1 influenza, and in the swine-origin pandemic H1N1. In seasonal H1N1, H274Y only became widespread after the occurrence of secondary mutations that counteracted this decrease. H274Y is currently rare in pandemic H1N1, and it remains unclear whether secondary mutations exist that might similarly counteract the decreased neuraminidase surface expression associated with this resistance mutation in pandemic H1N1. Here we investigate the possibility of predicting such secondary mutations. We first test the ability of several computational approaches to retrospectively identify the secondary mutations that enhanced levels of surface-expressed neuraminidase protein and activity in seasonal H1N1 shortly before the emergence of oseltamivir resistance. We then use the most successful computational approach to predict a set of candidate secondary mutations to the pandemic H1N1 neuraminidase. We experimentally screen these mutations, and find that several of them do indeed partially counteract the decrease in neuraminidase surface expression caused by H274Y. Two of the secondary mutations together restore surface-expressed neuraminidase activity to wildtype levels, and also eliminate the very slight decrease in viral growth in tissue-culture caused by H274Y. Our work therefore demonstrates a combined computational-experimental approach for identifying mutations that enhance neuraminidase surface expression, and describes several specific mutations with the potential to be of relevance to the spread of oseltamivir resistance in pandemic H1N1.", "doi": "10.1371/journal.pone.0022201", "pmcid": "PMC3140507", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2011-07-20", "series_number": "7", "volume": "6", "issue": "7", "pages": "Art. No. e22201" }, { "id": "authors:pkgat-sww37", "collection": "authors", "collection_id": "pkgat-sww37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110627-164327215", "type": "article", "title": "miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice", "author": [ { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Kalwani", "given_name": "Manorama", "clpid": "Kalwani-Manorama" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Luong", "given_name": "Mui", "clpid": "Luong-Mui" }, { "family_name": "Devrekanli", "given_name": "Asli", "clpid": "Devrekanli-Asli" }, { "family_name": "Xu", "given_name": "Jessica", "clpid": "Xu-Jessica" }, { "family_name": "Sun", "given_name": "Guizhen", "clpid": "Sun-Guizhen" }, { "family_name": "Tay", "given_name": "Jia", "clpid": "Tay-Jia" }, { "family_name": "Linsley", "given_name": "Peter S.", "clpid": "Linsley-Peter-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ~22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.", "doi": "10.1084/jem.20101823", "pmcid": "PMC3173243", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2011-06-06", "series_number": "6", "volume": "208", "issue": "6", "pages": "1189-1201" }, { "id": "authors:4qm21-ys919", "collection": "authors", "collection_id": "4qm21-ys919", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110613-152322859", "type": "article", "title": "NF-\u03baB dysregulation in microRNA-146a\u2013deficient mice drives the development of myeloid malignancies", "author": [ { "family_name": "Zhao", "given_name": "Jimmy L.", "clpid": "Zhao-Jimmy-L" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNA miR-146a has been implicated as a negative feedback regulator of NF-\u03baB activation. Knockout of the miR-146a gene in C57BL/6 mice leads to histologically and immunophenotypically defined myeloid sarcomas and some lymphomas. The sarcomas are transplantable to immunologically compromised hosts, showing that they are true malignancies. The animals also exhibit chronic myeloproliferation in their bone marrow. Spleen and marrow cells show increased transcription of NF-\u03baB\u2013regulated genes and tumors have higher nuclear p65. Genetic ablation of NF-\u03baB p50 suppresses the myeloproliferation, showing that dysregulation of NF-\u03baB is responsible for the myeloproliferative disease.", "doi": "10.1073/pnas.1105398108", "pmcid": "PMC3107319", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2011-05-31", "series_number": "22", "volume": "108", "issue": "22", "pages": "9184-9189" }, { "id": "authors:52gjb-m3h53", "collection": "authors", "collection_id": "52gjb-m3h53", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110401-155348899", "type": "article", "title": "Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells", "author": [ { "family_name": "Ramakrishnan", "given_name": "P.", "orcid": "0000-0002-1314-827X", "clpid": "Ramakrishnan-Parameswaran" }, { "family_name": "Kahn", "given_name": "D. A.", "clpid": "Kahn-Daniel-A" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Thymocyte development is a tightly controlled multi-step process involving selective elimination of self-reactive and non-functional T cells by apoptosis. This developmental process depends on signaling by Notch, IL-7 and active glucose metabolism. In this study, we explored the requirement of glucose for thymocyte survival and found that in addition to metabolic regulation, glucose leads to the expression of anti-apoptotic genes. Under hyperglycemic conditions, both mouse and human thymocytes demonstrate enhanced survival. We show that glucose-induced anti-apoptotic genes are dependent on NF-\u03baB p65 because high glucose is unable to attenuate normal ongoing apoptosis of thymocytes isolated from p65 knockout mice. Furthermore, we demonstrate that in vivo hyperglycemia decreases apoptosis of thymocytes allowing for survival of potentially self-reactive thymocytes. These results imply that hyperglycemic conditions could contribute to the development of autoimmunity through dysregulated thymic selection.", "doi": "10.1038/cdd.2010.163", "pmcid": "PMC3131907", "issn": "1350-9047", "publisher": "Nature Publishing", "publication": "Cell Death and Differentiation", "publication_date": "2011-04", "series_number": "4", "volume": "18", "issue": "4", "pages": "690-699" }, { "id": "authors:xz737-8an10", "collection": "authors", "collection_id": "xz737-8an10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110228-114858253", "type": "article", "title": "Exploring the limits of ultrafast polymerase chain reaction using liquid for thermal heat exchange: A proof of principle", "author": [ { "family_name": "Maltezos", "given_name": "George", "clpid": "Maltezos-George" }, { "family_name": "Johnston", "given_name": "Matthew", "clpid": "Johnston-Matthew-L" }, { "family_name": "Taganov", "given_name": "Konstantin", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Srichantaratsamee", "given_name": "Chutatip", "clpid": "Srichantaratsamee-Chutatip" }, { "family_name": "Gorman", "given_name": "John", "clpid": "Gorman-John" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Chantratita", "given_name": "Wasun", "clpid": "Chantratita-Wasun" }, { "family_name": "Scherer", "given_name": "Axel", "orcid": "0000-0002-2160-9064", "clpid": "Scherer-A" } ], "abstract": "Thermal ramp rate is a major limiting factor in using real-time polymerase chain reaction (PCR) for routine diagnostics. We explored the limits of speed by using liquid for thermal exchange rather than metal as in traditional devices, and by testing different polymerases. In a clinical setting, our system equaled or surpassed state-of-the-art devices for accuracy in amplifying DNA/RNA of avian influenza, cytomegalovirus, and human immunodeficiency virus. Using Thermococcus kodakaraensis polymerase and optimizing both electrical and chemical systems, we obtained an accurate, 35 cycle amplification of an 85-base pair fragment of E. coli O157:H7 Shiga toxin gene in as little as 94.1 s, a significant improvement over a typical 1 h PCR amplification.", "doi": "10.1063/1.3530452", "pmcid": "PMC3026011", "issn": "0003-6951", "publisher": "American Institute of Physics", "publication": "Applied Physics Letters", "publication_date": "2010-12-27", "series_number": "26", "volume": "97", "issue": "26", "pages": "Art. No. 264101" }, { "id": "authors:pyytt-hrs45", "collection": "authors", "collection_id": "pyytt-hrs45", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110307-113044022", "type": "article", "title": "Dimeric 2G12 as a Potent Protection against HIV-1", "author": [ { "family_name": "Luo", "given_name": "Xin M.", "clpid": "Luo-Xin-M" }, { "family_name": "Lei", "given_name": "Margarida Y. Y.", "clpid": "Lei-Margarida-Y-Y" }, { "family_name": "Feidi", "given_name": "Rana A.", "clpid": "Feidi-Rana-A" }, { "family_name": "West", "given_name": "Anthony P., Jr.", "clpid": "West-A-P-Jr" }, { "family_name": "Balazs", "given_name": "Alejandro Benjamin", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Bjorkman", "given_name": "Pamela J.", "orcid": "0000-0002-2277-3990", "clpid": "Bjorkman-P-J" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We previously showed that broadly neutralizing anti-HIV-1 antibody 2G12 (human IgG1) naturally forms dimers that are more potent than monomeric 2G12 in in vitro neutralization of various strains of HIV-1. In this study, we have investigated the protective effects of monomeric versus dimeric 2G12 against HIV-1 infection in vivo using a humanized mouse model. Our results showed that passively transferred, purified 2G12 dimer is more potent than 2G12 monomer at preventing CD4 T cell loss and suppressing the increase of viral load following HIV-1 infection of humanized mice. Using humanized mice bearing IgG \"backpack\" tumors that provided 2G12 antibodies continuously, we found that a sustained dimer concentration of 5\u201325 \u00b5g/ml during the course of infection provides effective protection against HIV-1. Importantly, 2G12 dimer at this concentration does not favor mutations of the HIV-1 envelope that would cause the virus to completely escape 2G12 neutralization. We have therefore identified dimeric 2G12 as a potent prophylactic reagent against HIV-1 in vivo, which could be used as part of an antibody cocktail to prevent HIV-1 infection.", "doi": "10.1371/journal.ppat.1001225", "pmcid": "PMC3002980", "issn": "1553-7366", "publisher": "Public Library of Science", "publication": "PLoS Pathogens", "publication_date": "2010-12", "series_number": "12", "volume": "6", "issue": "12", "pages": "Art. No. e1001225" }, { "id": "authors:z5zst-2nz12", "collection": "authors", "collection_id": "z5zst-2nz12", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20101213-114734795", "type": "article", "title": "MicroRNA-155 Promotes Autoimmune Inflammation by Enhancing Inflammatory T Cell Development", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Kahn", "given_name": "Daniel A.", "clpid": "Kahn-Daniel-A" }, { "family_name": "Gibson", "given_name": "William S. J.", "clpid": "Gibson-William-S-J" }, { "family_name": "Round", "given_name": "June L.", "clpid": "Round-June-L" }, { "family_name": "Scholz", "given_name": "Rebecca L.", "clpid": "Scholz-Rebecc-L" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-A-A" }, { "family_name": "Kahn", "given_name": "Melissa E.", "clpid": "Kahn-Melissa-E" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155^(\u2212/\u2212) mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4^+ T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders.", "doi": "10.1016/j.immuni.2010.09.009", "pmcid": "PMC2966521", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2010-10-29", "series_number": "4", "volume": "33", "issue": "4", "pages": "607-619" }, { "id": "authors:x86vq-a9802", "collection": "authors", "collection_id": "x86vq-a9802", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20101012-085533074", "type": "article", "title": "Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses", "author": [ { "family_name": "Lu", "given_name": "Li-Fan", "clpid": "Lu-Li-Fan" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Chaudhry", "given_name": "Ashutosh", "clpid": "Chaudhry-Ashutosh" }, { "family_name": "Lin", "given_name": "Ling-Li", "clpid": "Lin-Ling-Li" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Hanada", "given_name": "Toshikatsu", "clpid": "Hanada-Toshikatsu" }, { "family_name": "Yoshimura", "given_name": "Akihiko", "clpid": "Yoshimura-Akihiko" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Rudensky", "given_name": "Alexander Y.", "clpid": "Rudensky-Alexander-Y" } ], "abstract": "Foxp3^+ regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFN\u03b3-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFN\u03b3 receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity.", "doi": "10.1016/j.cell.2010.08.012", "pmcid": "PMC3049116", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2010-09-17", "series_number": "6", "volume": "142", "issue": "6", "pages": "914-929" }, { "id": "authors:q77w8-yk337", "collection": "authors", "collection_id": "q77w8-yk337", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100913-113144776", "type": "article", "title": "MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Gibson", "given_name": "William S. J.", "clpid": "Gibson-William-S-J" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.", "doi": "10.1073/pnas.1009798107", "pmcid": "PMC2922591", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2010-08-10", "series_number": "32", "volume": "107", "issue": "32", "pages": "14235-14240" }, { "id": "authors:12x83-ba778", "collection": "authors", "collection_id": "12x83-ba778", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100901-164229801", "type": "article", "title": "Lentiviral Vector Delivery of Human Interleukin-7 (hIL-7) to Human Immune System (HIS) Mice Expands T Lymphocyte Populations", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Balazs", "given_name": "Alejandro B.", "orcid": "0000-0002-1767-3944", "clpid": "Balazs-Alejandro-B" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Kivork", "given_name": "Christine", "clpid": "Kivork-Christine" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Genetically modified mice carrying engrafted human tissues provide useful models to study human cell biology in physiologically relevant contexts. However, there remain several obstacles limiting the compatibility of human cells within their mouse hosts. Among these is inadequate cross-reactvitiy between certain mouse cytokines and human cellular receptors, depriving the graft of important survival and growth signals. To circumvent this problem, we utilized a lentivirus-based delivery system to express physiologically relevant levels of human interleukin-7 (hIL-7) in Rag2-/-\u03b3c-/- mice following a single intravenous injection. hIL-7 promoted homeostatic proliferation of both adoptively transferred and endogenously generated T-cells in Rag2-/-\u03b3c-/- Human Immune System (HIS) mice. Interestingly, we found that hIL-7 increased T lymphocyte numbers in the spleens of HIV infected HIS mice without affecting viral load. Taken together, our study unveils a versatile approach to deliver human cytokines to HIS mice, to both improve engraftment and determine the impact of cytokines on human diseases.", "doi": "10.1371/journal.pone.0012009", "pmcid": "PMC2917362", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2010-08-06", "series_number": "8", "volume": "5", "issue": "8", "pages": "e12009" }, { "id": "authors:xhtty-5eb45", "collection": "authors", "collection_id": "xhtty-5eb45", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100817-084630441", "type": "article", "title": "MicroRNA-34a Perturbs B Lymphocyte Development by Repressing the Forkhead Box Transcription Factor Foxp1", "author": [ { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "Garcia-Flores", "given_name": "Yvette", "clpid": "Garcia-Flores-Yvette" }, { "family_name": "Geiger", "given_name": "Theresa L.", "clpid": "Geiger-Theresa-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs (miRNAs) can influence lineage choice or affect critical developmental checkpoints during hematopoiesis. We examined the role of the p53-induced microRNA miR-34a in hematopoiesis by gain-of-function analysis in murine bone marrow. Constitutive expression of miR-34a led to a block in B cell development at the pro-B-cell-to-pre-B-cell transition, leading to a reduction in mature B cells. This block appeared to be mediated primarily by inhibited expression of the transcription factor Foxp1. Foxp1 was a direct target of miR-34a in a 3\u2032-untranslated region (UTR)-dependent fashion. Knockdown of Foxp1 by siRNA recapitulated the B cell developmental phenotype induced by miR-34a, whereas cotransduction of Foxp1 lacking its 3\u2032 UTR with miR-34a rescued B cell maturation. Knockdown of miR-34a resulted in increased amounts of Foxp1 and mature B cells. These findings identify a role for miR-34a in connecting the p53 network with suppression of Foxp1, a known B cell oncogene.", "doi": "10.1016/j.immuni.2010.06.013", "pmcid": "PMC2911227", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2010-07-23", "series_number": "1", "volume": "33", "issue": "1", "pages": "48-59" }, { "id": "authors:xj0n6-3ke68", "collection": "authors", "collection_id": "xj0n6-3ke68", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100616-095540151", "type": "article", "title": "Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance", "author": [ { "family_name": "Bloom", "given_name": "Jesse D.", "orcid": "0000-0003-1267-3408", "clpid": "Bloom-J-D" }, { "family_name": "Gong", "given_name": "Lizhi Ian", "clpid": "Gong-Lizhi-Ian" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The His^(274)\u2192Tyr^(274) (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007\u20132008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness. Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by \"permissive\" mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.", "doi": "10.1126/science.1187816", "pmcid": "PMC2913718", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2010-06-04", "series_number": "5983", "volume": "328", "issue": "5983", "pages": "1272-1275" }, { "id": "authors:znqdg-v8x13", "collection": "authors", "collection_id": "znqdg-v8x13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100608-075607749", "type": "article", "title": "Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance", "author": [ { "family_name": "Kahn", "given_name": "Daniel A.", "clpid": "Kahn-Daniel-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A fetus is inherently antigenic to its mother and yet is not rejected. The T regulatory (Treg) subset of CD4^+ T cells can limit immune responses and has been implicated in maternal tolerance of the fetus. Using virgin inbred mice undergoing a first syngenic pregnancy, in which only the male fetuses are antigenic, we demonstrate a maternal splenocyte proliferative response to the CD4^+ T cell restricted epitope of the male antigen (H-Y) in proportion to the fetal antigen load. A portion of the maternal immune response to fetal antigens is Treg in nature. The bystander suppressive function of pregnancy-generated Tregs requires the presence of the fetal antigen, demonstrating their inherent antigen specificity. In vivo targeting of diphtheria toxin to kill Tregs leads to a lower fraction of live male offspring and a selective reduction in mass of the surviving males. Thus, Tregs generated in the context of pregnancy function in an antigen-specific manner to limit the maternal immune response to the fetus in a successful pregnancy.", "doi": "10.1073/pnas.1003909107", "pmcid": "PMC2889122", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2010-05-18", "series_number": "20", "volume": "107", "issue": "20", "pages": "9299-9304" }, { "id": "authors:dzbdh-td120", "collection": "authors", "collection_id": "dzbdh-td120", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100907-153526243", "type": "article", "title": "I\u03baB\u03b2 acts to inhibit and activate gene expression during the inflammatory response", "author": [ { "family_name": "Rao", "given_name": "Ping", "clpid": "Rao-Ping" }, { "family_name": "Hayden", "given_name": "Matthew S.", "clpid": "Hayden-Matthew-S" }, { "family_name": "Long", "given_name": "Meixiao", "clpid": "Long-Meixiao" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "West", "given_name": "A. Philip", "clpid": "West-A-P-Jr" }, { "family_name": "Zhang", "given_name": "Dekai", "clpid": "Zhang-Dekai" }, { "family_name": "Oeckinghaus", "given_name": "Andrea", "clpid": "Oeckinghaus-Andrea" }, { "family_name": "Lynch", "given_name": "Candace", "clpid": "Lynch-Candace" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" } ], "abstract": "The activation of pro-inflammatory gene programs by nuclear factor-\u03baB (NF-\u03baB) is primarily regulated through cytoplasmic sequestration of NF-\u03baB by the inhibitor of \u03baB (I\u03baB) family of proteins1. I\u03baB\u03b2, a major isoform of I\u03baB, can sequester NF-\u03baB in the cytoplasm2, although its biological role remains unclear. Although cells lacking I\u03baB\u03b2 have been reported3, 4, in vivo studies have been limited and suggested redundancy between I\u03baB\u03b1 and I\u03baB\u03b25. Like I\u03baB\u03b1, I\u03baB\u03b2 is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6, 7, 8, 9, 10, 11. The crystal structure of I\u03baB\u03b2 bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated I\u03baB\u03b2 can bind DNA with p65 and c-Rel, and the DNA-bound NF-\u03baB:I\u03baB\u03b2 complexes are resistant to I\u03baB\u03b1, suggesting hypophosphorylated, nuclear I\u03baB\u03b2 may prolong the expression of certain genes9, 10, 11. Here we report that in vivo I\u03baB\u03b2 serves both to inhibit and facilitate the inflammatory response. I\u03baB\u03b2 degradation releases NF-\u03baB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-\u03b1 (TNF-\u03b1). Surprisingly, absence of I\u03baB\u03b2 results in a dramatic reduction of TNF-\u03b1 in response to LPS even though activation of NF-\u03baB is normal. The inhibition of TNF-\u03b1 messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-I\u03baB\u03b2 bound to p65:c-Rel heterodimers at a specific \u03baB site on the TNF-\u03b1 promoter. Therefore I\u03baB\u03b2 acts through p65:c-Rel dimers to maintain prolonged expression of TNF-\u03b1. As a result, I\u03baB\u03b2^(\u2212/\u2212) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking I\u03baB\u03b2 might be a promising new strategy for selectively inhibiting the chronic phase of TNF-\u03b1 production during the inflammatory response.", "doi": "10.1038/nature09283", "pmcid": "PMC2946371", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2010-04-26", "series_number": "7310", "volume": "466", "issue": "7310", "pages": "1115-1119" }, { "id": "authors:bj49r-pbk10", "collection": "authors", "collection_id": "bj49r-pbk10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100406-161129907", "type": "article", "title": "Overcoming barriers to programming a therapeutic cellular immune response to fight melanoma", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Economou", "given_name": "James", "clpid": "Economou-James-S" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" } ], "abstract": "No abstract.", "doi": "10.1111/j.1755-148X.2010.00666.x", "issn": "1755-1471", "publisher": "Blackwell", "publication": "Pigment Cell and Melanoma Research", "publication_date": "2010-04", "series_number": "2", "volume": "23", "issue": "2", "pages": "288-289" }, { "id": "authors:3b7e1-n9409", "collection": "authors", "collection_id": "3b7e1-n9409", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100217-110341370", "type": "article", "title": "Physiological and pathological roles for microRNAs in the immune system", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.", "doi": "10.1038/nri2708", "issn": "1474-1733", "publisher": "Nature Publishing Group", "publication": "Nature Reviews. Immunology", "publication_date": "2010-02", "series_number": "2", "volume": "10", "issue": "2", "pages": "111-122" }, { "id": "authors:k37xz-rs766", "collection": "authors", "collection_id": "k37xz-rs766", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100329-094147120", "type": "article", "title": "2020 Visions", "author": [ { "family_name": "Norvig", "given_name": "Peter", "clpid": "Norvig-P" }, { "family_name": "Relman", "given_name": "David A.", "clpid": "Relman-D-A" }, { "family_name": "Goldstein", "given_name": "David B.", "clpid": "Goldstein-D-B" }, { "family_name": "Kammen", "given_name": "Daniel M.", "clpid": "Kammen-D-M" }, { "family_name": "Weinberger", "given_name": "Daniel R.", "clpid": "Weinberger-D-R" }, { "family_name": "Aiello", "given_name": "Leslie C.", "clpid": "Aiello-L-C" }, { "family_name": "Church", "given_name": "George", "clpid": "Church-G" }, { "family_name": "Hennessy", "given_name": "John L.", "clpid": "Hennessy-J-L" }, { "family_name": "Sachs", "given_name": "Jefrey", "clpid": "Sachs-J" }, { "family_name": "Burrows", "given_name": "Adam", "orcid": "0000-0002-3099-5024", "clpid": "Burrows-A-S" }, { "family_name": "Pisano", "given_name": "Gary P.", "clpid": "Pisano-G-P" }, { "family_name": "Goldstein", "given_name": "Joshua R.", "clpid": "Goldstein-J-R" }, { "family_name": "Anastas", "given_name": "Paul", "clpid": "Anastas-P" }, { "family_name": "Klausner", "given_name": "Richard", "clpid": "Klausner-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Montgomery", "given_name": "David R.", "clpid": "Montgomery-D-R" }, { "family_name": "Baer", "given_name": "Thomas M.", "clpid": "Baer-T-M" }, { "family_name": "Bigelow", "given_name": "Nicholas P.", "clpid": "Bigelow-N-P" }, { "family_name": "Holt", "given_name": "Robert D.", "clpid": "Hold-R-D" }, { "family_name": "Nicholson", "given_name": "Jeremy K.", "clpid": "Nicholson-J-K" } ], "abstract": "For the first issue of the new decade, Nature asked a selection of leading researchers and policy-makers where their fields will be ten years from now. We invited them to identify the key questions their disciplines face, the major roadblocks and the pressing next steps.", "doi": "10.1038/463026a", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2010-01-07", "series_number": "7277", "volume": "463", "issue": "7277", "pages": "26-32" }, { "id": "authors:knhht-3pt80", "collection": "authors", "collection_id": "knhht-3pt80", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20091218-143706210", "type": "article", "title": "HIV-1 Gag-specific immunity induced by a lentivector-based vaccine directed to dendritic cells", "author": [ { "family_name": "Dai", "given_name": "Bingbing", "clpid": "Dai-Bingbing" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Yang", "given_name": "Haiguang", "clpid": "Yang-Haiguang" }, { "family_name": "Hu", "given_name": "Biliang", "clpid": "Hu-Biliang" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" } ], "abstract": "Lentivectors (LVs) have attracted considerable interest for their potential as a vaccine delivery vehicle. In this study, we evaluate in mice a dendritic cell (DC)-directed LV system encoding the Gag protein of human immunodeficiency virus (HIV) (LV-Gag) as a potential vaccine for inducing an anti-HIV immune response. The DC-directed specificity is achieved through pseudotyping the vector with an engineered Sindbis virus glycoprotein capable of selectively binding to the DC-SIGN protein. A single immunization by this vector induces a durable HIV Gag-specific immune response. We investigated the antigen-specific immunity and T-cell memory generated by a prime/boost vaccine regimen delivered by either successive LV-Gag injections or a DNA prime/LV-Gag boost protocol. We found that both prime/boost regimens significantly enhance cellular and humoral immune responses. Importantly, a heterologous DNA prime/LV-Gag boost regimen results in superior Gag-specific T-cell responses as compared with a DNA prime/adenovector boost immunization. It induces not only a higher magnitude response, as measured by Gag-specific tetramer analysis and intracellular IFN-\u03b3 staining, but also a better quality of response evidenced by a wider mix of cytokines produced by the Gag-specific CD8^+ and CD4^+ T cells. A boosting immunization with LV-Gag also generates T cells reactive to a broader range of Gag-derived epitopes. These results demonstrate that this DC-directed LV immunization is a potent modality for eliciting anti-HIV immune responses.", "doi": "10.1073/pnas.0911742106", "pmcid": "PMC2777969", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2009-12-01", "series_number": "48", "volume": "106", "issue": "48", "pages": "20382-20387" }, { "id": "authors:rqb26-n3806", "collection": "authors", "collection_id": "rqb26-n3806", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20091209-093326396", "type": "article", "title": "Regulation of NF-\u03baB activity through lysine\n monomethylation of p65", "author": [ { "family_name": "Ea", "given_name": "Chee-Kwee", "clpid": "Ea-Chee-Kwee" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-\u03baB is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-\u03baB regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNF\u03b1 and IL-1\u03b2 treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-\u03baB target genes in response to TNF\u03b1 stimulation.", "doi": "10.1073/pnas.0910439106", "pmcid": "PMC2770010", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2009-11-10", "series_number": "45", "volume": "106", "issue": "45", "pages": "18972-18977" }, { "id": "authors:bfykr-pvq93", "collection": "authors", "collection_id": "bfykr-pvq93", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100621-110418241", "type": "article", "title": "Discovering NF-\u03baB", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "David Baltimore recalls the experiments that led to the discovery of the NF-\u03baB transcription factor more than 20 years ago.", "doi": "10.1101/cshperspect.a000026", "pmcid": "PMC2742082", "issn": "1943-0264", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Cold Spring Harbor Perspectives in Biology", "publication_date": "2009-07", "series_number": "1", "volume": "1", "issue": "1", "pages": "Art. No. a000026" }, { "id": "authors:kwv9z-7vy79", "collection": "authors", "collection_id": "kwv9z-7vy79", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090729-133539829", "type": "article", "title": "Inositol phosphatase SHIP1 is a primary target of miR-155", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3\u2032UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3\u2032UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155\u2212/\u2212 primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology.", "doi": "10.1073/pnas.0902636106", "pmcid": "PMC2678424", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2009-04-28", "series_number": "17", "volume": "106", "issue": "17", "pages": "7113-7118" }, { "id": "authors:knxt9-3a496", "collection": "authors", "collection_id": "knxt9-3a496", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090413-083201541", "type": "article", "title": "The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules", "author": [ { "family_name": "Hao", "given_name": "Shengli", "clpid": "Hao-Shengli" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The inflammatory response plays out over time in a reproducible and organized way after an initiating stimulus. Here we show that genes activated in cultured mouse fibroblasts in response to the cytokine tumor necrosis factor could be categorized into roughly three groups, each with different induction kinetics. Although differences in transcription were important in determining the grouping of these genes, differences in mRNA stability also exerted a strong influence on the temporal order of gene expression, in some cases overriding that of transcriptional control elements. Transcripts of mRNA expressed early had abundant AU-rich elements in their 3' untranslated regions, whereas those expressed later had fewer. Thus, mRNA stability and transcriptional control, two intrinsic characteristics of genes, control the kinetics of gene expression induced by proinflammatory cytokines.", "doi": "10.1038/ni.1699", "pmcid": "PMC2775040", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2009-03", "series_number": "3", "volume": "10", "issue": "3", "pages": "281-288" }, { "id": "authors:fhx5r-tjv89", "collection": "authors", "collection_id": "fhx5r-tjv89", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090828-115250714", "type": "article", "title": "Engineering human hematopoietic stem/progenitor cells to produce a broadly neutralizing anti-HIV antibody after in vitro maturation to human B lymphocytes", "author": [ { "family_name": "Luo", "given_name": "Xin M.", "clpid": "Luo-Xin-M" }, { "family_name": "Maarschalk", "given_name": "Emily", "clpid": "Maarschalk-Emily" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Broadly neutralizing anti-HIV antibodies are rare and have proved hard to elicit with any immunogen. We have tested in vitro the notion that such antibodies or other antiviral proteins could be made by lentivirus-mediated gene transfer into human hematopoietic stem/progenitor cells (HSPCs), followed by differentiation of the transduced cells into B cells, the most potent antibody-producing cells. To do this, we have developed a highly efficient system for in vitro maturation of secreting B lymphocytes and plasma cells from CD34^+ HSPCs. It is a 3-stage, in vitro culture system that supports normal human B-lineage development from HSPCs to antibody-secreting plasmablasts (~36%) and plasma cells (~20%). By transducing human cord blood CD34^+ cells with lentiviral vectors encoding a secretory monoclonal anti-HIV antibody, b12 (IgG1), we were able to program human B cells to produce in vitro up to 1.5 \u00b5g/mL of this broadly neutralizing antibody. Our results suggest that an HIV vaccine might be delivered by autologous transplantation of in vitro\u2013programmed HSPCs, which would develop into antibody-secreting B cells in vivo and provide a continuous supply of anti-HIV neutralizing antibodies.", "doi": "10.1182/blood-2008-09-177139", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2009-02-12", "series_number": "7", "volume": "113", "issue": "7", "pages": "1422-1431" }, { "id": "authors:e74ra-w2z28", "collection": "authors", "collection_id": "e74ra-w2z28", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BALsci08a", "type": "article", "title": "Presidential address : a global perspective on science and technology", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The United States is a huge ocean-flanked country that, since World War II, has led the\nworld in the development of science and technology. But other countries are now catching\nup. The American Association for the Advancement of Science (AAAS) has been a support for the development of American science since the 19th century, but as the rest of the world becomes increasingly relevant, it has chosen to expand its purview to become more of an international friend of science. At the 174th annual meeting of the AAAS, we chose to reflect this new perspective.", "doi": "10.1126/science.1166647", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2008-10-24", "series_number": "5901", "volume": "322", "issue": "5901", "pages": "544-551" }, { "id": "authors:2c5qy-r6p47", "collection": "authors", "collection_id": "2c5qy-r6p47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142716572", "type": "article", "title": "[An interview with...] David Baltimore", "author": [ { "family_name": "Friedberg", "given_name": "Errol C.", "clpid": "Friedberg-E-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "David Baltimore was born in 1938. He attended Swarthmore College, Pennsylvania, as an undergraduate and obtained his Ph.D. from the Rockefeller Institute, New York, USA. He was a faculty member of the Salk Institute, California, and of the Massachusetts Institute of Technology (MIT) for many years. While at MIT, Baltimore received (at the age of 37) the Nobel Prize in Physiology or Medicine together with Howard Temin, for the discovery of reverse transcriptase. He was founding director of the Whitehead Institute, an academic affiliate of MIT. He has served as President of Rockefeller University and the California Institute of Technology (Caltech). He is currently President Emeritus and a professor at Caltech.", "doi": "10.1038/nrm2482", "issn": "1471-0072", "publisher": "Nature Publishing Group", "publication": "Nature Reviews. Molecular Cell Biology", "publication_date": "2008-09", "series_number": "9", "volume": "9", "issue": "9", "pages": "670-671" }, { "id": "authors:z74qn-63t28", "collection": "authors", "collection_id": "z74qn-63t28", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ZIEhgt08", "type": "article", "title": "Targeting lentiviral vectors to antigen-specific immunoglobulins", "author": [ { "family_name": "Ziegler", "given_name": "Leslie", "clpid": "Ziegler-Leslie" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Joo", "given_name": "Kye il", "clpid": "Joo-Kye-il" }, { "family_name": "Yang", "given_name": "Haiguang", "clpid": "Yang-Haiguang" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" } ], "abstract": "Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell Populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient rnethod to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and hi vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral Surface. This engineered vector could specifically bind to cells expressing Surface immunoglobulin recognizing CD20 (\u03b1CD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing \u03b1CD20. These results show the feasibility of engineering lentivectors to target immunoglobulin-specific cells to deliver a therapeutic effect. Such targeting lentivectors also Could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology.", "doi": "10.1089/hum.2007.149", "pmcid": "PMC2599792", "issn": "1043-0342", "publisher": "Mary Ann Liebert", "publication": "Human Gene Therapy", "publication_date": "2008-09", "series_number": "9", "volume": "19", "issue": "9", "pages": "861-872" }, { "id": "authors:8rt1g-8pn76", "collection": "authors", "collection_id": "8rt1g-8pn76", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200421-065944620", "type": "article", "title": "Encoding NF-\u03baB temporal control in response to TNF: distinct roles for the negative regulators I\u03baB\u03b1 and A20", "author": [ { "family_name": "Werner", "given_name": "Shannon L.", "clpid": "Werner-S-L" }, { "family_name": "Kearns", "given_name": "Jeffrey D.", "clpid": "Kearns-J-D" }, { "family_name": "Zadorozhnaya", "given_name": "Victoria", "clpid": "Zadorozhnaya-V" }, { "family_name": "Lynch", "given_name": "Candace", "clpid": "Lynch-Candace" }, { "family_name": "O'Dea", "given_name": "Ellen", "clpid": "O'Dea-E" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Ma", "given_name": "Averil", "clpid": "Ma-Averil" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" } ], "abstract": "TNF-induced NF-\u03baB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps\u2014one determined by the obligate negative feedback regulator I\u03baB\u03b1\u2014that define the duration of the first phase of NF-\u03baB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of i\u03bab\u03b1 and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.", "doi": "10.1101/gad.1680708", "pmcid": "PMC2492747", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "2008-08-01", "series_number": "15", "volume": "22", "issue": "15", "pages": "2093-2101" }, { "id": "authors:2z1sj-46g37", "collection": "authors", "collection_id": "2z1sj-46g37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142716682", "type": "article", "title": "MicroRNAs: new regulators of immune cell development and function", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" } ], "abstract": "Decades of research went into understanding immune cell development and function without awareness that consideration of a key element, microRNA (miRNA), was lacking. The discovery of miRNAs as regulators of developmental events in model organisms suggested to many investigators that miRNA might be involved in the immune system. In the past few years, widespread examination of this possibility has produced notable results. Results have shown that miRNAs affect mammalian immune cell differentiation, the outcome of immune responses to infection and the development of diseases of immunological origin. Some miRNAs repress expression of target proteins with well established functions in hematopoiesis. Here we bring together much of this work, which has so far only scratched the surface of this very fertile field of investigation, and show how the results illuminate many historic questions about hematopoiesis and immune function.", "doi": "10.1038/ni.f.209", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2008-08", "series_number": "8", "volume": "9", "issue": "8", "pages": "839-845" }, { "id": "authors:gfmjh-xfj65", "collection": "authors", "collection_id": "gfmjh-xfj65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142716754", "type": "article", "title": "CD4\u207aCD25\u207b T Cells Transduced to Express MHC Class I-Restricted Epitope-Specific TCR Synthesize Th1 Cytokines and Exhibit MHC Class I-Restricted Cytolytic Effector Function in a Human Melanoma Model", "author": [ { "family_name": "Chhabra", "given_name": "Arvind", "clpid": "Chhabra-A" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" }, { "family_name": "Comin-Anduix", "given_name": "Bego\u00f1a", "clpid": "Comin-Anduix-Bego\u00f1a" }, { "family_name": "Das", "given_name": "Raja", "clpid": "Das-Raja" }, { "family_name": "Chakraborty", "given_name": "Nitya G.", "clpid": "Chakraborty-Nitya-G" }, { "family_name": "Ray", "given_name": "Swagatam", "clpid": "Ray-Swagatam" }, { "family_name": "Mehrotra", "given_name": "Shikhar", "clpid": "Mehrotra-Shikhar" }, { "family_name": "Yang", "given_name": "Haiguang", "clpid": "Yang-Haiguang" }, { "family_name": "Hardee", "given_name": "Cinnamon L.", "clpid": "Hardee-Cinnamon-L" }, { "family_name": "Hollis", "given_name": "Roger", "clpid": "Hollis-Roger" }, { "family_name": "Dorsky", "given_name": "David I.", "clpid": "Dorsky-D-I" }, { "family_name": "Koya", "given_name": "Richard", "clpid": "Koya-R-C" }, { "family_name": "Kohn", "given_name": "Donald B.", "clpid": "Kohn-Donald-B" }, { "family_name": "Ribas", "given_name": "Antoni", "clpid": "Ribas-Antoni" }, { "family_name": "Economou", "given_name": "James S.", "clpid": "Economou-James-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Mukherji", "given_name": "Bijay", "clpid": "Mukherji-Bijay" } ], "abstract": "Cytolytic T cell-centric active specific and adoptive immunotherapeutic approaches might benefit from the simultaneous engagement of CD4\u207a T cells. Considering the difficulties in simultaneously engagingCD4\u207a and CD8\u207a T cells in tumor immunotherapy, especially in an Ag-specific manner, redirecting CD4\u207a T cells to MHC class I-restricted epitopes through engineered expression of MHC class I-restricted epitope-specific TCRs in CD4\u207a T cells has emerged as a strategic consideration. Such TCR-engineered CD4\u207a T cells have been shown to be capable of synthesizing cytokines as well as lysing target cells. We have conducted a critical examination of functional characteristics of CD4\u207a T cells engineered to express the \u03b1- and \u03b2-chains of a high functional avidity TCR specific for the melanoma epitope, MART-1, as a prototypic human tumor Ag system. We found that unpolarized CD4\u207aCD25\u207b T cells engineered to express the MART-1 TCR selectively synthesize Th1 cytokines and exhibit a potent Ag-specific lytic granule exocytosis-mediated cytolytic effector function of comparable efficacy to that of CD8\u207a CTL. Such TCR engineered CD4\u207a T cells, therefore, might be useful in clinical immunotherapy.", "doi": "10.4049/jimmunol.181.2.1063", "pmcid": "PMC2715965", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2008-07-15", "series_number": "2", "volume": "181", "issue": "2", "pages": "1063-1070" }, { "id": "authors:vpkns-ktz50", "collection": "authors", "collection_id": "vpkns-ktz50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:OCOjem08", "type": "article", "title": "Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Rao", "given_name": "Dinesh S.", "orcid": "0000-0002-0794-9337", "clpid": "Rao-Dinesh-S" }, { "family_name": "Chaudhuri", "given_name": "Aadel A.", "clpid": "Chaudhuri-Aadel-A" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Nicoll", "given_name": "John", "clpid": "Nicoll-John" }, { "family_name": "Paquette", "given_name": "Ronald L.", "clpid": "Paquette-Ronald-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficiency of miR-155 to drive GM expansion, enforced expression in mouse bone marrow cells caused GM proliferation in a manner reminiscent of LPS treatment. However, the miR-155\u2013induced GM populations displayed pathological features characteristic of myeloid neoplasia. Of possible relevance to human disease, miR-155 was found to be overexpressed in the bone marrow of patients with certain subtypes of acute myeloid leukemia (AML). Furthermore, miR-155 repressed a subset of genes implicated in hematopoietic development and disease. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress.", "doi": "10.1084/jem.20072108", "pmcid": "PMC2275382", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2008-03-17", "series_number": "3", "volume": "205", "issue": "3", "pages": "585-594" }, { "id": "authors:qqf96-xc645", "collection": "authors", "collection_id": "qqf96-xc645", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142716949", "type": "article", "title": "Engineered lentivector targeting of dendritic cells for in vivo immunization", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Yang", "given_name": "Haiguang", "clpid": "Yang-Haiguang" }, { "family_name": "Rideout", "given_name": "Kendra", "clpid": "Rideout-K" }, { "family_name": "Cho", "given_name": "Taehoon", "clpid": "Cho-Taehoon" }, { "family_name": "Joo", "given_name": "Kye il", "clpid": "Joo-Kye-il" }, { "family_name": "Ziegler", "given_name": "Leslie", "clpid": "Ziegler-Leslie" }, { "family_name": "Elliott", "given_name": "Abigail", "clpid": "Elliott-A" }, { "family_name": "Walls", "given_name": "Anthony", "clpid": "Walls-Anthony" }, { "family_name": "Yu", "given_name": "Dongzi", "clpid": "Yu-Dongzi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" } ], "abstract": "We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell\u2013surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN\u2013specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens.", "doi": "10.1038/nbt1390", "pmcid": "PMC2366162", "issn": "1087-0156", "publisher": "Nature Publishing Group", "publication": "Nature Biotechnology", "publication_date": "2008-03", "series_number": "3", "volume": "26", "issue": "3", "pages": "326-334" }, { "id": "authors:vpxr8-1xr41", "collection": "authors", "collection_id": "vpxr8-1xr41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-072046193", "type": "article", "title": "The V(D)J Recombination Activating Gene, RAG-1", "author": [ { "family_name": "Schatz", "given_name": "David G.", "clpid": "Schatz-David-G" }, { "family_name": "Oettinger", "given_name": "Marjorie A.", "clpid": "Oettinger-M-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The RAG-1 (recombination activating gene-1) genomic locus, which activates V(D)J recombination when introduced into NIH 3T3 fibroblasts, was isolated by serial genomic transfections of oligonucleotide-tagged DNA. A genomic walk spanning 55 kb yielded a RAG-1 genomic probe that detects a single 6.6\u20137.0 kb mRNA species in transfectants and pre-B and pre-T cells. RAG-1 genomic and cDNA clones were biologically active when introduced into NIH 3T3 cells. Nucleotide sequencing of human and mouse RAG-1 cDNA clones predicts 119 kd proteins of 1043 and 1040 amino acids, respectively, with 90% sequence identity. RAG-1 has been conserved between species that carry out V(D)J recombination, and its pattern of expression correlates exactly with the pattern of expression of V(D)J recombinase activity. RAG-1 may activate V(D)J recombination indirectly, or it may encode the V(D)J recombinase itself.", "doi": "10.1016/0092-8674(89)90760-5", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2008-01-01", "series_number": "1", "volume": "180", "issue": "1", "pages": "5-18" }, { "id": "authors:zpjk0-8bg92", "collection": "authors", "collection_id": "zpjk0-8bg92", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ANDpnas07", "type": "article", "title": "Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates", "author": [ { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Donahue", "given_name": "Robert E.", "clpid": "Donahue-Robert-E" }, { "family_name": "Kamata", "given_name": "Masakazu", "clpid": "Kamata-Masakazu" }, { "family_name": "Poon", "given_name": "Betty", "clpid": "Poon-Betty" }, { "family_name": "Metzger", "given_name": "Mark", "clpid": "Metzger-Mark" }, { "family_name": "Mao", "given_name": "Si-Hua", "clpid": "Mao-Si-Hua" }, { "family_name": "Bonifadno", "given_name": "Aylin", "clpid": "Bonifadno-Aylin" }, { "family_name": "Krouse", "given_name": "Allen E.", "clpid": "Krouse-Allen-E" }, { "family_name": "Darlix", "given_name": "Jean-Luc", "clpid": "Darlix-Jean-Luc" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Qin", "given_name": "F. Xiao-Feng", "clpid": "Qin-F-Xiao-Feng" }, { "family_name": "Chen", "given_name": "Irvin S. Y.", "clpid": "Chen-Irvin-S-Y" } ], "abstract": "RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.", "doi": "10.1073/pnas.0705474104", "pmcid": "PMC1941789", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2007-08-07", "series_number": "32", "volume": "104", "issue": "32", "pages": "13110-13115" }, { "id": "authors:vet8g-aqs68", "collection": "authors", "collection_id": "vet8g-aqs68", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142717402", "type": "article", "title": "MicroRNAs and Immunity: Tiny Players in a Big Field", "author": [ { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "MicroRNAs (miRNAs) are found in most metazoan organisms as well as in viruses and are implicated in an increasingly wide variety of biological processes in animals. Here, Taganov et al. discuss the role of miRNAs in the innate immune response to microbial infection.", "doi": "10.1016/j.immuni.2007.02.005", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "2007-02-23", "series_number": "2", "volume": "26", "issue": "2", "pages": "133-137" }, { "id": "authors:69ztm-e2f26", "collection": "authors", "collection_id": "69ztm-e2f26", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:OCOpnas07", "type": "article", "title": "MicroRNA-155 is induced during the macrophage inflammatory response", "author": [ { "family_name": "O'Connell", "given_name": "Ryan M.", "clpid": "O'Connell-Ryan-M" }, { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The mammalian inflammatory response to infection involves the induction of several hundred genes, a process that must be carefully regulated to achieve pathogen clearance and prevent the consequences of unregulated expression, such as cancer. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators that has also been linked to cancer. However, the relationship between inflammation, innate immunity, and miRNA expression is just beginning to be explored. In the present study, we use microarray technology to identify miRNAs induced in primary murine macrophages after exposure to polyriboinosinic:polyribocytidylic acid or the cytokine IFN-{beta}. miR-155 was the only miRNA of those tested that was substantially up-regulated by both stimuli. It also was induced by several Toll-like receptor ligands through myeloid differentiation factor 88- or TRIF-dependent pathways, whereas up-regulation by IFNs was shown to involve TNF-{alpha} autocrine signaling. Pharmacological inhibition of the kinase JNK blocked induction of miR-155 in response to either polyriboinosinic:polyribocytidylic acid or TNF-{alpha}, suggesting that miR-155-inducing signals use the JNK pathway. Together, these findings characterize miR-155 as a common target of a broad range of inflammatory mediators. Importantly, because miR-155 is known to function as an oncogene, these observations identify a potential link between inflammation and cancer.", "doi": "10.1073/pnas.0610731104", "pmcid": "PMC1780072", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2007-01-30", "series_number": "5", "volume": "105", "issue": "5", "pages": "1604-1609" }, { "id": "authors:dgp34-gz556", "collection": "authors", "collection_id": "dgp34-gz556", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-073832282", "type": "article", "title": "Multiple Nuclear Factors Interact with the Immunoglobulin Enhancer Sequences", "author": [ { "family_name": "Sen", "given_name": "Ranjan", "clpid": "Sen-Ranjan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To characterize proteins that bind to the immunoglobulin (Ig) heavy chain and the \u03ba light chain enhancers, an electrophoretic mobility shift assay with end-labeled DNA fragments was used. Three binding proteins have been found. One is NF-A, a factor found in all tested cell types that binds to the octamer sequence found upstream of all Ig variable region gene segments and to the same octamer in the heavy chain enhancer. The second, also ubiquitous, protein binds to a sequence in both the heavy chain and the \u03ba enhancers that was previously shown to be protected from methylation in vivo. Other closely related sites do not compete for this binding, implying a restriction enzyme-like binding specificity. The third protein binds to a sequence in the \u03ba enhancer (and to an identical sequence in the SV40 enhancer) and is restricted in its occurrence to B cells.", "doi": "10.1016/0092-8674(86)90346-6", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2006-12-01", "series_number": "11", "volume": "177", "issue": "11", "pages": "7485-7496" }, { "id": "authors:3qfmp-f2w12", "collection": "authors", "collection_id": "3qfmp-f2w12", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142717499", "type": "article", "title": "Optimization and Functional Effects of Stable Short Hairpin RNA Expression in Primary Human Lymphocytes via Lentiviral Vectors", "author": [ { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Qin", "given_name": "F. Xiao-Feng", "clpid": "Qin-F-Xiao-Feng" }, { "family_name": "Auyeung", "given_name": "Vincent C.", "orcid": "0000-0001-6273-1595", "clpid": "Auyeung-Vincent-C" }, { "family_name": "Mao", "given_name": "Si Hua", "clpid": "Mao-Si-Hua" }, { "family_name": "Kung", "given_name": "Sam K. P.", "clpid": "Kung-Sam-K-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Chen", "given_name": "Irvin S. Y.", "clpid": "Chen-Irvin-S-Y" } ], "abstract": "Specific, potent, and sustained short hairpin RNA (shRNA)-mediated gene silencing is crucial for the successful application of RNA interference technology to therapeutic interventions. We examined the effects of shRNA expression in primary human lymphocytes (PBLs) using lentiviral vectors bearing different RNA polymerase III promoters. We found that the U6 promoter is more efficient than the H1 promoter for shRNA expression and for reducing expression of CCR5 in PBLs. However, shRNA expression from the U6 promoter resulted in a gradual decline of the transduced cell populations. With one CCR5 shRNA this decline could be attributed to elevated apoptosis but another CCR5 shRNA that caused cytotoxicity did not show evidence of apoptosis, suggesting sequence-specific mechanisms for cytotoxicity. In contrast to the U6 promoter, PBLs transduced by vectors expressing shRNAs from the H1 promoter could be maintained without major cytotoxic effects. Since a lower level of shRNA expression appears to be advantageous to maintaining the shRNA-transduced population, lentiviral vectors bearing the H1 promoter are more suitable for stable transduction and expression of shRNA in primary human T lymphocytes. Our results suggest that functional shRNA screens should include tests for both potency and adverse metabolic effects upon primary cells.", "doi": "10.1016/j.ymthe.2006.05.015", "pmcid": "PMC2562632", "issn": "1525-0016", "publisher": "American Society of Gene & Cell Therapy", "publication": "Molecular Therapy", "publication_date": "2006-10", "series_number": "4", "volume": "14", "issue": "4", "pages": "494-504" }, { "id": "authors:qphtd-ve766", "collection": "authors", "collection_id": "qphtd-ve766", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:TAGpnas06", "type": "article", "title": "NF-{kappa}B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses", "author": [ { "family_name": "Taganov", "given_name": "Konstantin D.", "clpid": "Taganov-Konstantin-D" }, { "family_name": "Boldin", "given_name": "Mark P.", "orcid": "0000-0003-4593-0669", "clpid": "Boldin-M-P" }, { "family_name": "Chang", "given_name": "Kuang-Jung", "clpid": "Chang-Kuang-Jung" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-{kappa}B-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3' UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.", "doi": "10.1073/pnas.0605298103", "pmcid": "PMC1567904", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2006-08-15", "series_number": "33", "volume": "103", "issue": "33", "pages": "12481-12486" }, { "id": "authors:tme6h-6ht98", "collection": "authors", "collection_id": "tme6h-6ht98", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:YANpnas06", "type": "article", "title": "Targeting lentiviral vectors to specific cell types in vivo", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Bailey", "given_name": "Leslie", "clpid": "Bailey-Lesie" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wang", "given_name": "Pin", "clpid": "Wang-Pin" } ], "abstract": "We have developed an efficient method to target lentivirus-mediated gene transduction to a desired cell type. It involves incorporation of antibody and fusogenic protein as two distinct molecules into the lentiviral surface. The fusogen is constructed by modifying viral envelope proteins, so that they lack the ability to bind to their cognate receptor but still retain the ability to trigger pH-dependent membrane fusion. Thus, the specificity of such a lentiviral vector is solely determined by the antibody, which is chosen to recognize a specific surface antigen of the desired cell type. This specific binding then induces endocytosis of the surface antigen, bringing the lentivirus into an endosome. There, the fusogen responds to the low pH environment and mediates membrane fusion, allowing the virus core to enter the cytosol. Using CD20 as a target antigen for human B cells, we have demonstrated that this targeting strategy is effective both in vitro and in intact animals. This methodology is flexible and can be extended to other forms of cell type-specific recognition to mediate targeting. The only requirement is that the antibody (or other binding protein) must be endocytosed after interaction with its cell surface-binding determinant.", "doi": "10.1073/pnas.0604993103", "pmcid": "PMC1518805", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2006-08-01", "series_number": "31", "volume": "103", "issue": "31", "pages": "11479-11484" }, { "id": "authors:0jhr3-m1g02", "collection": "authors", "collection_id": "0jhr3-m1g02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HOFir06", "type": "article", "title": "Circuitry of nuclear factor \u03baB signaling", "author": [ { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Over the past few years, the transcription factor nuclear factor (NF)-\u03baB and the proteins that regulate it have emerged as a signaling system of pre-eminent importance in human physiology and in an increasing number of pathologies. While NF-\u03baB is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B-cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF-\u03baB's functioning in the immune system. NF-\u03baB has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF-\u03baB is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll-like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF-\u03baB in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type-specific and stimulus-specific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF-\u03baB functionalities involves system-wide measurements, biophysical studies, and computational modeling.", "doi": "10.1111/j.0105-2896.2006.00375.x", "issn": "0105-2896", "publisher": "Wiley", "publication": "Immunological Reviews", "publication_date": "2006-04", "series_number": "1", "volume": "210", "issue": "1", "pages": "171-186" }, { "id": "authors:r294h-m3198", "collection": "authors", "collection_id": "r294h-m3198", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-075734432", "type": "article", "title": "Science For Life: A Conversation With Nobel Laureate David Baltimore", "author": [ { "family_name": "Culliton", "given_name": "Barbara J.", "clpid": "Culliton-B-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "As a man with equal interests in science and science policy, David Baltimore has been at the forefront of many of the important debates that have shaped science since the 1970s. Very much engaged in the initial discussions about the use of recombinant DNA technology, Baltimore had a front-row seat as the biotechnology industry developed. He was also a major player in the decision that resulted in funding of the Human Genome Project by the National Institutes of Health (NIH). Baltimore discusses biotechnology, science education, and the need for a strong dialogue among scientists and scholars in the health policy community.", "doi": "10.1377/hlthaff.25.w235", "issn": "0278-2715", "publisher": "Health Affairs", "publication": "Health Affairs", "publication_date": "2006-01", "series_number": "S1", "volume": "25", "issue": "S1", "pages": "W235-W240" }, { "id": "authors:8w0gq-h9g19", "collection": "authors", "collection_id": "8w0gq-h9g19", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141117-143614166", "type": "article", "title": "Achieving Stability of Lipopolysaccharide-Induced NF-\u03baB Activation", "author": [ { "family_name": "Covert", "given_name": "Markus W.", "clpid": "Covert-Markus-W" }, { "family_name": "Leung", "given_name": "Thomas H.", "clpid": "Leung-Thomas-H" }, { "family_name": "Gaston", "given_name": "Jahlionais E.", "clpid": "Gaston-Jahlionais-E" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The activation dynamics of the transcription factor NF-\u03baB exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor\u2013\u03b1 (TNF\u03b1) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-\u03baB that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early anti-phase activation of NF-\u03baB by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3\u2013dependent expression of TNF\u03b1 to activate NF-\u03baB, and the time required for TNF\u03b1 synthesis established the delay.", "doi": "10.1126/science.1112304", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2005-09-16", "series_number": "5742", "volume": "309", "issue": "5742", "pages": "1854-1857" }, { "id": "authors:pqpdg-e0h94", "collection": "authors", "collection_id": "pqpdg-e0h94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-081208273", "type": "article", "title": "An interview with David Baltimore", "author": [ { "family_name": "Glorioso", "given_name": "J.", "clpid": "Glorioso-J" }, { "family_name": "Jacoby", "given_name": "J.", "clpid": "Jacoby-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "President of Caltech since 1997, Professor David Baltimore is best known for his Nobel Prize winning discovery of reverse transcriptase and the mechanisms that retroviruses use to infect cells. His work has greatly contributed to the understanding of cancer and AIDS, and his commitment to public policy has earned him numerous awards, including a 1999 National Medal of Science. He kindly agreed to talk to Gene Therapy.", "doi": "10.1038/sj.gt.3302526", "issn": "0969-7128", "publisher": "Nature Publishing Group", "publication": "Gene Therapy", "publication_date": "2005-09-01", "series_number": "17", "volume": "12", "issue": "17", "pages": "1291-1293" }, { "id": "authors:20d9e-r5b24", "collection": "authors", "collection_id": "20d9e-r5b24", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:YANpnas05", "type": "article", "title": "Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A method to genetically program mouse hematopoietic stem cells to develop into functional CD8 or CD4 T cells of defined specificity in vivo is described. For this purpose, a bicistronic retroviral vector was engineered that efficiently delivers genes for both [alpha] and [beta] chains of T cell receptor (TCR) to hematopoietic stem cells. When modified cell populations were used to reconstruct the hematopoietic lineages of recipient mice, significant percentages of antigen-specific CD8 or CD4 T cells were observed. These cells expressed normal surface markers and responded to peptide antigen stimulation by proliferation and cytokine production. Moreover, they could mature into memory cells after peptide stimulation. Using TCRs specific for a model tumor antigen, we found that the recipient mice were able to partially resist a challenge with tumor cells carrying the antigen. By combining cells modified with CD8- and CD4-specific TCRs, and boosting with dendritic cells pulsed with cognate peptides, complete suppression of tumor could be achieved and even tumors that had become established would regress and be eliminated after dendritic cell/peptide immunization. This methodology of ''instructive immunotherapy'' could be developed for controlling the growth of human tumors and attacking established pathogens.", "doi": "10.1073/pnas.0500600102", "pmcid": "PMC553287", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2005-03-22", "series_number": "12", "volume": "102", "issue": "12", "pages": "4518-4523" }, { "id": "authors:azw3c-3wd49", "collection": "authors", "collection_id": "azw3c-3wd49", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-103522723", "type": "article", "title": "Physiological functions for brain NF-\u03baB", "author": [ { "family_name": "Meffert", "given_name": "Mollie K.", "clpid": "Meffert-M-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Members of the nuclear factor \u03baB (NF-\u03baB) family of transcription factors are activated within the CNS in pathological settings of apoptosis and neurological disease. Recent work using several model systems provides accumulating evidence that these transcription factors also participate in the regulation of neuronal activity-dependent transcription and behavior under physiological conditions. This review highlights advances in our understanding of the mechanisms of Ca\u00b2\u207a-responsive activation and synaptic signaling to the nucleus by NF-\u03baB transcription factors within the CNS, and the relevance of this transcription factor family for learning and memory.", "doi": "10.1016/j.tins.2004.11.002", "issn": "0166-2236", "publisher": "Elsevier", "publication": "Trends in Neurosciences", "publication_date": "2005-01", "series_number": "1", "volume": "28", "issue": "1", "pages": "37-43" }, { "id": "authors:e5gqc-gwk05", "collection": "authors", "collection_id": "e5gqc-gwk05", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150327-132120615", "type": "article", "title": "New Year's wishes: All I want for 2005 is...", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Students, scholars and at least one Nobel prizewinner have had trouble getting into the United States this year, thanks to immigration rules that have grown ever tighter since the terrorist attacks of 11 September 2001. Zhores Alferov, who won the 2000 Nobel Prize in Physics for his work on semiconductors, stormed out of the US consulate in St Petersburg, Russia, this September without his visa after being grilled about the nature of his work.", "doi": "10.1038/432942a", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2004-12-23", "series_number": "7020", "volume": "432", "issue": "7020", "pages": "942" }, { "id": "authors:574m0-1d637", "collection": "authors", "collection_id": "574m0-1d637", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150958391", "type": "article", "title": "Mammalian Ryk Is a Wnt Coreceptor Required for Stimulation of Neurite Outgrowth", "author": [ { "family_name": "Lu", "given_name": "Wange", "clpid": "Lu-Wange" }, { "family_name": "Yamamoto", "given_name": "Vicky", "clpid": "Yamamoto-Vicky" }, { "family_name": "Ortega", "given_name": "Blanca", "clpid": "Ortega-Blanca" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Ryk receptor belongs to the atypical receptor tyrosine kinase family. It is a new member of the family of Wnt receptor proteins. However, the molecular mechanisms by which the Ryk receptor functions remain unknown. Here, we report that mammalian Ryk, unlike the Drosophila Ryk homolog Derailed, functions as a coreceptor along with Frizzled for Wnt ligands. Ryk also binds to Dishevelled, through which it activates the canonical Wnt pathway, providing a link between Wnt and Dishevelled. Transgenic mice expressing Ryk siRNA exhibit defects in axon guidance, and Ryk is required for neurite outgrowth induced by Wnt-3a and in the activation of T cell factor (TCF) induced by Wnt-1. Thus, Ryk appears to play a crucial role in Wnt-mediated signaling.", "doi": "10.1016/j.cell.2004.09.019", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2004-10-01", "series_number": "1", "volume": "119", "issue": "1", "pages": "97-108" }, { "id": "authors:yqhgb-1zg10", "collection": "authors", "collection_id": "yqhgb-1zg10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142718028", "type": "article", "title": "One Nucleotide in a \u03baB Site Can Determine Cofactor Specificity for NF-\u03baB Dimers", "author": [ { "family_name": "Leung", "given_name": "Thomas H.", "clpid": "Leung-Thomas-H" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The transcription factor NF-\u03baB regulates a wide variety of genes involved in multiple processes. Although the apparent consensus sequence of DNA binding sites for NF-\u03baB (\u03baB sites) is very broad, the sites active in any one gene show remarkable evolutionary stability. Using a lentivirus-based methodology for implantation of gene regulatory sequences we show that for genes with two \u03baB sites, both are required for activity. Swapping sites between \u03baB-dependent genes altered NF-\u03baB dimer specificity of the promoters and revealed that two \u03baB sites can function together as a module to regulate gene activation. Further, although the sequence of the \u03baB site is important for determining \u03baB family member specificity, rather than determining the ability of a particular dimer to bind effectively, the sequence affects which coactivators will form productive interactions with the bound NF-\u03baB dimer. This suggests that binding sites may impart a specific configuration to bound transcription factors.", "doi": "10.1016/j.cell.2004.08.007", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2004-08-20", "series_number": "4", "volume": "118", "issue": "4", "pages": "453-464" }, { "id": "authors:24dc7-g2y44", "collection": "authors", "collection_id": "24dc7-g2y44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ZARpnas04", "type": "article", "title": "Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappa B activation pathways", "author": [ { "family_name": "Zarnegar", "given_name": "Brian", "clpid": "Zarnegar-Brian" }, { "family_name": "He", "given_name": "Jeannie Q.", "clpid": "He-Jeannie-Q" }, { "family_name": "Oganesyan", "given_name": "Gagik", "clpid": "Oganesyan-Gagik" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" } ], "abstract": "B lymphocytes can be activated by many different stimuli. However, the mechanisms responsible for the signaling and functional specificities of individual stimuli remain to be elucidated. Here, we have compared the contribution of the type 1 (p50-dependent) and type 2 (p52-dependent) NF-kappaB activation pathways to cell survival, proliferation, homotypic aggregation, and specific gene regulation of murine primary B lymphocytes. Whereas lipopolysaccharide (LPS) and B cell activation factor (BAFF) mainly activate the type 1 or type 2 pathways, respectively, CD40 ligand (CD40L) strongly activates both. Rescue of spontaneous apoptosis is diminished in p52(-/-) B cells after BAFF stimulation and in p50(-/-)c-Rel(-/-) B cells after LPS stimulation. Interestingly, significant CD40-induced B cell survival is still observed even in p50(-/-)c-Rel(-/-)p65(-/+) B cells, which is correlated with the ability of CD40L to up-regulate Bcl-x(L) expression in these cells. CD40L- and LPS-induced B cell proliferation, as well as up-regulation of proliferation-related genes, however, are greatly reduced in c-Rel(-/-) and p50(-/-)c-Rel(-/-) B cells but are normal in p52(-/-) B cells. We have further demonstrated that both c-Rel and p52 are required for CD40-mediated B cell homotypic aggregation, which explains well why neither LPS nor BAFF has this function. Overall, our studies suggest that both type 1 and type 2 NF-kappaB pathways contribute to the gene expression and biological program unique for CD40 in B cell activation.", "doi": "10.1073/pnas.0402629101", "pmcid": "PMC419565", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2004-05-25", "series_number": "21", "volume": "101", "issue": "21", "pages": "8108-8113" }, { "id": "authors:rmzng-sm596", "collection": "authors", "collection_id": "rmzng-sm596", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150826-100830598", "type": "article", "title": "The Sudden Death of a Coral Reef - Response", "author": [ { "family_name": "Klausner", "given_name": "Richard D.", "clpid": "Klausner-Richard-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "As articulated in our policy forum and\nby Zinkernagel, the development of an HIV\nvaccine is one of the most complex scientific\nchallenges that modern biomedical research is\nconfronting. However, it is exactly because\nthis effort will be so difficult, and because we\nrecognize that there are few blueprints for how\nto go about creating successful vaccines for\norganisms that have the characteristics that\nZinkernagel describes, that we have proposed\na more interactive systematic scientific\napproach organized to best support the\nscience, both preclinical and clinical, required\nto make progress through experimentation.\nWe strongly believe that basic scientific\nresearch should be conducted in coordination\nwith well-planned clinical trials, in an iterative\nprocess that leads to incremental increase in\nknowledge and, eventually, to a safe and effective\nHIV vaccine. We do not believe that\n\"hygienic measures, sufficient nutrition,\nchemotherapeutic agents \u2026 and serious \u2026\nepidemiological surveys and prevention\nprograms\" alone will stop the HIV pandemic,\nespecially in the poorest countries of the\nworld, where 95% of all HIV infections are\noccurring. An HIV vaccine would be a\npowerful complement to these interventions\nand is essential to worldwide control of the\npandemic. We, therefore, feel responsible to\nharness the power of science to accelerate its\ndevelopment.", "doi": "10.1126/science.303.5662.1293b", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2004-02-27", "series_number": "5662", "volume": "303", "issue": "5662", "pages": "1296-1297" }, { "id": "authors:08krc-3p336", "collection": "authors", "collection_id": "08krc-3p336", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142718122", "type": "article", "title": "Uncovering the V(D)J recombinase", "author": [ { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "As any good high school student can tell you, normal developmental processes give rise to individuals in which each cell contains an identical copy of the genome present in the original, fertilized egg. This comfortable image of a static and inviolate genetic blueprint was shattered in the late 1970s, however, when Susumu Tonegawa and colleagues showed that the genes that encode immunoglobulin heavy and light chains have a different structure in embryonic cells from that found in tumors derived from B cells (see accompanying Commentary by Tonegawa, 2004). Over the next decade, it would emerge that developing B lymphocytes assemble immunoglobulin genes from widely scattered gene segments, using a somatic DNA rearrangement process known as V(D)J recombination (Figure 1), and that developing T cells play the same trick to assemble functional T cell receptor genes.", "doi": "10.1016/s0092-8674(04)00042-x", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "2004-01-23", "series_number": "S2", "volume": "116", "issue": "S2", "pages": "S103-S108" }, { "id": "authors:fg59j-10k18", "collection": "authors", "collection_id": "fg59j-10k18", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142718187", "type": "article", "title": "Genetic analysis of NF-\u03baB/Rel transcription factors defines functional specificities", "author": [ { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Leung", "given_name": "Thomas H.", "clpid": "Leung-Thomas-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The NF\u2010\u03baB transcription factors consist of dimeric proteins of the Rel homology family. They activate many promoters containing highly divergent \u03baB\u2010site sequences. We have generated cell lines lacking individual and multiple NF\u2010\u03baB proteins and used them to establish interactions between components of the NF\u2010\u03baB\u2013I\u03baB signaling system. Functional compensation within the family of dimers was evident in knockout cell lines. Analysis of transiently transfected genes gave an impression of promiscuity that was not borne out by analysis of endogenous genes. Using TNF\u03b1 as an inducer, a panel of endogenous genes showed a wide range of subunit specificities as well as highly variable kinetics of induction. Comparing the function and subunit specificity of genes with the sequence of the \u03baB DNA\u2010binding site we found little correlation, indicating that NF\u2010\u03baB family member specificity for endogenous promoters is not solely encoded by the \u03baB site sequence itself.", "doi": "10.1093/emboj/cdg534", "pmcid": "PMC213788", "issn": "1460-2075", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "2003-10-15", "series_number": "20", "volume": "22", "issue": "20", "pages": "5530-5539" }, { "id": "authors:cmfqt-96955", "collection": "authors", "collection_id": "cmfqt-96955", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200417-142718273", "type": "article", "title": "Essential Role for STAT5 Signaling in CD25\u207aCD4\u207a Regulatory T Cell Homeostasis and the Maintenance of Self-Tolerance", "author": [ { "family_name": "Antov", "given_name": "Andrey", "clpid": "Antov-Andrey" }, { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Vig", "given_name": "Monika", "clpid": "Vig-Monika" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Van Parijs", "given_name": "Luk", "clpid": "Van-Parijs-Luk" } ], "abstract": "A population of CD25\u207aCD4\u207a regulatory T cells (T regs) functions to maintain immunological self tolerance by inhibiting autoreactive T cell responses. CD25\u207aCD4\u207a T regs are present in low, but steady, numbers in the peripheral lymphoid tissues of healthy mice. Recent studies have shown that IL-2 is an essential growth factor for these cells. How this cytokine functions to regulate CD25\u207aCD4\u207a T reg homeostasis and prevent autoimmune disease remains unknown. In conventional CD4\u207a T cells, IL-2 triggers signaling pathways that promote proliferation and survival by activating the STAT5 transcription factor and by increasing the expression of the antiapoptotic protein, Bcl-2. We show here that bcl-2 deficiency does not affect CD25\u207aCD4\u207a T reg homeostasis, and that ectopic expression of this molecule fails to rescue CD25\u207aCD4\u207a T reg numbers or to prevent the development of autoimmunity in IL-2-deficient mice. Furthermore, transient activation of STAT5 is sufficient to increase CD25\u207aCD4\u207a T reg numbers in IL-2-deficient mice. Our study uncovers an essential role for STAT5 in maintaining CD25\u207aCD4\u207a T reg homeostasis and self-tolerance.", "doi": "10.4049/jimmunol.171.7.3435", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2003-10-01", "series_number": "7", "volume": "171", "issue": "7", "pages": "3435-3441" }, { "id": "authors:ttc5q-c7385", "collection": "authors", "collection_id": "ttc5q-c7385", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150409-082723140", "type": "article", "title": "NF-kB functions in synaptic signaling and behavior", "author": [ { "family_name": "Meffert", "given_name": "Mollie K.", "clpid": "Meffert-Mollie-K" }, { "family_name": "Chang", "given_name": "Jolene M.", "clpid": "Chang-Jolene-M" }, { "family_name": "Wiltgen", "given_name": "Brian J.", "clpid": "Wiltgen-Brian-J" }, { "family_name": "Fanselow", "given_name": "Michael S.", "clpid": "Fanselow-Michael-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Ca^(2+)-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-kB transcription factor by a pathway requiring the Ca^(2+)/calmodulin-dependent kinase CaMKII and local submembranous Ca^(2+) elevation. The p65:p50 NF-kB form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-kB. Activated NF-kB moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-kB nuclear translocation and gene activation.", "doi": "10.1038/nn1110", "issn": "1097-6256", "publisher": "Nature Publishing Group", "publication": "Nature Neuroscience", "publication_date": "2003-10", "series_number": "10", "volume": "6", "issue": "10", "pages": "1072-1078" }, { "id": "authors:02a5r-rf688", "collection": "authors", "collection_id": "02a5r-rf688", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141112-100406843", "type": "article", "title": "Universities in the marketplace - The commercialization of higher education [Book Review]", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Most universities are nonprofit institutions\nand like to think that makes\nthem fundamentally different from\nprofit-making ventures. They are and they\naren't. Their goal is not maximizing a bottom\nline but rather serving the\npublic interest with education\nand research. But financially,\nthey need to at least break\neven, which generally requires\nthat they maximize their multiple\nsources of income. So\nthey are businesses, and when\nviewed financially, they often\nare hard to distinguish from\nprofit-making enterprises.", "doi": "10.1126/science.1087592", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2003-08-22", "series_number": "5636", "volume": "301", "issue": "5636", "pages": "1050-1051" }, { "id": "authors:bjpsh-z1175", "collection": "authors", "collection_id": "bjpsh-z1175", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141117-135530827", "type": "article", "title": "The need for a global HIV vaccine enterprise", "author": [ { "family_name": "Klausner", "given_name": "Richard D.", "clpid": "Klausner-R-D" }, { "family_name": "Fauci", "given_name": "Anthony S.", "clpid": "Fauci-A-S" }, { "family_name": "Corey", "given_name": "Lawrence", "clpid": "Corey-L" }, { "family_name": "Nabel", "given_name": "Gary J.", "clpid": "Nabel-G-J" }, { "family_name": "Gayle", "given_name": "Helene", "clpid": "Gayle-H" }, { "family_name": "Berkley", "given_name": "Seth", "clpid": "Berkley-S" }, { "family_name": "Haynes", "given_name": "Barton F.", "clpid": "Haynes-B-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Collins", "given_name": "Chris", "clpid": "Collins-C-A" }, { "family_name": "Douglas", "given_name": "R. Gordon", "clpid": "Douglas-R-G" }, { "family_name": "Esparza", "given_name": "Jose", "clpid": "Esparza-J" }, { "family_name": "Francis", "given_name": "Donald P.", "clpid": "Francis-D-P" }, { "family_name": "Ganguly", "given_name": "N. K.", "clpid": "Ganguly-N-K" }, { "family_name": "Gerberding", "given_name": "Julie Louise", "clpid": "Gerberding-J-L" }, { "family_name": "Johnston", "given_name": "Margaret I.", "clpid": "Johnston-M-I" }, { "family_name": "Kazatchkine", "given_name": "Michel D.", "clpid": "Kazatchkine-M-D" }, { "family_name": "McMichael", "given_name": "Andrew J.", "clpid": "McMichael-A-J" }, { "family_name": "Makgoba", "given_name": "Malegapuru W.", "clpid": "Makgoba-M-W" }, { "family_name": "Pantaleo", "given_name": "Giuseppe", "clpid": "Pantaleo-G" }, { "family_name": "Piot", "given_name": "Peter", "clpid": "Piot-P" }, { "family_name": "Shao", "given_name": "Yiming", "clpid": "Shao-Yiming" }, { "family_name": "Tramont", "given_name": "Edmund", "clpid": "Tramont-E" }, { "family_name": "Varmus", "given_name": "Harold", "clpid": "Varmus-Harold-E" }, { "family_name": "Wasserheit", "given_name": "Judith N.", "clpid": "Wasserheit-J-N" } ], "abstract": "A new collaborative model of research is needed to increase resources, to prioritize the R&D agenda of the major public- and private-sector stakeholders, and ultimately to increase the probability and shorten the time to development of effective HIV vaccines for global use. The thrust of our proposal is (i) to increase the scale and organization for solving science problems and developing novel HIV vaccine approaches; (ii) to increase the pace, reduce the overlap, and more systematically explore the elements of and delivery systems for vaccines; (iii) to use common standards for the prompt comparative testing of vaccine candidates; (iv) to expand resources for manufacturing vaccine candidates to speed their use in human trials; and (v) to increase the capacity for international clinical trials and to focus this effort toward quickly measuring the effectiveness of vaccine protection as prototype vaccine candidates are identified.", "doi": "10.1126/science.1086916", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2003-06-27", "series_number": "5628", "volume": "300", "issue": "5628", "pages": "2036-2039" }, { "id": "authors:89aj4-75428", "collection": "authors", "collection_id": "89aj4-75428", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141117-133924656", "type": "article", "title": "Chimeric nucleases stimulate gene targeting in human cells", "author": [ { "family_name": "Porteus", "given_name": "Matthew H.", "clpid": "Porteus-Matthew-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Correction of gene defects in human somatic cells by targeting as has been used in murine embryonic stem cells (1, 2) has been precluded by the low spontaneous rate of gene targeting (3). However, creation of a DNA double-stranded break (DSB) in the genomic target (DSB-GT) can stimulate homologous recombination by over 1000-fold (4). \n\nWe can rapidly and quantitatively measure gene targeting by correcting a mutation in a green fluorescent protein (GFP) gene that has been stably integrated into the genome (5) (fig. S1). With an optimized GFP gene targeting system, the introduction of a DSB by I\u2013Sce I (Sce) stimulated GT >40,000-fold and the absolute rate of gene targeting reached 3 to 5% (fig. S2). Such a system, however, depends on the prior introduction of a Sce binding site into the target gene and cannot be used for endogenous genes. Chimeric nucleases (CNs) have the potential to create sequence-specific DSBs (6). CNs\u2014fusions between zinc finger binding DNA binding domains and the endonuclease domain of Fok I\u2014can sitespecifically cleave naked DNA in vitro (6), extrachromosomal DNA in Xenopus oocytes (7), and chromosomal DNA in Drosophila (8). CNs work as dimers, and their efficiency depends on the spacing and orientation of the zinc finger binding sites with respect to the length of the amino acid linker between the DNA binding and endonuclease domains (7, 9). \n\nQQR is an artificial zinc finger DNA binding domain that recognizes the sequence 5\u2032-GGGGAAGAA-3\u2032 with nanomolar affinity (10). We modified QQR chimeric nucleases (QQR-CNs) (7, 9) (Fig. 1A) and tested whether they stimulated gene targeting (Fig. 1B). The background rate of gene targeting was 0.71 events per million transfected cells (fig. S1C). QQRL18-CN stimulated gene targeting 17-fold on target QQR6 and 260-fold on target QQR8 (Fig. 1B). QQRL0-CN did not stimulate gene targeting on target QQR8, but it was as efficient as Sce in stimulating gene targeting by over 2000-fold on target QQR6 (Fig. 1B). QQRL18-CN showed some preference for an 8\u2013base pair (bp) spacing between binding sites whereas QQRL0-CN preferred 6-bp spacing. Thus, removing the linker between the zinc spacfinger and the nuclease domains increased the activity and specificity of the fusion protein in mammalian cells. As controls, we showed that the CNs did not stimulate gene targeting if (i) they lacked a nuclear localization signal, (ii) there was a single binding site rather than an inverted repeat binding site in the target, and (iii) the cognate binding site was changed. Thus, homodimers of CNs are potent stimulators of gene targeting in human somatic cells.", "doi": "10.1126/science.1078395", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2003-05-02", "series_number": "5620", "volume": "300", "issue": "5620", "pages": "763" }, { "id": "authors:j38ae-gp777", "collection": "authors", "collection_id": "j38ae-gp777", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PORmcb03", "type": "article", "title": "Efficient Gene Targeting Mediated by Adeno-Associated Virus and DNA Double-Strand Breaks", "author": [ { "family_name": "Porteus", "given_name": "Matthew H.", "clpid": "Porteus-Matthew-H" }, { "family_name": "Cathomen", "given_name": "Toni", "clpid": "Cathomen-Toni" }, { "family_name": "Weitzman", "given_name": "Matthew D.", "clpid": "Weitzman-Matthew-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Gene targeting is the in situ manipulation of the sequence of an endogenous gene by the introduction of homologous exogenous DNA. Presently, the rate of gene targeting is too low for it to be broadly used in mammalian somatic cell genetics or to cure genetic diseases. Recently, it has been demonstrated that infection with recombinant adeno-associated virus (rAAV) vectors can mediate gene targeting in somatic cells, but the mechanism is unclear. This paper explores the balance between random integration and gene targeting with rAAV. Both random integration and spontaneous gene targeting are dependent on the multiplicity of infection (MOI) of rAAV. It has previously been shown that the introduction of a DNA double-stranded break (DSB) in a target gene can stimulate gene targeting by several-thousand-fold in somatic cells. Creation of a DSB stimulates the frequency of rAAV-mediated gene targeting by over 100-fold, suggesting that the mechanism of rAAV-mediated gene targeting involves, at least in part, the repair of DSBs by homologous recombination. Absolute gene targeting frequencies reach 0.8% with a dual vector system in which one rAAV vector provides a gene targeting substrate and a second vector expresses the nuclease that creates a DSB in the target gene. The frequencies of gene targeting that we achieved with relatively low MOIs suggest that combining rAAV vectors with DSBs is a promising strategy to broaden the application of gene targeting.", "doi": "10.1128/MCB.23.10.3558-3565.2003", "pmcid": "PMC164769", "issn": "1098-5549", "publisher": "American Society for Microbiology", "publication": "Molecular And Cellular Biology", "publication_date": "2003-05", "series_number": "10", "volume": "23", "issue": "10", "pages": "3558-3565" }, { "id": "authors:ewxvn-wen39", "collection": "authors", "collection_id": "ewxvn-wen39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-070705550", "type": "article", "title": "Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance", "author": [ { "family_name": "Brown", "given_name": "Eric J.", "clpid": "Brown-Eric-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A Cre/lox-conditional mouse line was generated to evaluate the role of ATR in checkpoint responses to ionizing radiation (IR) and stalled DNA replication. We demonstrate that after IR treatment, ATR and ATM each contribute to early delay in M-phase entry but that ATR regulates a majority of the late phase (2\u20139 h post-IR). Double deletion of ATR and ATM eliminates nearly all IR-induced delay, indicating that ATR and ATM cooperate in the IR-induced G2/M-phase checkpoint. In contrast to the IR-induced checkpoint, checkpoint delay in response to stalled DNA replication is intact in ATR knockout cells and ATR/ATM andATR/p53 double-knockout cells. The DNA replication checkpoint remains intact in ATR knockout cells even though the checkpoint-stimulated inhibitory phosphorylation of Cdc2 on T14/Y15 and activating phosphorylation of the Chk1 kinase no longer occur. Thus, incomplete DNA replication in mammalian cells can prevent M-phase entry independently of ATR and inhibitory phosphorylation of Cdc2. When DNA replication inhibitors are removed, ATR knockout cells proceed to mitosis but do so with chromosome breaks, indicating that ATR provides a key genome maintenance function in S phase.", "doi": "10.1101/gad.1067403", "pmcid": "PMC196009", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "2003-03-01", "series_number": "5", "volume": "17", "issue": "5", "pages": "615-628" }, { "id": "authors:sctze-w0r40", "collection": "authors", "collection_id": "sctze-w0r40", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:QINpnas03", "type": "article", "title": "Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5", "author": [ { "family_name": "Qin", "given_name": "Xiao-Feng", "clpid": "Qin-Xiao-Feng" }, { "family_name": "An", "given_name": "Dong Sung", "clpid": "An-Dong-Sung" }, { "family_name": "Chen", "given_name": "Irvin S. Y.", "clpid": "Chen-Irvin-S-Y" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Double-stranded RNAs approximate to 21 nucleotides long [small interfering RNA (siRNA)] are recognized as powerful reagents to reduce the expression of specific genes. To use them as reagents to protect cells against viral infection, effective methods for introducing siRNAs into primary cells are required. Here, we describe success in constructing a lentivirus-based vector to introduce siRNAs against the HIV-1 coreceptor, CCR5, into human peripheral blood T lymphocytes. With high-titer vector stocks, >40% of the peripheral blood T lymphocytes could be transduced, and the expression of a potent CCR5-siRNA resulted in up to 10-fold inhibition of CCR5 expression on the cell surface over a period of 2 weeks in the absence of selection. In contrast, the expression of another major HIV-1 coreceptor, CXCR4, was not affected. Importantly, blocking CCR5 expression by siRNAs provided a substantial protection for the lymphocyte populations from CCR5-tropic HIV-1 virus infection, dropping infected cells by 3- to 7-fold; only a minimal effect on infection by a CXCR4-tropic virus was observed. Thus, our studies demonstrate the feasibility and potential of lentiviral vector-mediated delivery of siRNAs as a general means of intracellular immunization for the treatment of HIV-1 and other viral diseases.", "doi": "10.1073/pnas.232688199", "pmcid": "PMC140921", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2003-01-07", "series_number": "1", "volume": "100", "issue": "1", "pages": "183-188" }, { "id": "authors:ztknc-mhk16", "collection": "authors", "collection_id": "ztknc-mhk16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141118-101943703", "type": "article", "title": "Chimeric nucleases stimulate gene targeting in human cells", "author": [ { "family_name": "Porteus", "given_name": "Matthew", "clpid": "Porteus-Matthew-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Gene targeting is a powerful technique to introduce genetic change into the genome of\neukaryotic cells. It is widely used to create defined mutations in murine embryonic stem\ncells and theoretically could be used to create or repair mutations in somatic cells. In this\nway gene targeting could be a powerful form of gene correction type gene therapy. Despite\nits potential, gene targeting has not been widely used in somatic cells because of its low\nefficiency. We report on a system based on the correction of a mutated GFP gene that allows\nthe efficient study of gene targeting in somatic cells. Using this system we show that gene\ntargeting is stimulated over 2000-fold by the introduction of a DNA double-stranded break\nin the target locus (DSB-GT). We find that the rate of DSB-GT can be increased by increasing\nthe amount of repair substrate, the amount of homology between the gene target and repair\nsubstrate, and by increasing the frequency of double-stranded break creation. When we\noptimize conditions for DSB-GT we obtain targeting rates of 3-5%. Finally, we show that\nchimeric nucleases, protein fusions between zinc finger DNA binding domains and the\nendonuclease domain of the Fokl restriction enzyme, can stimulate gene targeting in the\ngenome of human somatic cells by several-thousand fold. Our data provides a paradigm for\nthe use of gene targeting as a form of gene therapy for monogenic diseases.", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "2002-11-16", "series_number": "11", "volume": "100", "issue": "11", "pages": "219A" }, { "id": "authors:5ewwh-94n76", "collection": "authors", "collection_id": "5ewwh-94n76", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141119-073353518", "type": "article", "title": "The IkB\u2013NF-kB Signaling Module: Temporal Control and Selective Gene Activation", "author": [ { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Levchenko", "given_name": "Andre", "clpid": "Levchenko-Andre" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Nuclear localization of the transcriptional activator NF-\u03baB (nuclear factor \u03baB) is controlled in mammalian cells by three isoforms of NF-\u03baB inhibitor protein: I\u03baB\u03b1, -\u03b2, and -\u025b. Based on simplifying reductions of the I\u03baB\u2013NF-\u03baB signaling module in knockout cell lines, we present a computational model that describes the temporal control of NF-\u03baB activation by the coordinated degradation and synthesis of I\u03baB proteins. The model demonstrates that I\u03baB\u03b1 is responsible for strong negative feedback that allows for a fast turn-off of the NF-\u03baB response, whereas I\u03baB\u03b2 and -\u025b function to reduce the system's oscillatory potential and stabilize NF-\u03baB responses during longer stimulations. Bimodal signal-processing characteristics with respect to stimulus duration are revealed by the model and are shown to generate specificity in gene expression.", "doi": "10.1126/science.1071914", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2002-11-08", "series_number": "5596", "volume": "298", "issue": "5596", "pages": "1241-1245" }, { "id": "authors:dc4fy-fnb17", "collection": "authors", "collection_id": "dc4fy-fnb17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-080808066", "type": "article", "title": "CARD11 mediates factor-specific activation of NF-\u03baB by the T cell receptor complex", "author": [ { "family_name": "Pomerantz", "given_name": "Joel L.", "clpid": "Pomerantz-J-L" }, { "family_name": "Denny", "given_name": "Elissa M.", "clpid": "Denny-E-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF\u2010\u03baB is a critical target of signaling downstream of the T cell receptor (TCR) complex, but how TCR signaling activates NF\u2010\u03baB is poorly understood. We have developed an expression cloning strategy that can identify catalytic and noncatalytic molecules that participate in different pathways of NF\u2010\u03baB activation. Screening of a mouse thymus cDNA library yielded CARD11, a membrane\u2010associated guanylate kinase (MAGUK) family member containing CARD, PDZ, SH3 and GUK domains. Using a CARD\u2010deleted variant of CARD11 and RNA interference (RNAi), we demonstrate that CARD11 mediates NF\u2010\u03baB activation by \u03b1CD3/\u03b1CD28 cross\u2010linking and PMA/ionomycin treatment, but not by TNF\u03b1 or dsRNA. CARD11 is not required for TCR\u2010mediated induction of NFAT or AP\u20101. CARD11 functions upstream of the I\u03baB\u2010kinase (IKK) complex and cooperates with Bcl10 in a CARD domain\u2010dependent manner. RNAi\u2010rescue experiments suggest that the CARD, coiled\u2010coil, SH3 and GUK domains of CARD11 are critical for its signaling function. These results implicate CARD11 in factor\u2010 specific activation of NF\u2010\u03baB by the TCR complex and establish a role for a MAGUK family member in antigen receptor signaling.", "doi": "10.1093/emboj/cdf505", "pmcid": "PMC129028", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "2002-10-01", "series_number": "19", "volume": "21", "issue": "19", "pages": "5184-5194" }, { "id": "authors:av72j-qmm11", "collection": "authors", "collection_id": "av72j-qmm11", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-080213324", "type": "article", "title": "Two Pathways to NF-\u03baB", "author": [ { "family_name": "Pomerantz", "given_name": "Joel L.", "clpid": "Pomerantz-J-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB is a transcription factor that is critical for innate and adaptive immunity. Recently, a noncanonical pathway for NF-\u03baB activation has emerged. Four recent papers provide physiological roles for this pathway and expand our understanding of lymphoid development and organogenesis with potential applications in the treatment of autoimmune disease.", "doi": "10.1016/s1097-2765(02)00697-4", "issn": "1097-2765", "publisher": "Elsevier", "publication": "Molecular Cell", "publication_date": "2002-10", "series_number": "4", "volume": "10", "issue": "4", "pages": "693-695" }, { "id": "authors:rvy0k-5vv14", "collection": "authors", "collection_id": "rvy0k-5vv14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160510-082724327", "type": "article", "title": "Inhibition of DNA Binding by NF-\u03baB with Pyrrole-Imidazole Polyamides", "author": [ { "family_name": "Wurtz", "given_name": "Nicholas R.", "clpid": "Wurtz-Nicholas-R" }, { "family_name": "Pomerantz", "given_name": "Joel L.", "clpid": "Pomerantz-Joel-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Dervan", "given_name": "Peter B.", "orcid": "0000-0001-8852-7306", "clpid": "Dervan-P-B" } ], "abstract": "Synthetic ligands that bind to predetermined DNA sequences will offer a chemical approach to gene regulation if inhibition of a broad range of transcription factors can be achieved. NF-\u03baB is a transcription factor that regulates a multitude of genes, including those involved in immune, inflammatory, and anti-apoptotic responses. NF-\u03baB binds as heterodimer predominantly in the major groove. We report the design of polyamides that bind in the minor groove and target overlapping portions of an NF-\u03baB binding site (5'-GGGACTTTCC-3'). We find that compounds that target the 5'-GGGACT-3' portion of the site can inhibit DNA binding by NF-\u03baB while those that target the 5'-ACTTTCC-3' portion do not. Addition of NF-\u03baB to the list of protein\u2212DNA complexes that can be disrupted by minor groove binding ligands potentially increases the utility of polyamides as regulators of gene expression.", "doi": "10.1021/bi020114i", "issn": "0006-2960", "publisher": "American Chemical Society", "publication": "Biochemistry", "publication_date": "2002-06-18", "series_number": "24", "volume": "41", "issue": "24", "pages": "7604-7609" }, { "id": "authors:j625k-nn575", "collection": "authors", "collection_id": "j625k-nn575", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150513-151007815", "type": "article", "title": "Essential roles of the \u03ba light chain intronic enhancer and 3' enhancer in \u03ba rearrangement and demethylation", "author": [ { "family_name": "Inlay", "given_name": "Matthew", "clpid": "Inlay-Matthew" }, { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" } ], "abstract": "The \u03ba intronic (MiE_\u03ba) and 3' (3'E_\u03ba) enhancers are both quantitatively important to, but not essential for, immunoglobulin kappa rearrangement. To determine the functional redundancy between these two enhancers, B cells derived from mutant embryonic stem cells\u2014in which both MiE_\u03ba and 3'E_\u03ba were deleted on both kappa alleles\u2014were analyzed for \u03ba rearrangement. Our findings indicate that these double-mutant B cells have essentially no \u03ba rearrangement but do rearrange and express lambda. Therefore, these two kappa enhancers share essential roles in activating V_\u03baJ_\u03ba rearrangement. Our findings also indicate that the two \u03ba enhancers play overlapping and distinct roles in the demethylation of \u03ba in B cells.", "doi": "10.1038/ni790", "issn": "1529-2908", "publisher": "Nature Publishing Group", "publication": "Nature Immunology", "publication_date": "2002-05", "series_number": "5", "volume": "3", "issue": "5", "pages": "463-468" }, { "id": "authors:wm7vw-snh07", "collection": "authors", "collection_id": "wm7vw-snh07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:YANpnas02", "type": "article", "title": "Generation of functional antigen-specific T cells in defined genetic backgrounds by retrovirus-mediated expression of TCR cDNAs in hematopoietic precursor cells", "author": [ { "family_name": "Yang", "given_name": "Lili", "clpid": "Yang-Lili" }, { "family_name": "Qin", "given_name": "Xiao-Feng", "clpid": "Qin-Xiao-Feng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Van Parijs", "given_name": "Luk", "clpid": "Van-Parijs-Luk" } ], "abstract": "We have developed an alternative to transgenesis for producing antigen-specific T cells in vivo. In this system, clonal naive T cells with defined antigen specificity are generated by retrovirus-mediated expression of T cell antigen receptor cDNAs in RAG1-deficient murine hematopoietic precursor cells. These T cells can be stimulated to proliferate and produce cytokines by exposure to antigen in vitro, and they become activated and expand in vivo after immunization. IL-2-deficient T cells generated by this technique show decreased proliferation and cytokine production, both of which can be rescued by exogenous addition of this growth factor. Thus, retrovirus-mediated expression of T cell antigen receptor cDNAs in hematopoietic precursor cells permits the rapid and efficient analysis of the life history of antigen-specific T cells in different genetic backgrounds and may allow for the long-term production of antigen-specific T cells with different functional properties for prophylactic and therapeutic purposes.", "doi": "10.1073/pnas.092154599", "pmcid": "PMC122927", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2002-04-30", "series_number": "9", "volume": "99", "issue": "9", "pages": "6204-6209" }, { "id": "authors:8eh0h-0tv38", "collection": "authors", "collection_id": "8eh0h-0tv38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:POHpnas02", "type": "article", "title": "The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells", "author": [ { "family_name": "Pohl", "given_name": "Thomas", "clpid": "Pohl-Thomas" }, { "family_name": "Gugasyan", "given_name": "Raffi", "clpid": "Gugasyan-Raffi" }, { "family_name": "Grumont", "given_name": "Raelene J.", "clpid": "Grumont-Raelene-J" }, { "family_name": "Strasser", "given_name": "Andreas", "clpid": "Strasser-Andreas" }, { "family_name": "Metcalf", "given_name": "Donald", "clpid": "Metcalf-Donald" }, { "family_name": "Tarlinton", "given_name": "David", "clpid": "Tarlinton-David" }, { "family_name": "Sha", "given_name": "William", "clpid": "Sha-William-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Gerondakis", "given_name": "Steve", "clpid": "Gerondakis-Steve" } ], "abstract": "Transcription factors NF-KB1 and c-Rel, individually dispensable during embryogenesis, serve similar, yet distinct, roles in the function of mature hemopoietic cells. Redundancy among Rel/ NF-KB family members prompted an examination of the combined roles of c-Rel and NF-KB1 by using mice that lack both proteins. Embryonic development and the maturation of hemopoietic progenitors were unaffected in nfkb1(-/-)c-rel(-/-) mice. Peripheral T cell populations developed normally, but follicular, marginal zone, and CD5(+) peritoneal B cell populations all were reduced. In culture, a failure of mitogen-stimulated nfkb1(-/-)c-rel(-/-) B cells to proliferate was caused by a cell cycle defect in early G(1) that prevented growth. In vivo, defects in humoral immunity and splenic architecture seen in nfkbl(-/-) and c-rel(-/-) mice were exacerbated in the double mutant mice. These findings demonstrate that in the B lineage overlapping roles for NF-K81 and c-Rel appear to be restricted to regulating the activation and function of mature cells.", "doi": "10.1073/pnas.072071599", "pmcid": "PMC123679", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2002-04-02", "series_number": "7", "volume": "99", "issue": "7", "pages": "4514-4519" }, { "id": "authors:vcjke-bk985", "collection": "authors", "collection_id": "vcjke-bk985", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DADpnas02", "type": "article", "title": "Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes", "author": [ { "family_name": "Dadgostar", "given_name": "Hajir", "clpid": "Dadgostar-Hajir" }, { "family_name": "Zarnegar", "given_name": "Brian", "clpid": "Zarnegar-Brian" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Qin", "given_name": "Xiao-Feng", "clpid": "Qin-Xiao-Feng" }, { "family_name": "Truong", "given_name": "Uyen", "clpid": "Truong-Uyen" }, { "family_name": "Rao", "given_name": "Govinda", "clpid": "Rao-Govinda" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" } ], "abstract": "CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappaB pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.", "doi": "10.1073/pnas.032665099", "pmcid": "PMC122219", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2002-02-05", "series_number": "3", "volume": "99", "issue": "3", "pages": "1497-1502" }, { "id": "authors:0rxsn-gex86", "collection": "authors", "collection_id": "0rxsn-gex86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141117-132359069", "type": "article", "title": "Germline Transmission and Tissue-Specific Expression of Transgenes Delivered by Lentiviral Vectors", "author": [ { "family_name": "Lois", "given_name": "Carlos", "orcid": "0000-0002-7305-2317", "clpid": "Lois-C" }, { "family_name": "Hong", "given_name": "Elizabeth J.", "orcid": "0000-0003-3866-418X", "clpid": "Hong-Elizabeth-J" }, { "family_name": "Pease", "given_name": "Shirley", "clpid": "Pease-Shirley-S" }, { "family_name": "Brown", "given_name": "Eric J.", "clpid": "Brown-Eric-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Single-cell mouse embryos were infected in vitro with recombinant lentiviral vectors to generate transgenic mice carrying the green fluorescent protein (GFP) gene driven by a ubiquitously expressing promoter. Eighty percent of founder mice carried at least one copy of the transgene, and 90% of these expressed GFP at high levels. Progeny inherited the transgene(s) and displayed green fluorescence. Mice generated using lentiviral vectors with muscle-specific and T lymphocyte\u2013specific promoters expressed high levels of GFP only in the appropriate cell types. We have also generated transgenic rats that express GFP at high levels, suggesting that this technique can be used to produce other transgenic animal species.", "doi": "10.1126/science.1067081", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2002-02-01", "series_number": "5556", "volume": "295", "issue": "5556", "pages": "868-872" }, { "id": "authors:n71px-zgy58", "collection": "authors", "collection_id": "n71px-zgy58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ALCjem02", "type": "article", "title": "Requirement for the NF-kappa B family member Re1A in the development of secondary lymphoid organs", "author": [ { "family_name": "Alcamo", "given_name": "Elizabeth", "clpid": "Alcamo-Elizabeth" }, { "family_name": "Hacohen", "given_name": "Nir", "clpid": "Hacohen-Nir" }, { "family_name": "Schulte", "given_name": "Leah C.", "clpid": "Schulte-Leah-C" }, { "family_name": "Rennert", "given_name": "Paul D.", "clpid": "Rennert-Paul-D" }, { "family_name": "Hynes", "given_name": "Richard O.", "clpid": "Hynes-Richard-O" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The transcription factor nuclear factor (NF)-kappaB has been suggested to be a key mediator of the development of lymph nodes and Peyer's patches. However, targeted deletion of NF-kappaB/ Rel family members has not yet corroborated such a function. Here we report that when mice lacking the RelA subunit of NF-kappaB are brought to term by breeding onto a tumor necrosis factor receptor (TNFR)1-deficient background, the trice that are born lack lymph nodes, foyer's patches, and an organized splenic microarchitecture, and have a profound defect in T cell-dependent antigen responses. Analyses of TNFR1/1RelA-deficient embryonic tissues and of radiation chimeras suggest that the dependence on RelA is manifest not in hematopoietic cells but rather in radioresistant stromal cells needed for the development of secondary lymphoid organs.", "doi": "10.1084/jem.20011885", "pmcid": "PMC2193608", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2002-01-21", "series_number": "2", "volume": "195", "issue": "2", "pages": "233-244" }, { "id": "authors:qbe52-kyc84", "collection": "authors", "collection_id": "qbe52-kyc84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-102014044", "type": "article", "title": "Targeted Mutation of TNF Receptor I Rescues the RelA-Deficient Mouse and Reveals a Critical Role for NF-\u03baB in Leukocyte Recruitment", "author": [ { "family_name": "Alcamo", "given_name": "Elizabeth", "clpid": "Alcamo-Elizabeth" }, { "family_name": "Mizgerd", "given_name": "Joseph P.", "clpid": "Mizgerd-J-P" }, { "family_name": "Horwitz", "given_name": "Bruce H.", "clpid": "Horwitz-B-H" }, { "family_name": "Bronson", "given_name": "Rod", "clpid": "Bronson-R-T" }, { "family_name": "Beg", "given_name": "Amer A.", "clpid": "Beg-A-A" }, { "family_name": "Scott", "given_name": "Martin", "clpid": "Scott-M-L" }, { "family_name": "Doerschuk", "given_name": "Claire M.", "clpid": "Doerschuk-C-M" }, { "family_name": "Hynes", "given_name": "Richard O.", "clpid": "Hynes-Richard-O" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB binding sites are present in the promoter regions of many acute phase and inflammatory response genes, suggesting that NF-\u03baB plays an important role in the initiation of innate immune responses. However, targeted mutations of the various NF-\u03baB family members have yet to identify members responsible for this critical role. RelA-deficient mice die on embryonic day 15 from TNF-\u03b1-induced liver degeneration. To investigate the importance of RelA in innate immunity, we genetically suppressed this embryonic lethality by breeding the RelA deficiency onto a TNFR type 1 (TNFR1)-deficient background. TNFR1/RelA-deficient mice were born healthy, but were susceptible to bacterial infections and bacteremia and died within a few weeks after birth. Hemopoiesis was intact in TNFR1/RelA-deficient newborns, but neutrophil emigration to alveoli during LPS-induced pneumonia was severely reduced relative to that in wild-type or TNFR1-deficient mice. In contrast, radiation chimeras reconstituted with RelA or TNFR1/RelA-deficient hemopoietic cells were healthy and demonstrated no defect in neutrophil emigration during LPS-induced pneumonia. Analysis of RNA harvested from the lungs of mice 4 h after LPS insufflation revealed that the induction of several genes important for neutrophil recruitment to the lung was significantly reduced in TNFR1/RelA-deficient mice relative to that in wild-type or TNFR1-deficient mice. These results suggest that TNFR1-independent activation of RelA is essential in cells of nonhemopoietic origin during the initiation of an innate immune response.", "doi": "10.4049/jimmunol.167.3.1592", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "2001-08-01", "series_number": "3", "volume": "167", "issue": "3", "pages": "1592-1600" }, { "id": "authors:nd874-1kt03", "collection": "authors", "collection_id": "nd874-1kt03", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-102832171", "type": "article", "title": "Our genome unveiled", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The draft sequences of the human genome are remarkable achievements. They provide an outline of the information needed to create a human being and show, for the first time, the overall organization of a vertebrate's DNA.", "doi": "10.1038/35057267", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2001-02-15", "series_number": "6822", "volume": "409", "issue": "6822", "pages": "815-816" }, { "id": "authors:rf333-nqf84", "collection": "authors", "collection_id": "rf333-nqf84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SONjbc01", "type": "article", "title": "Domain-dependent Function of the rasGAP-binding Protein p62Dok in Cell Signaling", "author": [ { "family_name": "Songyang", "given_name": "Zhou", "clpid": "Songyang-Zhou" }, { "family_name": "Yamanashi", "given_name": "Yuji", "clpid": "Yamanashi-Yuji" }, { "family_name": "Liu", "given_name": "Dan", "clpid": "Liu-Dan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "p62Dok, the rasGAP-binding protein, is a common target of protein-tyrosine kinases. It is one of the major tyrosine-phosphorylated molecules in v-Src-transformed cells. Dok consists of an amino-terminal Pleckstrin homology domain, a putative phosphotyrosine binding domain, and a carboxyl-terminal tail containing multiple tyrosine phosphorylation sites. The importance and function of these sequences in Dok signaling remain largely unknown. We have demonstrated here that the expression of Dok can inhibit cellular transformation by the Src tyrosine kinase. Both the phosphotyrosine binding domain and the carboxyl-terminal tail of Dok (in particular residues 336-363) are necessary for such activity. Using a combinatorial peptide library approach, we have shown that the Dok phosphotyrosine binding domain binds phosphopeptides with the consensus motif of Y/MXXNXL-phosphotyrosine. Furthermore, Dok can homodimerize through its phosphotyrosine binding domain and Tyr146 at the amino-terminal region. Mutations of this domain or Tyr146 that block homodimerization significantly reduce the ability of Dok to inhibit Src transformation. Our results suggest that Dok oligomerization through its multiple domains plays a critical role in Dok signaling in response to tyrosine kinase activation.", "doi": "10.1074/jbc.M005504200", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "2001-01-26", "series_number": "4", "volume": "276", "issue": "4", "pages": "2459-2465" }, { "id": "authors:sztdh-0sj23", "collection": "authors", "collection_id": "sztdh-0sj23", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ELLjem00", "type": "article", "title": "Severe B Cell Deficiency in Mice Lacking the Tec Kinase Family Members Tec and Btk", "author": [ { "family_name": "Ellmeier", "given_name": "Wilfried", "clpid": "Ellmeier-Wilfried" }, { "family_name": "Jung", "given_name": "Steffen", "clpid": "Jung-Steffen" }, { "family_name": "Sunshine", "given_name": "Mary Jean", "clpid": "Sunshine-Mary-Jean" }, { "family_name": "Hatam", "given_name": "Farah", "clpid": "Hatam-Farah" }, { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Mano", "given_name": "Hiroyuki", "clpid": "Mano-Hiroyuki" }, { "family_name": "Littman", "given_name": "Dan R.", "clpid": "Littman-Dan-R" } ], "abstract": "The cytoplasmic protein tyrosine kinase Tec has been proposed to have important functions in hematopoiesis and lymphocyte signal transduction. Here we show that Tec-deficient mice developed normally and had no major phenotypic alterations of the immune system. To reveal potential compensatory roles of other Tec kinases such as Bruton's tyrosine kinase (Btk), Tec/Btk double-deficient mice were generated. These mice exhibited a block at the B220+CD43+ stage of B cell development and displayed a severe reduction of peripheral B cell numbers, particularly immunoglobulin (Ig)MloIgDhi B cells. Although Tec/Btknull mice were able to form germinal centers, the response to T cell\u2013dependent antigens was impaired. Thus, Tec and Btk together have an important role both during B cell development and in the generation and/or function of the peripheral B cell pool. The ability of Tec to compensate for Btk may also explain phenotypic differences in X-linked immunodeficiency (xid) mice compared with human X-linked agammaglobulinemia (XLA) patients.", "doi": "10.1084/jem.192.11.1611", "pmcid": "PMC2193106", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "2000-12-04", "series_number": "11", "volume": "192", "issue": "11", "pages": "1611-1623" }, { "id": "authors:t14b3-jr087", "collection": "authors", "collection_id": "t14b3-jr087", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SANpnas00", "type": "article", "title": "Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages", "author": [ { "family_name": "Sanjabi", "given_name": "Shomyseh", "clpid": "Sanjabi-Shomyseh" }, { "family_name": "Hoffmann", "given_name": "Alexander", "clpid": "Hoffmann-Alexander" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Smale", "given_name": "Stephen T.", "clpid": "Smale-Stephen-T" } ], "abstract": "A major challenge in the study of gene regulation by NF-kappaB/Rel transcription factors is to understand, at the biological and mechanistic levels, the selective functions of individual Rel family members. To study selectivity, we have examined the NF-kappaB/Rel protein binding site (Rel site) within the IL-12 p40 promoter. IL-12 is a proinflammatory cytokine expressed by activated macrophages that serves as an essential inducer of T helper 1 cell development. In nuclear extracts from lipopolysaccharide-activated macrophages, the predominant Rel dimers capable of binding the IL-12 p40 Rel site were the p50/p65 and p50/c-Rel heterodimers and p50/p50 homodimer. The two heterodimers bound the site with comparable affinities and exhibited comparable transactivation activities. In striking contrast, p40 mRNA and protein concentrations were reduced dramatically in c-Rel(-/-) macrophages and only modestly in p65(-/-) macrophages. Other proinflammatory cytokine mRNAs and proteins were not significantly reduced in c-Rel(-/-) macrophages. These results reveal that a c-Rel-containing complex is an essential and selective activator of p40 transcription, which may reflect unique regulatory mechanisms or biological functions of IL-12. Furthermore, because selectivity was not observed in vitro or in transient transactivation experiments, these findings suggest that an understanding of the selectivity mechanism may require an analysis of the endogenous p40 locus.", "doi": "10.1073/pnas.230436397", "pmcid": "PMC18828", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2000-11-07", "series_number": "23", "volume": "97", "issue": "23", "pages": "12705-12710" }, { "id": "authors:cxnhv-m3g78", "collection": "authors", "collection_id": "cxnhv-m3g78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEmcb00", "type": "article", "title": "Retroviral Expression in Embryonic Stem Cells and Hematopoietic Stem Cells", "author": [ { "family_name": "Cherry", "given_name": "Sara R.", "clpid": "Cherry-S-R" }, { "family_name": "Biniszkiewicz", "given_name": "D.", "clpid": "Biniszkiewicz-D" }, { "family_name": "van Parijs", "given_name": "L.", "clpid": "van-Parijs-L" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Jaenisch", "given_name": "R.", "clpid": "Jaenisch-R" } ], "abstract": "Achieving long-term retroviral expression in primary cells has been problematic. De novo DNA methylation of infecting proviruses has been proposed as a major cause of this transcriptional repression. Here we report the development of a mouse stem cell virus (MSCV) long terminal repeat-based retroviral vector that is expressed in both embryonic stem (ES) cells and hematopoietic stem (HS) cells. Infected HS cells and their differentiated descendants maintained long-term and stable retroviral expression after serial adoptive transfers. In addition, retrovirally infected ES cells showed detectable expression level of the green fluorescent protein (GFP). Moreover, GFP expression of integrated proviruses was maintained after in vitro differentiation of infected ES cells. Long-term passage of infected ES cells resulted in methylation-mediated silencing, while short-term expression was methylation independent. Tissues of transgenic animals, which we derived from ES cells carrying the MSCV-based provirus, did not express GFP. However, treatment with the demethylating agent 5-azadeoxycytidine reactivated the silent provirus, demonstrating that DNA methylation is involved in the maintenance of retroviral repression. Our results indicate that retroviral expression in ES cells is repressed by methylation-dependent as well as methylation-independent mechanisms.", "doi": "10.1128/mcb.20.20.7419-7426.2000", "pmcid": "PMC86295", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "2000-10", "series_number": "20", "volume": "20", "issue": "20", "pages": "7419-7426" }, { "id": "authors:xqpe1-vx672", "collection": "authors", "collection_id": "xqpe1-vx672", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:COHjbc00", "type": "article", "title": "The Human Thioesterase II Protein Binds to a Site on HIV-1 Nef Critical for CD4 Down-regulation", "author": [ { "family_name": "Cohen", "given_name": "George B.", "clpid": "Cohen-G-B" }, { "family_name": "Rangan", "given_name": "Vangipuram S.", "clpid": "Rangan-V-S" }, { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-B-K" }, { "family_name": "Smith", "given_name": "Stuart", "clpid": "Smith-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A HIV-1 Nef affinity column was used to purify a 35-kDa Nef-interacting protein from T-cell lysates. The 35-kDa protein was identified by peptide microsequence analysis as the human thioesterase II (hTE) enzyme, an enzyme previously identified in a yeast two-hybrid screen as a potential Nef-interacting protein. Immunofluorescence studies showed that hTE localizes to peroxisomes and that coexpression of Nef and hTE leads to relocalization of Nef to peroxisomes. Interaction of Nef and hTE was abolished by point mutations in Nef at residues Asp108, Leu112, Phe121, Pro122, and Asp123. All of these mutations also abrogated the ability of Nef to down-regulate CD4 from the surface of HIV-infected cells. Based on the x-ray and NMR structures of Nef, these residues define a surface on Nef critical for CD4 down-regulation. A subset of these mutations also affected the ability of Nef to down-regulate major histocompatibility complex class I. These results, taken together with previous studies, identify a region on Nef critical for most of its known functions. However, not all Nef alleles bind to hTE with high affinity, so the role of hTE during HIV infection remains uncertain.", "doi": "10.1074/jbc.M000536200", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "2000-07-28", "series_number": "30", "volume": "275", "issue": "30", "pages": "23097-23105" }, { "id": "authors:agxgt-b7e63", "collection": "authors", "collection_id": "agxgt-b7e63", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150327-131151072", "type": "article", "title": "Signal transduction - A cellular rescue team", "author": [ { "family_name": "Pomerantz", "given_name": "Joel L.", "clpid": "Pomerantz-J-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A protein called glycogen synthase kinase-3\u03b2 is already known to participate in early embryonic development and cell-fate determination. Now it seems that the protein is also involved in a cell's decision to live or die.", "doi": "10.1038/35017673", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2000-07-06", "series_number": "6791", "volume": "406", "issue": "6791", "pages": "26-29" }, { "id": "authors:sme29-red26", "collection": "authors", "collection_id": "sme29-red26", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEpnas00", "type": "article", "title": "V(D)J recombination is not activated by demethylation of the kappa locus", "author": [ { "family_name": "Cherry", "given_name": "Sara R.", "clpid": "Cherry-S-R" }, { "family_name": "Beard", "given_name": "Caroline", "clpid": "Beard-C" }, { "family_name": "Jaenisch", "given_name": "Rudolf", "clpid": "Jaenisch-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "V(D)J recombination is thought to be regulated by changes in the accessibility of target sites, such as modulation of methylation. To test whether demethylation of the kappa locus can activate recombination, we generated two recombinationally active B cell lines in which the gene for maintenance of genomic DNA methylation, Dnmt1, was flanked with loxP sites. Transduction with a retrovirus expressing both the cre recombinase and green fluorescent protein allowed us to purify recombinationally active cells devoid of methylation. Loss of methylation of the kappa locus was\nnot sufficient to activate recombination, although transcription was activated in one line. It appears that demethylation of the kappa locus is not the rate-limiting step for altering accessibility and thus regulated demethylation does not generate specificity of recombination.", "doi": "10.1073/pnas.150218497", "pmcid": "PMC26971", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2000-07-04", "series_number": "15", "volume": "97", "issue": "15", "pages": "8467-8472" }, { "id": "authors:adf2p-dbp65", "collection": "authors", "collection_id": "adf2p-dbp65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-104739180", "type": "article", "title": "ATR disruption leads to chromosomal fragmentation and early embryonic lethality", "author": [ { "family_name": "Brown", "given_name": "Eric J.", "clpid": "Brown-Eric-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Although a small decrease in survival and increase in tumor incidence was observed in ATR^(+/\u2212) mice, ATR^(\u2212/\u2212) embryos die early in development, subsequent to the blastocyst stage and prior to 7.5 days p.c. In culture, ATR^(\u2212/\u2212) blastocysts cells continue to cycle into mitosis for 2 days but subsequently fail to expand and die of caspase-dependent apoptosis. Importantly, caspase-independent chromosome breaks are observed in ATR^(\u2212/\u2212) cells prior to widespread apoptosis, implying that apoptosis is caused by a loss of genomic integrity. These data show that ATR is essential for early embryonic development and must function in processes other than regulation of p53.", "doi": "10.1101/gad.14.4.397", "pmcid": "PMC316378", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "2000-02-15", "series_number": "4", "volume": "14", "issue": "4", "pages": "397-402" }, { "id": "authors:xjbb3-4ss60", "collection": "authors", "collection_id": "xjbb3-4ss60", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-142242679", "type": "article", "title": "Role of the rasGAP-associated docking protein p62^(dok) in negative regulation of B cell receptor-mediated signaling", "author": [ { "family_name": "Yamanashi", "given_name": "Yuji", "clpid": "Yamanashi-Yuji" }, { "family_name": "Tamura", "given_name": "Toshiki", "clpid": "Tamura-Toshiki" }, { "family_name": "Kanamori", "given_name": "Toshihide", "clpid": "Kanamori-Toshihide" }, { "family_name": "Yamane", "given_name": "Hidehiro", "clpid": "Yamane-Hidehiro" }, { "family_name": "Nariuchi", "given_name": "Hideo", "clpid": "Nariuchi-Hideo" }, { "family_name": "Yamamoto", "given_name": "Tadashi", "clpid": "Yamamoto-Tadashi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Antigenic stimulation of the B-cell receptor (BCR) is a central event in the immune response. In contrast, antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor Fc\u03b3RIIB. Here we show that upon cross-linking of BCR or BCR with Fc\u03b3RIIB, the rasGAP-associated protein p62^(dok) is prominently tyrosine phosphorylated in a Lyn-dependent manner. Inactivation of the dok gene by homologous recombination has shown that upon BCR cross-linking, p62^(dok) suppresses MAP kinase and is indispensable for Fc\u03b3RIIB-mediated negative regulation of cell proliferation. We propose that p62^(dok), a downstream target of many PTKs, plays a negative role in various signaling situations.", "doi": "10.1101/gad.14.1.11", "pmcid": "PMC316343", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "2000-01-01", "series_number": "1", "volume": "14", "issue": "1", "pages": "11-16" }, { "id": "authors:nnaex-bhd28", "collection": "authors", "collection_id": "nnaex-bhd28", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-145226410", "type": "article", "title": "NF-\u03baB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase", "author": [ { "family_name": "Pomerantz", "given_name": "Joel L.", "clpid": "Pomerantz-J-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The activation of NF\u2010\u03baB by receptors in the tumor necrosis factor (TNF) receptor and Toll/interleukin\u20101 (IL\u20101) receptor families requires the TRAF family of adaptor proteins. Receptor oligomerization causes the recruitment of TRAFs to the receptor complex, followed by the activation of a kinase cascade that results in the phosphorylation of I\u03baB. TANK is a TRAF\u2010binding protein that can inhibit the binding of TRAFs to receptor tails and can also inhibit NF\u2010\u03baB activation by these receptors. However, TANK also displays the ability to stimulate TRAF\u2010mediated NF\u2010\u03baB activation. In this report, we investigate the mechanism of the stimulatory activity of TANK. We find that TANK interacts with TBK1 (TANK\u2010binding kinase 1), a novel IKK\u2010related kinase that can activate NF\u2010\u03baB in a kinase\u2010dependent manner. TBK1, TANK and TRAF2 can form a ternary complex, and complex formation appears to be required for TBK1 activity. Kinase\u2010inactive TBK1 inhibits TANK\u2010mediated NF\u2010\u03baB activation but does not block the activation mediated by TNF\u2010\u03b1, IL\u20101 or CD40. The TBK1\u2013TANK\u2013TRAF2 signaling complex functions upstream of NIK and the IKK complex and represents an alternative to the receptor signaling complex for TRAF\u2010mediated activation of NF\u2010\u03baB.", "doi": "10.1093/emboj/18.23.6694", "pmcid": "PMC1171732", "issn": "1460-2075", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1999-12-01", "series_number": "23", "volume": "18", "issue": "23", "pages": "6694-6704" }, { "id": "authors:kvbry-21535", "collection": "authors", "collection_id": "kvbry-21535", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GROpnas99", "type": "article", "title": "The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects", "author": [ { "family_name": "Grossmann", "given_name": "Mathis", "clpid": "Grossmann-Mathis" }, { "family_name": "Metcalf", "given_name": "Donald", "clpid": "Metcalf-Donald" }, { "family_name": "Merryfull", "given_name": "Julie", "clpid": "Merryfull-Julie" }, { "family_name": "Beg", "given_name": "Amer", "clpid": "Beg-Amer" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Gerondakis", "given_name": "Steve", "clpid": "Gerondakis-Steve" } ], "abstract": "Individual Rel/NF-kappa B transcription factors, although dispensable for the development and maturation of most hemopoietic cells, are critical regulators of normal immune function. Redundancy among these proteins prompted us to examine the role of Rel and RelA in hemopoiesis by using mice that lack both subunits. Because of the death of double-mutant fetuses at day 13.5 of gestation (E13.5), E12 fetal liver hemopoietic progenitors were used for in vitro cultures and for repopulating stem cell studies in lethally irradiated normal recipient mice. Most striking, Rel/RelA-deficient hemopoietic precursors failed to promote the survival of myeloablated mice. This phenotype was associated with several defects including a reduction of spleen colony-forming unit progenitors, impaired erythropoiesis, and a deregulated expansion of granulocytes. In vitro progenitor assays also revealed that Rel or RelA serves an antiapoptotic role during monocyte differentiation. Despite the combined loss of Rel and RelA leading to these hemopoietic defects, c-rel(-/-)rela(-/-) stem cells contributed to the development of all lineages in mice engrafted with double-mutant fetal liver cells and normal bone marrow cells, albeit in a reduced fashion compared with controls. Collectively, these data indicate the loss of Rel and RelA does not appear to affect pluripotent stem cells; rather, Rel and RelA serve redundant functions in regulating differentiation and survival of committed progenitors in multiple hemopoietic lineages.", "doi": "10.1073/pnas.96.21.11848", "pmcid": "PMC18375", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1999-10-12", "series_number": "21", "volume": "96", "issue": "21", "pages": "11848-11853" }, { "id": "authors:skfjd-r7r19", "collection": "authors", "collection_id": "skfjd-r7r19", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEpnas99", "type": "article", "title": "Chromatin remodeling directly activates V(D)J recombination", "author": [ { "family_name": "Cherry", "given_name": "Sara R.", "clpid": "Cherry-Sara-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "V(D)J recombination substrate choice is regulated to ensure that the appropriate gene segments are rearranged during lymphocyte development. It has been proposed that regulation of substrate usage is determined by changes in accessibility of the DNA targets. We show that Rag-mediated recombination of an episomal substrate in cells is affected by its packaging into chromatin. Chromatinized substrates were inefficiently rearranged, and methylation further reduced recombination. Disruption of nucleosomes by using butyrate on methylated substrates was sufficient to activate recombination, and dexamethasone could activate recombination in the absence of detectable transcription. Therefore, chromatin structure, and its manipulation by altering nucleosome positioning, can directly affect recombination efficiencies.", "doi": "10.1073/pnas.96.19.10788", "pmcid": "PMC17961", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1999-09-14", "series_number": "19", "volume": "96", "issue": "19", "pages": "10788-10793" }, { "id": "authors:scctm-par91", "collection": "authors", "collection_id": "scctm-par91", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-153313792", "type": "article", "title": "Modelling T-cell memory by genetic marking of memory T cells in vivo", "author": [ { "family_name": "Jacob", "given_name": "Joshy", "clpid": "Jacob-Joshy" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Immunological memory is the ability of the immune system to respond with enhanced vigour to pathogens that have been encountered in the past. Following infection or immunization, most effector T cells undergo apoptotic cell death, but a small fraction of these cells, proportional to the early antigen load and initial clonal burst size, persist in the host as a stable pool of memory T cells. The existence of immunological memory has been recognized for over 2,000 years, but our understanding of this phenomenon is limited, primarily because memory lymphocytes cannot be unequivocally identified as they lack specific, permanent markers. Here we have developed a transgenic mouse model system whereby memory T cells and their precursors can be irreversibly marked with a reporter gene and thus can be unambiguously identified. Adoptive transfer of marked CD8\u207a T cells specific for lymphocytic choriomeningitis virus protected naive recipients following viral challenge, demonstrating that we have marked memory T cells. We also show that cytotoxic effector lymphocytes that develop into memory T cells can be identified in the primary response.", "doi": "10.1038/21208", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1999-06-10", "series_number": "6736", "volume": "399", "issue": "6736", "pages": "593-597" }, { "id": "authors:s4jke-0p683", "collection": "authors", "collection_id": "s4jke-0p683", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-102017979", "type": "article", "title": "The Selective Downregulation of Class I Major Histocompatibility Complex Proteins by HIV-1 Protects HIV-Infected Cells from NK Cells", "author": [ { "family_name": "Cohen", "given_name": "George B.", "clpid": "Cohen-G-B" }, { "family_name": "Gandhi", "given_name": "Rajesh T.", "clpid": "Gandhi-Rajesh-T" }, { "family_name": "Davis", "given_name": "Daniel M.", "clpid": "Davis-D-M" }, { "family_name": "Mandelboim", "given_name": "Ofer", "clpid": "Mandelboim-O" }, { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Strominger", "given_name": "Jack L.", "clpid": "Strominger-J-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C and HLA-E that protect them from HIV downregulation. This selective downregulation allows HIV-infected cells to avoid NK cell\u2013mediated lysis and may represent for HIV a balance between escape from CTL and maintenance of protection from NK cells. These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV.", "doi": "10.1016/s1074-7613(00)80065-5", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1999-06-01", "series_number": "6", "volume": "10", "issue": "6", "pages": "661-671" }, { "id": "authors:vz1r6-n4143", "collection": "authors", "collection_id": "vz1r6-n4143", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEjbc99", "type": "article", "title": "Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl", "author": [ { "family_name": "Chen", "given_name": "Gang", "clpid": "Chen-Gang" }, { "family_name": "Yuan", "given_name": "Shyng-Shiou F.", "clpid": "Yuan-Shyng-Shiou-F" }, { "family_name": "Liu", "given_name": "Wei", "clpid": "Liu-Wei" }, { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Trujillo", "given_name": "Kelly", "clpid": "Trujillo-Kelly" }, { "family_name": "Song", "given_name": "Binwei", "clpid": "Song-Binwei" }, { "family_name": "Cong", "given_name": "Feng", "clpid": "Cong-Feng" }, { "family_name": "Goff", "given_name": "Stephen P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Wu", "given_name": "Yun", "clpid": "Wu-Yun" }, { "family_name": "Arlinghaus", "given_name": "Ralph", "clpid": "Arlinghaus-Ralph" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Gasser", "given_name": "Paul J.", "clpid": "Gasser-Paul-J" }, { "family_name": "Park", "given_name": "Min S.", "clpid": "Park-Min-S" }, { "family_name": "Sung", "given_name": "Patrick", "clpid": "Sung-Patrick" }, { "family_name": "Lee", "given_name": "Eva Y.-H. P.", "clpid": "Lee-Eva-Y-H-P" } ], "abstract": "Cells from individuals with the recessive cancer-prone disorder ataxia telangiectasia (A-T) are hypersensitive to ionizing radiation (I-R). ATM (mutated in A-T) is a protein kinase whose activity is stimulated by I-R. c-Abl, a nonreceptor tyrosine kinase, interacts with ATM and is activated by ATM following I-R. Rad51 is a homologue of bacterial RecA protein required for DNA recombination and repair. Here we demonstrate that there is an I-R-induced Rad51 tyrosine phosphorylation, and this induction is dependent on both ATM and c-Abl. ATM, c-Abl, and Rad51 can be co-immunoprecipitated from cell extracts. Consistent with the physical interaction, c-Abl phosphorylates Rad51 in vitro and in vivo. In assays using purified components, phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. After I-R, an increase in association between Rad51 and Rad52 occurs in wild-type cells but not in cells with mutations that compromise ATM or c-Abl. Our data suggest signaling mediated through ATM, and c-Abl is required for the correct post-translational modification of Rad51, which is critical for the assembly of Rad51 repair protein complex following I-R.", "doi": "10.1074/jbc.274.18.12748", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1999-04-30", "series_number": "18", "volume": "274", "issue": "18", "pages": "12748-12752" }, { "id": "authors:feye3-hsk03", "collection": "authors", "collection_id": "feye3-hsk03", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-102606426", "type": "article", "title": "HIV's evasion of the cellular immune response", "author": [ { "family_name": "Collins", "given_name": "Kathleen L.", "clpid": "Collins-K-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Despite a strong cytotoxic T\u2010lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV\u20101) develop AIDS, We have found that primary T cells infected with HIV\u20101 downregulate surface MHC class I antigens and are resistant to lysis by HLA\u2010A2\u2010restricted CTL clones. In contrast, cells infected with an HIV\u20101 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide\u2010specific manner. In primary T cells HLA\u2010A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on ceils expressing individual MHC class I alietes have revealed that nef does not downmodulate HLA\u2010C and HLA\u2010E antigens, This selective downmodulation allows Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA\u2010A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV\u20101 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV\u20101 from immune surveillance.", "doi": "10.1111/j.1600-065x.1999.tb01283.x", "issn": "0105-2896", "publisher": "Wiley", "publication": "Immunological Reviews", "publication_date": "1999-04", "series_number": "1", "volume": "168", "issue": "1", "pages": "65-74" }, { "id": "authors:7p2c2-4nm84", "collection": "authors", "collection_id": "7p2c2-4nm84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHApnas99", "type": "article", "title": "Dissecting Fas signaling with an altered-specificity death-domain mutant: Requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation", "author": [ { "family_name": "Chang", "given_name": "Howard Y.", "clpid": "Chang-Howard-Y" }, { "family_name": "Yang", "given_name": "Xiaolu", "clpid": "Yang-Xiaolu" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Fas is a cell surface death receptor that regulates peripheral tolerance and lymphoid homeostasis. In many pathologic conditions, ectopic Fas activation mediates tissue destruction. Several proteins that can bind to the cytoplasmic death domain of Fas have been implicated in Fas signal transduction. Here we show that FADD, which couples Fas to pro-caspase-8, and, Daxx, which couples Fas to the Jun N-terminal kinase pathway, bind independently to the Fas death domain. We have isolated a death domain mutant, termed Fas delta, that selectively binds Daxx but not FADD. In tranfected tissue culture cells, Fas delta activated Jun N-terminal kinase normally but was impaired in cell death induction. These results suggest that FADD and Daxx activate two independent pathways downstream of Fas and confirm the\nessential role of FADD binding in apoptosis induction.", "doi": "10.1073/pnas.96.4.1252", "pmcid": "PMC15449", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1999-02-16", "series_number": "4", "volume": "96", "issue": "4", "pages": "1252-1256" }, { "id": "authors:zg8p8-0wy44", "collection": "authors", "collection_id": "zg8p8-0wy44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LEEpnas99", "type": "article", "title": "Specificities of CD40 signaling: Involvement of TRAF2 in CD40-induced NF-kappa B activation and intercellular adhesion molecule-1 up-regulation", "author": [ { "family_name": "Lee", "given_name": "Ho H.", "clpid": "Lee-Ho-H" }, { "family_name": "Dempsey", "given_name": "Paul W.", "clpid": "Dempsey-P-Waul" }, { "family_name": "Parks", "given_name": "Thomas P.", "clpid": "Parks-Thomas-P" }, { "family_name": "Zhu", "given_name": "Xiaoqing", "clpid": "Zhu-Xiaoqing" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" } ], "abstract": "Several tumor necrosis factor receptor-associated factor (TRAF) family proteins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been implicated as potential mediators of CD40 signaling. An extensive in vitro binding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic tail (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 and TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incapable of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-kappa B and stress-activated protein kinase activation, as well as the up-regulation of the intercellular adhesion molecule-1 (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable for all of these functions. Overexpression of a dominantly active I kappa B alpha strongly inhibited CD40-induced NF-kappa B activation, ICAM-1 promoter activity, and cell-surface ICAM-1 up regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcriptional activation of the ICAM-1 gene.", "doi": "10.1073/pnas.96.4.1421", "pmcid": "PMC15478", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1999-02-16", "series_number": "4", "volume": "96", "issue": "4", "pages": "1421-1426" }, { "id": "authors:513ps-36f29", "collection": "authors", "collection_id": "513ps-36f29", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-103042991", "type": "article", "title": "The p65 Subunit of NF-\u03baB Is Redundant with p50 During B Cell Proliferative Responses, and Is Required for Germline C_H Transcription and Class Switching to IgG3", "author": [ { "family_name": "Horwitz", "given_name": "Bruce H.", "clpid": "Horwitz-B-H" }, { "family_name": "Zelazowski", "given_name": "Piotr", "clpid": "Zelazowski-P" }, { "family_name": "Shen", "given_name": "Yi", "clpid": "Shen-Yi" }, { "family_name": "Wolcott", "given_name": "Karen M.", "clpid": "Wolcott-K-M" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Snapper", "given_name": "Clifford M.", "clpid": "Snapper-C-M" } ], "abstract": "B cells lacking individual NF-\u03baB/Rel family members exhibit defects in activation programs. We generated small resting B cells lacking p65 or p50 alone, or lacking both p50 and p65, then evaluated the ability of these cells to proliferate, secrete Ig, and undergo Ig class switching. B cells lacking p65 proliferated well in response to all stimuli tested. However, these cells demonstrated an isolated defect in switching to IgG3, which was associated with a decrease in \u03b33 germline C_H gene expression. Whereas, previously reported, B cells lacking p50 alone had a severe proliferative defect in response to LPS, a moderate defect in response to CD40 ligand (CD40L), and normal proliferation to Ag receptor cross-linking using dextran-conjugated anti-IgD Abs (\u03b1\u03b4-dex), B cells lacking both p50 and p65 exhibited severely impaired proliferation in response to LPS, \u03b1\u03b4-dex, and CD40L. This defect could be overcome by simultaneous administration of \u03b1\u03b4-dex and CD40L. In response to this latter combination of stimuli, B cells lacking both p50 and p65 secreted Ig and underwent isotype switching to IgG1 as efficiently as B cells lacking p50 alone. These data demonstrate a role for the p65 subunit of NF-\u03baB in germline C_H gene expression as well as functional redundancy between p50 and p65 during proliferative responses.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "1999-02-15", "series_number": "4", "volume": "162", "issue": "4", "pages": "1941-1946" }, { "id": "authors:z1cqf-qz705", "collection": "authors", "collection_id": "z1cqf-qz705", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200506-154851801", "type": "article", "title": "Essential Roles for the Abl and Arg Tyrosine Kinases in Neurulation", "author": [ { "family_name": "Koleske", "given_name": "Anthony J.", "clpid": "Koleske-Anthony-J" }, { "family_name": "Gifford", "given_name": "Ann M.", "clpid": "Gifford-Ann-M" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Nee", "given_name": "Michelle", "clpid": "Nee-Michelle" }, { "family_name": "Bronson", "given_name": "Roderick T.", "clpid": "Bronson-R-T" }, { "family_name": "Miczek", "given_name": "Klaus A.", "clpid": "Miczek-K-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. Arg^(\u2212/\u2212) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg^(\u2212/\u2212) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl^(\u2212/\u2212)arg^(\u2212/\u2212) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.", "doi": "10.1016/s0896-6273(00)80646-7", "issn": "0896-6273", "publisher": "Cell Press", "publication": "Neuron", "publication_date": "1998-12", "series_number": "6", "volume": "21", "issue": "6", "pages": "1259-1272" }, { "id": "authors:8d71c-d4361", "collection": "authors", "collection_id": "8d71c-d4361", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120111-132505555", "type": "article", "title": "Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow", "author": [ { "family_name": "Pear", "given_name": "Warren S.", "clpid": "Pear-Warren-S" }, { "family_name": "Miller", "given_name": "Juli P.", "clpid": "Miller-Juli-P" }, { "family_name": "Xu", "given_name": "Lanwei", "clpid": "Xu-Lanwei" }, { "family_name": "Pui", "given_name": "John C.", "clpid": "Pui-John-C" }, { "family_name": "Soffer", "given_name": "Benny", "clpid": "Soffer-Benny" }, { "family_name": "Quackenbush", "given_name": "Robert C.", "clpid": "Quackenbush-Robert-C" }, { "family_name": "Pendergast", "given_name": "Ann Marie", "clpid": "Pendergast-Ann-Marie" }, { "family_name": "Bronson", "given_name": "Roderick", "clpid": "Bronson-Roderick" }, { "family_name": "Aster", "given_name": "Jon C.", "clpid": "Aster-Jon-C" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Expression of the 210-kD bcr/abl fusion oncoprotein can cause a chronic myelogenous leukemia (CML)-like disease in mice receiving bone marrow cells transduced by bcr/abl-encoding retroviruses. However, previous methods failed to yield this disease at a frequency sufficient enough to allow for its use in the study of CML pathogenesis. To overcome this limitation, we have developed an efficient and reproducible method for inducing a CML-like disease in mice receiving P210 bcr/abl-transduced bone marrow cells. All mice receiving P210 bcr/abl-transduced bone marrow cells succumb to a myeloproliferative disease between 3 and 5 weeks after bone marrow transplantation. The myeloproliferative disease recapitulates many of the hallmarks of human CML and is characterized by high white blood cell counts and extensive extramedullary hematopoiesis in the spleen, liver, bone marrow, and lungs. Use of a retroviral vector coexpressing P210 bcr/abl and green fluorescent protein shows that the vast majority of bcr/abl-expressing cells are myeloid. Analysis of the proviral integration pattern shows that, in some mice, the myeloproliferative disease is clonal. In multiple mice, the CML-like disease has been transplantable, inducing a similar myeloproliferative syndrome within 1 month of transfer to sublethally irradiated syngeneic recipients. The disease in many of these mice has progressed to the development of acute lymphoma/leukemia resembling blast crisis. These results demonstrate that murine CML recapitulates important features of human CML. As such, it should be an excellent model for addressing specific issues relating to the pathogenesis and treatment of this disease.", "doi": "10.1182/blood.V92.10.3780", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "1998-11-15", "series_number": "10", "volume": "92", "issue": "10", "pages": "3780-3792" }, { "id": "authors:jgqph-20c87", "collection": "authors", "collection_id": "jgqph-20c87", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141201-144924408", "type": "article", "title": "Activation of Apoptosis Signal-Regulating Kinase 1 (ASK1) by the Adapter Protein Daxx", "author": [ { "family_name": "Chang", "given_name": "Howard Y.", "clpid": "Chang-Howard-Y" }, { "family_name": "Nishitoh", "given_name": "Hideki", "clpid": "Nishitoh-Hideki" }, { "family_name": "Yang", "given_name": "Xiaolu", "clpid": "Yang-Xiaolu" }, { "family_name": "Ichijo", "given_name": "Hidenori", "clpid": "Ichijo-Hidenori" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Fas death receptor can activate the Jun NH_2-terminal kinase (JNK) pathway through the receptor-associated protein Daxx. Daxx was found to activate the JNK kinase kinase ASK1, and overexpression of a kinase-deficient ASK1 mutant inhibited Fas- and Daxx-induced apoptosis and JNK activation. Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity. The Daxx-ASK1 connection completes a signaling pathway from a cell surface death receptor to kinase cascades that modulate nuclear transcription factors.", "doi": "10.1126/science.281.5384.1860", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1998-09-18", "series_number": "5384", "volume": "281", "issue": "5384", "pages": "1860-1863" }, { "id": "authors:k70fz-6jq25", "collection": "authors", "collection_id": "k70fz-6jq25", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141124-102100187", "type": "article", "title": "Essential Role of CED-4 Oligomerization in CED-3 Activation and Apoptosis", "author": [ { "family_name": "Yang", "given_name": "Xiaolu", "clpid": "Yang-Xiaolu" }, { "family_name": "Chang", "given_name": "Howard Y.", "clpid": "Chang-Howard-Y" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Control of the activation of apoptosis is important both in development and in protection against cancer. In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2\u2013like protein CED-9. Both processes are mediated by protein-protein interaction. Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death. CED-4 protein oligomerized in cells and in vitro. This oligomerization induced CED-3 proximity and competed with CED-4:CED-9 interaction. Mutations that abolished CED-4 oligomerization inactivated its ability to activate CED-3. Thus, the mechanism of control is that CED-3 in CED-3:CED-4 complexes is activated by CED-4 oligomerization, which is inhibited by binding of CED-9 to CED-4.", "doi": "10.1126/science.281.5381.1355", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1998-08-28", "series_number": "5381", "volume": "281", "issue": "5381", "pages": "1355-1357" }, { "id": "authors:hsh0n-bk761", "collection": "authors", "collection_id": "hsh0n-bk761", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:XUYmcb98", "type": "article", "title": "Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atm^(\u2212/\u2212) Mice", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Yang", "given_name": "Eva Marie", "clpid": "Yang-Eva-Marie" }, { "family_name": "Brugarolas", "given_name": "James", "clpid": "Brugarolas-Jaes" }, { "family_name": "Jacks", "given_name": "Tyler", "clpid": "Jacks-Tyler" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm-/- p53-/- mice develop lymphomas earlier than Atm-/- or p53-/- mice, indicating that mutations in these two genes lead to synergy in tumorigenesis. The cell cycle G1/S checkpoint is abolished in Atm-/- p53-/- mouse embryonic fibroblasts (MEFs) following gamma -irradiation, suggesting that the partial G1 cell cycle arrest in Atm-/- cells following gamma -irradiation is due to the residual p53 response in these cells. In addition, the Atm-/- p21-/- MEFs are more severely defective in their cell cycle G1 arrest following gamma -irradiation than Atm-/- and p21-/- MEFs. The Atm-/- MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm-/- p21-/- MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm-/- p53-/- MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm-/- cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm-/- MEFs is lower than that in Atm+/+ MEFs, suggesting that the higher level of constitutive p21 protein in Atm-/- MEFs is likely due to increased stability of the p21 protein.", "doi": "10.1128/mcb.18.7.4385", "pmcid": "PMC109022", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1998-07", "series_number": "7", "volume": "18", "issue": "7", "pages": "4385-4390" }, { "id": "authors:rw5hy-gw681", "collection": "authors", "collection_id": "rw5hy-gw681", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200424-092752044", "type": "article", "title": "HIV Vaccines: Prospects and Challenges", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Heilman", "given_name": "Carole", "clpid": "Heilman-Carole-A" } ], "abstract": "Unlike vaccines for many viruses, those for HIV may have to go beyond generating antibodies. Devising approaches that will fully activate the immune system is far from simple", "doi": "10.1038/scientificamerican0798-98", "issn": "0036-8733", "publisher": "Scientific American", "publication": "Scientific American", "publication_date": "1998-07", "series_number": "1", "volume": "279", "issue": "1", "pages": "98-103" }, { "id": "authors:crgmf-t1z83", "collection": "authors", "collection_id": "crgmf-t1z83", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150629-140449801", "type": "article", "title": "HIV vaccines - where are we going?", "author": [ { "family_name": "Heilman", "given_name": "Carole A.", "clpid": "Heilman-Carole-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Carole Heilman (Division of AIDS at the National Institutes of Allergy and Infectious Diseases) and David Baltimore (President of the California Institute of Technology) review current research efforts toward developing anti-HIV vaccines. While recognizing the extraordinary challenges involved in developing a vaccine, Heilman and Baltimore stress that important steps have been taken and that as such there is room for optimism.", "doi": "10.1038/nm0598supp-532", "issn": "1078-8956", "publisher": "Nature Publishing Group", "publication": "Nature Medicine", "publication_date": "1998-05", "series_number": "5", "volume": "4", "issue": "5", "pages": "532-534" }, { "id": "authors:707x4-amn51", "collection": "authors", "collection_id": "707x4-amn51", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GANjem98", "type": "article", "title": "HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism", "author": [ { "family_name": "Gandhi", "given_name": "Rajesh T.", "clpid": "Gandhi-Rajesh-T" }, { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Straus", "given_name": "Stephen E.", "clpid": "Straus-Stephen-E" }, { "family_name": "Dale", "given_name": "Janet K.", "clpid": "Dale-Janet-K" }, { "family_name": "Lenardo", "given_name": "Michael J.", "clpid": "Lenardo-Michael-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The mechanism by which HIV-1 induces CD4+ T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4+ T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism.", "doi": "10.1084/jem.187.7.1113", "pmcid": "PMC2212217", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1998-04-06", "series_number": "7", "volume": "187", "issue": "7", "pages": "1113-1122" }, { "id": "authors:03y8d-btx54", "collection": "authors", "collection_id": "03y8d-btx54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-103823040", "type": "article", "title": "HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes", "author": [ { "family_name": "Collins", "given_name": "Kathleen L.", "clpid": "Collins-K-L" }, { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Kalams", "given_name": "Spyros A.", "clpid": "Kalams-S-A" }, { "family_name": "Walker", "given_name": "Bruce D.", "clpid": "Walker-B-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Cytotoxic T lymphocytes (CTLs) lyse virally infected cells that display viral peptide epitopes in association with major histocompatibility complex (MHC) class I molecules on the cell surface. However, despite a strong CTL response directed against viral epitopes, untreated people infected with the human immunodeficiency virus (HIV-1) develop AIDS. To resolve this enigma, we have examined the ability of CTLs to recognize and kill infected primary T lymphocytes. We found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed. Resistance of infected cells to CTL killing correlated with nef-mediated downregulation of MHC class I (ref. 1) and could be overcome by adding an excess of the relevant HIV-1 epitope as soluble peptide. Thus, Nef protected infected cells by reducing the epitope density on their surface. This effect of nef may allow evasion of CTL lysis by HIV-1-infected cells.", "doi": "10.1038/34929", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1998-01-22", "series_number": "6665", "volume": "391", "issue": "6665", "pages": "397-401" }, { "id": "authors:emx01-ece02", "collection": "authors", "collection_id": "emx01-ece02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150958515", "type": "article", "title": "Autoproteolytic Activation of Pro-Caspases by Oligomerization", "author": [ { "family_name": "Yang", "given_name": "Xiaolu", "clpid": "Yang-Xiaolu" }, { "family_name": "Chang", "given_name": "Howard Y.", "clpid": "Chang-Howard-Y" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Initiation of apoptosis requires the conversion of pro-caspases to mature caspases. Here we show that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity. Deletion of the protein interaction motif DED from pro-caspase-8 greatly suppresses its apoptotic activity. Cell death activity can be restored by oligomerization of pro-caspase-8 protease domains by two heterologous inducible oligomerization systems. Induced oligomerization also activates the apoptotic activity of pro-caspase-1 but not pro-caspase-3. In vitro, oligomerization leads to pro-caspase processing to form the mature caspase subunits; this processing requires the intrinsic caspase activity of zymogens and proceeds via a novel order of cleavage events.", "doi": "10.1016/s1097-2765(00)80032-5", "issn": "1097-2765", "publisher": "Elsevier", "publication": "Molecular Cell", "publication_date": "1998-01", "series_number": "2", "volume": "1", "issue": "2", "pages": "319-325" }, { "id": "authors:skef4-5qb95", "collection": "authors", "collection_id": "skef4-5qb95", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150958617", "type": "article", "title": "ATM and RPA in meiotic chromosome synapsis and recombination", "author": [ { "family_name": "Plug", "given_name": "Annemieke W.", "clpid": "Plug-A-W" }, { "family_name": "Peters", "given_name": "Antoine H. F. M.", "clpid": "Peters-A-H-F-M" }, { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Keegan", "given_name": "Kathleen S.", "clpid": "Keegan-K-S" }, { "family_name": "Hoekstra", "given_name": "Merl F.", "clpid": "Hoekstra-M-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "de Boer", "given_name": "Peter", "clpid": "de-Boer-Peter" }, { "family_name": "Ashley", "given_name": "Terry", "clpid": "Ashley-Terry" } ], "abstract": "ATM is a member of the phosphatidylinositol 3-kinase (PIK)like kinases, some of which are active in regulating DNA damage-induced mitotic cell-cycle checkpoints. ATM also plays a role in meiosis. Spermatogenesis in Atm\u2212/\u2212 male mice is disrupted, with chromosome fragmentation leading to meiotic arrest; in human patients with ataxia-telangiectasia (A-T), gonadal atrophy is common. Immuno-localization studies indicate that ATM is associated with sites along the synaptonemal complex (SC), the specialized structure along which meiotic recombination occurs. Recombination, preceded by pairing of homologous chromosomes, is thought to require heteroduplex formation between homologous DNA, followed by strand exchange. These early meiotic steps (entailing the formation and processing of meiotic recombination intermediates with DNA-strand interruptions) require ssDNA-binding proteins such as replication protein A (RPA; refs 5-7). In somatic cells, DNA damage induces ATM-dependent phosphorylation of RPA. We demonstrate here that ATM and RPA co-localize along synapsed meiotic chromosomes and at sites where interactions between ectopic homologous chromosome regions appear to initiate. In Atm\u2212/\u2212 meiotic prophase sper-matocytes, immuno-localization shows that RPA is present along synapsing chromosomes and at sites of fragmentation of the SC. These results suggest that RPA and ATM co-localize at sites where interhomologous-DNA interactions occur during meiotic prophase and where breaks associated with meiotic recombination take place after synapsis, implying a possible functional interaction between these two proteins.", "doi": "10.1038/ng1297-457", "issn": "1061-4036", "publisher": "Nature Publishing Group", "publication": "Nature Genetics", "publication_date": "1997-12", "series_number": "4", "volume": "17", "issue": "4", "pages": "457-461" }, { "id": "authors:rprm5-ka839", "collection": "authors", "collection_id": "rprm5-ka839", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KULpnas97", "type": "article", "title": "Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia", "author": [ { "family_name": "Kuljis", "given_name": "Rodrigo O.", "clpid": "Kuljis-Rodrigo-O" }, { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Aguila", "given_name": "M. Cecilia", "clpid": "Aguila-M-Cecilia" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Neural degeneration is one of the clinical manifestations of ataxia-telangiectasia, a disorder caused by mutations in the Atm protein kinase gene, However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre-and postsynaptic degeneration, These findings are similar to those in patients with ataxia-telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.", "doi": "10.1073/pnas.94.23.12688", "pmcid": "PMC25086", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1997-11-11", "series_number": "23", "volume": "94", "issue": "23", "pages": "12688-12693" }, { "id": "authors:p5jtq-dt489", "collection": "authors", "collection_id": "p5jtq-dt489", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200423-120625235", "type": "article", "title": "NF-\u03baB Activation: The I\u03baB Kinase Revealed?", "author": [ { "family_name": "Stancovski", "given_name": "Ilana", "clpid": "Stancovski-I" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "More than a decade ago, the transcriptional activator NF-\u03baB was described as a protein that bound to a specific DNA site in the intronic enhancer of the immunoglobulin \u03ba light chain gene (Sen and Baltimore 1986). Following the cloning of genes encoding the p50 and p65 subunits of NF-\u03baB, it became evident that both subunits are members of the larger NF-\u03baB/Rel family of transcriptional regulator proteins. Since its initial description, our view of the role of NF-\u03baB in immune and inflammatory responses has broadened significantly (for reviews, see 1, 2).", "doi": "10.1016/s0092-8674(00)80413-4", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1997-10-31", "series_number": "3", "volume": "91", "issue": "3", "pages": "299-302" }, { "id": "authors:3dc7g-d8y54", "collection": "authors", "collection_id": "3dc7g-d8y54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SONpnas97", "type": "article", "title": "Interleukin 3-dependent survival by the Akt protein kinase", "author": [ { "family_name": "Songyang", "given_name": "Zhou", "clpid": "Songyang-Zhou" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cantley", "given_name": "Lewis C.", "clpid": "Cantley-Lewis-C" }, { "family_name": "Kaplan", "given_name": "David R.", "clpid": "Kaplan-David-R" }, { "family_name": "Franke", "given_name": "Thomas F.", "clpid": "Franke-Thomas-F" } ], "abstract": "Interleukin 3 (IL-3)-dependent survival of hematopoietic cells is known to rely on the activity of multiple signaling pathways, including a pathway leading to activation of phosphoinositide 3-kinase (PI 3-kinase), and protein kinase Akt is a direct target of PI 3-kinase. We find that Akt kinase activity is rapidly induced by the cytokine IL-3, suggesting a role for Akt in PI 3-kinase-dependent signaling in hematopoetic cells. Dominant-negative mutants of Akt specifically block Akt activation by IL-3 and interfere with IL-3-dependent proliferation. Overexpression of Akt or oncogenic v-akt protects 32D cells from apoptosis induced by IL-3 withdrawal. Apoptosis after IL-3 withdrawal is accelerated by expression of dominant-negative mutants of Akt, indicating that a functional Akt signaling pathway is necessary for cell survival mediated by the cytokine IL-3. Thus Akt appears to be an important mediator of anti-apoptotic signaling in this system.", "doi": "10.1073/pnas.94.21.11345", "pmcid": "PMC23462", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1997-10-14", "series_number": "21", "volume": "94", "issue": "21", "pages": "11345-11350" }, { "id": "authors:k3e1n-2rp98", "collection": "authors", "collection_id": "k3e1n-2rp98", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120119-140427290", "type": "article", "title": "Localization of the Major NF-\u03baB-activating Site and the Sole TRAF3 Binding Site of LMP-1 Defines Two Distinct Signaling Motifs", "author": [ { "family_name": "Brodeur", "given_name": "Scott R.", "clpid": "Brodeur-Scott-R" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Thorley-Lawson", "given_name": "David A.", "clpid": "Thorley-Lawson-David-A" } ], "abstract": "The TRAF3 molecule interacts with the cytoplasmic carboxyl terminus (COOH terminus) of the Epstein-Barr virus-encoded oncogene LMP-1. NF-\u03baB activation is a downstream signaling event of tumor necrosis factor receptor-associated factor (TRAF) molecules in other signaling systems (CD40 for example) and is an event caused by LMP-1 expression. One region capable of TRAF3 interaction in LMP-1 is the membrane-proximal 45 amino acids (188\u2013242) of the COOH terminus. We show that this region contains the only site for binding of TRAF3 in the 200-amino acid COOH terminus of LMP-1. The site also binds TRAF2 and TRAF5, but not TRAF6. TRAF3 binds to critical residues localized between amino acids 196 and 212 (HHDDSLPHPQQATDDSG), including the PXQX(T/S) motif, that share limited identity to the CD40 receptor TRAF binding site (TAAPVQETL). Mutation of critical residues in the TRAF3 binding site of LMP-1 that prevents binding of TRAF2, TRAF3, and TRAF5 does not affect NF-\u03baB-activating potential. Deletion mapping localized the major NF-\u03baB activating region of LMP-1 to critical residues in the distal 4 amino acids of the COOH terminus (383\u2013386). Therefore, TRAF3 binding and NF-\u03baB activation occur through two separate motifs at opposite ends of the LMP-1 COOH-terminal sequence.", "doi": "10.1074/jbc.272.32.19777", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1997-08-08", "series_number": "32", "volume": "272", "issue": "32", "pages": "19777-19784" }, { "id": "authors:wm2k2-0m877", "collection": "authors", "collection_id": "wm2k2-0m877", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150958808", "type": "article", "title": "Complementation of V(D)J Recombination Deficiency in RAG-1^(\u2212/\u2212) B Cells Reveals a Requirement for Novel Elements in the N-Terminus of RAG-1", "author": [ { "family_name": "Roman", "given_name": "Christopher A. J.", "clpid": "Roman-C-A-J" }, { "family_name": "Cherry", "given_name": "Sara R.", "clpid": "Cherry-Sara-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "RAG-1 is an essential component of the site-specific V(D)J recombinase. A new assay system has revealed a significant contribution of the catalytically dispensible N-terminal region of RAG-1 to recombination activity. The foundation for this system is an Abelson virus-transformed cell line derived from RAG-1^(-/-) mice that is dependent on the introduction of exogenous RAG-1 for rearrangement of either plasmid substrates or the endogenous immunoglobulin loci. Use of this line demonstrates that conserved and novel cysteine-containing elements in the N-terminal region are required for full RAG-1 activity when recombination activity is in a RAG-1 dose-responsive range. Our data suggest that the RAG-1 N-terminus enhances the formation of an active recombination complex that facilitates the rearrangement process.", "doi": "10.1016/s1074-7613(00)80506-3", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1997-07-01", "series_number": "1", "volume": "7", "issue": "1", "pages": "13-24" }, { "id": "authors:2cs8a-gf146", "collection": "authors", "collection_id": "2cs8a-gf146", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEjvir97", "type": "article", "title": "The kB sites in the human immunodeficiency virus type 1 long terminal repeat enhance virus replication yet are not absolutely required for viral growth", "author": [ { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The dependence of human immunodeficiency virus type 1 (HIV-1) on its NF- kappaB binding sites (kappaB sites) for replication in transformed and primary T-cell targets was examined by infecting cells with HIV-1 reporter viruses containing kappaB site enhancer mutations. Viral transcription was measured either with luciferase-expressing HIV-1 that infects for a single round or by flow cytometric analyses with HIV-1 expressing placental alkaline phosphatase (PLAP) or green-fluorescent protein (GFP). Both PLAP- and GFP-expressing viruses spread from cell to cell and allowed analysis of viral gene expression patterns in single cells. Infection of a panel of T-cell lines with different basal levels of NF-kappaB demonstrated a direct correlation between the amount of constitutive nuclear NF-kappaB and the degree to which a wild- type virus outperformed kappaB site mutants. One T-cell line with a constitutively high level of nuclear NF-kappaB, PM1, showed a 20-fold decrease in transcription when its kappaB sites were mutated. In contrast, in a T-cell line with a low basal level of NF-kappaB, SupT1, mutation of the kappaB site in the enhancer had no effect on viral transcription or growth rate. Phytohemagglutinin-activated peripheral blood mononuclear cells showed a large dependence on the kappaB sites for optimal virus growth. Viruses without marker genes corroborated the finding that mutations to the kappaB sites impair virus production in cells with a high basal level of NF-kappaB. These data show that in T cells, HIV-1 can use NF-kappaB to enhance its growth but the virus is clearly able to grow in its absence.", "pmcid": "PMC191791", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1997-07", "series_number": "7", "volume": "71", "issue": "7", "pages": "5495-5504" }, { "id": "authors:74h2t-j4237", "collection": "authors", "collection_id": "74h2t-j4237", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150958917", "type": "article", "title": "Daxx, a Novel Fas-Binding Protein That Activates JNK and Apoptosis", "author": [ { "family_name": "Yang", "given_name": "Xiaolu", "clpid": "Yang-Xiaolu" }, { "family_name": "Khosravi-Far", "given_name": "Roya", "clpid": "Khosravi-Far-R" }, { "family_name": "Chang", "given_name": "Howard Y.", "clpid": "Chang-Howard-Y" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Fas cell surface receptor induces apoptosis upon receptor oligomerization. We have identified a novel signaling protein, termed Daxx, that binds specifically to the Fas death domain. Overexpression of Daxx enhances Fas-mediated apoptosis and activates the Jun N-terminal kinase (JNK) pathway. A C-terminal portion of Daxx interacts with the Fas death domain, while a different region activates both JNK and apoptosis. The Fas-binding domain of Daxx is a dominant-negative inhibitor of both Fas-induced apoptosis and JNK activation, while the FADD death domain partially inhibits death but not JNK activation. The Daxx apoptotic pathway is sensitive to both Bcl-2 and dominant-negative JNK pathway components and acts cooperatively with the FADD pathway. Thus, Daxx and FADD define two distinct apoptotic pathways downstream of Fas.", "doi": "10.1016/s0092-8674(00)80294-9", "pmcid": "PMC2989411", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1997-06-27", "series_number": "7", "volume": "89", "issue": "7", "pages": "1067-1076" }, { "id": "authors:btxgd-rwh93", "collection": "authors", "collection_id": "btxgd-rwh93", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150959025", "type": "article", "title": "Failure of Lymphopoiesis after Adoptive Transfer of NF-\u03baB\u2013Deficient Fetal Liver Cells", "author": [ { "family_name": "Horwitz", "given_name": "Bruce H.", "clpid": "Horwitz-B-H" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Cherry", "given_name": "Sara R.", "clpid": "Cherry-Sara-R" }, { "family_name": "Bronson", "given_name": "Roderick T.", "clpid": "Bronson-R-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Mice deficient in the p65 subunit of NF-\u03baB die during fetal development. Introduction of p50/p65-deficient fetal liver cells into lethally irradiated hosts resulted in a severe deficit of fetal liver\u2013derived lymphocytes and their immediate precursors but an overabundance of fetal liver\u2013derived granulocytes. Surprisingly, simultaneous transplantation of wild-type bone marrow cells rescued the production of p50/p65-deficient lymphocytes. Expression of immunoglobulin \u03ba light chains on these rescued NF-\u03baB\u2013deficient B lymphocytes was normal. These results suggest that while p50 and p65 do not regulate the maturation of pre\u2013B cells, NF-\u03baB mediates the development or survival of an early lymphocyte precursor through regulation of an extracellular factor.", "doi": "10.1016/s1074-7613(00)80451-3", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1997-06-01", "series_number": "6", "volume": "6", "issue": "6", "pages": "765-772" }, { "id": "authors:v4kx7-hf443", "collection": "authors", "collection_id": "v4kx7-hf443", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151000038", "type": "article", "title": "Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation", "author": [ { "family_name": "Baskaran", "given_name": "R.", "clpid": "Baskaran-R" }, { "family_name": "Wood", "given_name": "L. D.", "clpid": "Wood-L-D" }, { "family_name": "Whitaker", "given_name": "L. L.", "clpid": "Whitaker-L-L" }, { "family_name": "Canman", "given_name": "C. E.", "clpid": "Canman-C-E" }, { "family_name": "Morgan", "given_name": "S. E.", "clpid": "Morgan-S-E" }, { "family_name": "Xu", "given_name": "Y.", "clpid": "Xu-Yang" }, { "family_name": "Barlow", "given_name": "C.", "clpid": "Barlow-C" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wynshaw-Boris", "given_name": "A.", "clpid": "Wynshaw-Boris-A" }, { "family_name": "Kastan", "given_name": "M. B.", "clpid": "Kastan-M-B" }, { "family_name": "Wang", "given_name": "J. Y. J.", "clpid": "Wang-J-Y-J" } ], "abstract": "Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm^(-/-) mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl/proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.", "doi": "10.1038/387516a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1997-05-29", "series_number": "6632", "volume": "387", "issue": "6632", "pages": "516-519" }, { "id": "authors:s5z0h-g2z13", "collection": "authors", "collection_id": "s5z0h-g2z13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120203-082031231", "type": "article", "title": "p50\u2013NF\u03baB Complexes Partially Compensate for the Absence of RelB: Severely Increased Pathology in p50^(-/-)relB^(-/-) Double-knockout Mice", "author": [ { "family_name": "Weih", "given_name": "Falk", "clpid": "Weih-Falk" }, { "family_name": "Durham", "given_name": "Stephen K.", "clpid": "Durham-Stephen-K" }, { "family_name": "Barton", "given_name": "Debra S.", "clpid": "Barton-Debra-S" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Bravo", "given_name": "Rodrigo", "clpid": "Bravo-Rodrigo" } ], "abstract": "RelB-deficient mice (relB^(\u2212/\u2212)) have a complex phenotype including multiorgan inflammation and hematopoietic abnormalities. To examine whether other NF-\u03baB/Rel family members are required for the development of this phenotype or have a compensatory role, we have initiated a program to generate double-mutant mice that are deficient in more than one family member. Here we report the phenotypic changes in relB^(\u2212/\u2212) mice that also lack the p50 subunit of NF\u03baB (p50^(\u2212/\u2212)). The inflammatory phenotype of p50^(\u2212/\u2212)relB^(\u2212/\u2212) double-mutant mice was markedly increased in both severity and extent of organ involvement, leading to premature death within three to four weeks after birth. Double-knockout mice also had strongly increased myeloid hyperplasia and thymic atrophy. Moreover, B cell development was impaired and, in contrast to relB^(\u2212/\u2212) single knockouts, B cells were absent from inflammatory infiltrates. Both p50^(\u2212/\u2212) and heterozygous relB^(\u2212/+) animals are disease-free. In the absence of the p50, however, relB^(\u2212/+) mice (p50^(\u2212/\u2212))relB^(\u2212/+) had a mild inflammatory phenotype and moderate myeloid hyperplasia. Neither elevated mRNA levels of other family members, nor increased \u03baB-binding activities of NF-\u03baB/Rel complexes could be detected in single- or double-mutant mice compared to control animals. These results indicate that the lack of RelB is, in part, compensated by other p50-containing complexes and that the \"classical\" p50-RelA\u2013NF-\u03baB activity is not required for the development of the inflammatory phenotype.", "doi": "10.1084/jem.185.7.1359", "pmcid": "PMC2196264", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1997-04-07", "series_number": "7", "volume": "185", "issue": "7", "pages": "1359-1370" }, { "id": "authors:y63tk-vdq35", "collection": "authors", "collection_id": "y63tk-vdq35", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151000172", "type": "article", "title": "Identification of the Abl- and rasGAP-Associated 62 kDa Protein as a Docking Protein, Dok", "author": [ { "family_name": "Yamanashi", "given_name": "Yuji", "clpid": "Yamanashi-Yuji" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A 62 kDa protein is highly phosphorylated in many cells containing activated tyrosine kinases. This protein, characterized mainly by its avid association with rasGAP, has proved elusive. Anti-phosphotyrosine antibody was used to purify p62. From peptide sequence, molecular cloning revealed a cDNA encoding a novel protein, p62^(dok), with little homology to others but with a prominent set of tyrosines and nearby sequences suggestive of SH2 binding sites. In cells, v-Abl tyrosine kinase binds and strongly phosphorylates p62^(dok), which then binds rasGAP. A monoclonal antibody, 2C4, to the rasGAP-associated p62 reacts with p62^(dok). Thus, p62^(dok) appears to be the long-sought major substrate of many tyrosine kinases.", "doi": "10.1016/s0092-8674(00)81841-3", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1997-01-24", "series_number": "2", "volume": "88", "issue": "2", "pages": "205-211" }, { "id": "authors:ef4mm-kdn86", "collection": "authors", "collection_id": "ef4mm-kdn86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CORpnas96", "type": "article", "title": "In vitro V(D)J recombination: Signal joint formation", "author": [ { "family_name": "Cortes", "given_name": "Patricia", "clpid": "Cortes-Patricia" }, { "family_name": "Weis-Garcia", "given_name": "Frances", "clpid": "Weis-Garcia-Frances" }, { "family_name": "Misulovin", "given_name": "Ziva", "clpid": "Misulovin-Ziva" }, { "family_name": "Nussenzweig", "given_name": "Andre", "orcid": "0000-0003-0037-7898", "clpid": "Nussenzweig-A" }, { "family_name": "Lai", "given_name": "Jiann-Shiun", "clpid": "Lai-Jiann-Shiun" }, { "family_name": "Li", "given_name": "Gloria", "clpid": "Li-Gloria" }, { "family_name": "Nussenzweig", "given_name": "Michel C.", "orcid": "0000-0003-0592-8564", "clpid": "Nussenzweig-M-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The first step of V(D)J recombination, specific cleavage at the recombination signal sequence (RSS), can be carried out by the recombination activating proteins RAG1 and RAG2. In vivo, the cleaved coding and signal ends must be rejoined to generate functional antigen receptors and maintain chromosomal integrity. We have investigated signal joint formation using deletion and inversion substrates in a cell free system. RAG1 and RAG2 alone or in combination were unable to generate signal joints. However, RAG1 and RAG2 complemented with nuclear extracts were able to recombine an extrachromosomal substrate and form precise signal joints. The in vitro reaction resembled authentic V(D)J recombination in being Ku-antigen-dependent.", "pmcid": "PMC19485", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1996-11-26", "series_number": "24", "volume": "93", "issue": "24", "pages": "14008-14013" }, { "id": "authors:8eyjc-ty536", "collection": "authors", "collection_id": "8eyjc-ty536", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151000419", "type": "article", "title": "An Essential Role for NF-\u03baB in Preventing TNF-\u03b1-Induced Cell Death", "author": [ { "family_name": "Beg", "given_name": "Amer A,", "clpid": "Beg-A-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Studies on mice deficient in nuclear factor kappa B (NF-\u03baB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-\u03b1 (TNF-\u03b1)-dependent genes. Treatment of RelA-deficient (RelA^(\u2212/\u2212)) mouse fibroblasts and macrophages with TNF-\u03b1 resulted in a significant reduction in viability, whereas RelA^(+/+) cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA^(\u2212/\u2212) fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-\u03b1. These results have implications for the treatment of inflammatory and proliferative diseases.", "doi": "10.1126/science.274.5288.782", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1996-11-01", "series_number": "5288", "volume": "274", "issue": "5288", "pages": "782-784" }, { "id": "authors:z159e-4tq82", "collection": "authors", "collection_id": "z159e-4tq82", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151000309", "type": "article", "title": "Targeted Disruption of TRAF3 Leads to Postnatal Lethality and Defective T-Dependent Immune Responses", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "TRAF3 was found as a protein that binds to the cytoplasmic tail of CD40 but is part of a family of proteins with common structure and activity. To clarify the physiological roles of TRAF3, we introduced a TRAF3 null mutation in mice through homologous recombination. TRAF3-deficient mice appear normal at birth but become progressively runted, correlating with progressive hypoglycemia and depletion of peripheral white cells. The mutant mice die by 10 days of age. Fetal liver cells from TRAF3-deficient embryos can reconstitute all hematopoietic lineages in lethally irradiated mice. However, these reconstituted mice are impaired in their immune responses to T-dependent antigen, and their T cells are functionally defective. These findings indicate that TRAF3 is required for postnatal development and for a competent immune system.", "doi": "10.1016/s1074-7613(00)80497-5", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1996-11-01", "series_number": "5", "volume": "5", "issue": "5", "pages": "407-415" }, { "id": "authors:93aqd-xcw41", "collection": "authors", "collection_id": "93aqd-xcw41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-150841874", "type": "article", "title": "Both multiorgan inflammation and myeloid hyperplasia in RelB-deficient mice are T cell dependent", "author": [ { "family_name": "Weih", "given_name": "Falk", "clpid": "Weih-Falk" }, { "family_name": "Durham", "given_name": "Stephen K.", "clpid": "Durham-Stephen-K" }, { "family_name": "Barton", "given_name": "Debra S.", "clpid": "Barton-Debra-S" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Bravo", "given_name": "Rodrigo", "clpid": "Bravo-Rodrigo" } ], "abstract": "Mice with a targeted disruption of RelB, a member of the Rel/NF-\u03baB family of transcription factors, have multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, and splenomegaly due to extramedullary hemopoiesis. To elucidate the cellular requirements for this complex phenotype, we have bred RelB-deficient (RelB^(\u03baO)) animals to two strains of immunodeficient mice, recombinase-activating gene-1-deficient (RAG-1^(\u03baO), lacking B and T cells), and Nur77/N10-transgenic mice (Nur77/N10^(TG), lacking only T cells). We also generated mutant mice deficient in both RelB and the p50 subunit of NF-\u03baB (p50^(\u03baO), multiple defects in B cell function). RelB^(\u03baO)RAG-1^(\u03baO) and RelB^(\u03baO)Nur77/N10^(TG) mice are disease-free, while RelB^(\u03baO)p50^(\u03baO) double-mutant animals develop an even more severe phenotype despite the absence of B cells in the inflammatory infiltrates. Thus, both multiorgan inflammation and myeloid hyperplasia in RelB-deficient mice are T cell dependent, whereas B cells are not crucially involved.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "1996-11-01", "series_number": "9", "volume": "157", "issue": "9", "pages": "3974-3979" }, { "id": "authors:p44va-d5y61", "collection": "authors", "collection_id": "p44va-d5y61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151000513", "type": "article", "title": "The Homeodomain Region of Rag-1 Reveals the Parallel Mechanisms of Bacterial and V(D)J Recombination", "author": [ { "family_name": "Spanopoulou", "given_name": "Eugenia", "clpid": "Spanopolou-Eugenia" }, { "family_name": "Zaitseva", "given_name": "Florina", "clpid": "Zaitseva-F" }, { "family_name": "Wang", "given_name": "Fu-Hou", "clpid": "Wang-Fu-Hou" }, { "family_name": "Santagata", "given_name": "Sandro", "clpid": "Santagata-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Panayotou", "given_name": "George", "clpid": "Panayotou-G" } ], "abstract": "The V(D)J recombinase subunits Rag-1 and Rag-2 mediate assembly of antigen receptor gene segments. We studied the mechanisms of DNA recognition by Rag-1/Rag-2 using surface plasmon resonance. The critical step for signal recognition is binding of Rag-1 to the nonamer. This is achieved by a region of Rag-1 homologous to the DNA-binding domain of the Hin family of bacterial invertases and to homeodomain proteins. Strikingly, the Hin homeodomain can functionally substitute for the Rag-1 homologous region. Rag-1 also interacts with the heptamer but with low affinity. Rag-2 shows no direct binding to DNA. Once the Rag-1/Rag-2 complex is engaged on the DNA, subsequent cleavage is directed by the heptamer sequence. This order of events remarkably parallels mechanisms that mediate transposition in bacteria and nematodes.", "doi": "10.1016/s0092-8674(00)81344-6", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1996-10-18", "series_number": "2", "volume": "87", "issue": "2", "pages": "263-276" }, { "id": "authors:mvhhq-nef55", "collection": "authors", "collection_id": "mvhhq-nef55", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151001285", "type": "article", "title": "NF-\u03baB: Ten Years After", "author": [ { "family_name": "Baeuerle", "given_name": "Patrick A.", "clpid": "Baeuerle-P-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Almost exactly ten years following the first publication on NF-\u03baB (Sen and Baltimore 1986), researchers working on transcriptional regulation by NF-\u03baB/Rel and I\u03baB proteins gathered for the third time to discuss recent developments in the field (Madrid, July 8-10, 1996). The first meeting of its kind was a Howard Hughes workshop at the NIH in November 1992 and the second one a Banbury Conference held at Cold Spring Harbor in October 1993. This year's meeting was organized by R. Bravo (Bristol-Myers Squibb, Princeton) and P. S. Lazo (Universidad de Oviedo) and held at the Juan March Foundation in Madrid, Spain.", "doi": "10.1016/s0092-8674(00)81318-5", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1996-10-04", "series_number": "1", "volume": "87", "issue": "1", "pages": "13-20" }, { "id": "authors:ea38k-eyz79", "collection": "authors", "collection_id": "ea38k-eyz79", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200422-151001347", "type": "article", "title": "Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Ashley", "given_name": "Terry", "clpid": "Ashley-Terry" }, { "family_name": "Brainerd", "given_name": "Elizabeth E.", "clpid": "Brainerd-E-E" }, { "family_name": "Bronson", "given_name": "Roderick T.", "clpid": "Bronson-R-T" }, { "family_name": "Meyn", "given_name": "M. Stephen", "clpid": "Meyn-M-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control. To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination. Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM-/-) mice are viable, growth-retarded, and infertile. The infertility of ATM-/- mice results from meiotic failure. Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. Immune defects also are evident in ATM-/- mice, including reduced numbers of B220+CD43- pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses. The cerebella of ATM-/- mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression.", "doi": "10.1101/gad.10.19.2411", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1996-10-01", "series_number": "19", "volume": "10", "issue": "19", "pages": "2411-2422" }, { "id": "authors:pjvsd-77w88", "collection": "authors", "collection_id": "pjvsd-77w88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-110624593", "type": "article", "title": "Dual roles of ATM in the cellular response to radiation and in cell growth control", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The gene mutated in ataxia-telangiectasia (AT) patients, denoted ATM, encodes a putative protein or lipid kinase. To elucidate the functions of ATM, we disrupted the mouse ATM gene through homologous recombination in mice. Consistent with cellular defects of AT patients, the ATM-/- cells are hypersensitive to gamma-irradiation and defective in cell-cycle arrest following radiation, correlating with a defective up-regulation of p53. In addition, ATM-/- mouse thymocytes are more resistant to apoptosis induced by gamma-irradiation than normal thymocytes. ATM-/- fibroblasts are inefficient in G1 to S-phase progression following serum stimulation and senesce after only a few passages in culture. They have an increased constitutive level of p21CP1/WAF1. The ATM protein is therefore critical both for cellular responses to ionizing radiation and for normal cell-cycle progression. ATM+/- fibroblasts and thymocytes showed intermediately defective responses to irradiation but no growth defect, suggesting that the increased cancer risk of AT heterozygotes could be attributable to poor checkpoint function.", "doi": "10.1101/gad.10.19.2401", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1996-10-01", "series_number": "19", "volume": "10", "issue": "19", "pages": "2401-2410" }, { "id": "authors:cnhqm-yy076", "collection": "authors", "collection_id": "cnhqm-yy076", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEjvir96", "type": "article", "title": "CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef", "author": [ { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Ghandi", "given_name": "Rajesh T.", "clpid": "Ghandi-Rajesh-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The human immunodeficiency virus type 1 (HIV-1) genes vpu, env, and nef have all been implicated in modulating the levels of cell surface CD4 on infected cells. To quantitatively assess the relative contribution of each gene product to the regulation of CD4 during HIV infection of Jurkat T cells and peripheral blood mononuclear cells, we have developed an infectious HIV reporter system which expresses different combinations of these genes. To distinguish infected cells in the early or late stages of infection from uninfected cells, these viruses were designed to express human placental alkaline phosphatase with the kinetics of either early or late viral genes. Flow cytometry to detect placental alkaline phosphatase and CD4 in infected cells showed that vpu, env, and nef are independently capable of down-modulation of CD4. As predicted by their respective expression patterns, nef down- modulated CD4 rapidly during the early phase of virus infection whereas vpu and env functioned late in the infection. In both Jurkat cells and peripheral blood mononuclear cells, a combination of the three genes was more efficient than any one or two genes, demonstrating that all three genes are required to achieve maximal CD4 down-modulation. In primary cells, down-modulation of CD4 was less efficient than in Jurkat cells and there was a stronger dependence on nef function for reducing cell surface CD4. HIV therefore has three genes that are able to independently down-modulate CD4; together, they can eliminate the bulk of cell surface CD4.", "pmcid": "PMC190625", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1996-09", "series_number": "9", "volume": "70", "issue": "9", "pages": "6044-6053" }, { "id": "authors:nwync-29t16", "collection": "authors", "collection_id": "nwync-29t16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:RUBpnas96", "type": "article", "title": "In vivo tissue distribution of CD4 lymphocytes in mice determined by radioimmunoscintigraphy with an (111)In-labeled anti-CD4 monoclonal antibody", "author": [ { "family_name": "Rubin", "given_name": "Robert H.", "clpid": "Rubin-Robert-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Wilkinson", "given_name": "Robert A.", "clpid": "Wilkinson-Robert-A" }, { "family_name": "Fischman", "given_name": "Alan J.", "clpid": "Fischman-Alan-J" } ], "abstract": "The tissue distribution of CD4 lymphocytes in normal C57/BL mice and CD4 knockout mice was determined by biodistribution measurements and gamma camera imaging with an In-111-labeled rat IgG(2b) monoclonal antibody directed against the murine CD-4 antigen. In normal mice, high concentrations of antibody accumulated in the spleen and lymph nodes, at 45 hr after injection, the concentrations of radiolabel in the spleen and lymph nodes of normal mice were 10- to 20-fold greater than in the corresponding tissues of the CD4 knockout mice and nonlymphoid tissues of both types of mice. At 24 and 45 hr, gamma camera images showed high concentrations of radiolabeled antibody in lymph nodes and spleen of normal but not knockout mice. These results indicate that radioimmunoscintigraphy with In-111-anti-CD4 is an excellent method for studying tissue distribution of CD4 lymphocytes in mice. Using an equivalent anti-human CD4 antibody, this method might be useful for studying the pathophysiology of conditions in which these cells play a critical role and for monitoring therapies for these disorders.", "doi": "10.1073/pnas.93.15.7460", "pmcid": "PMC38766", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1996-07-23", "series_number": "15", "volume": "93", "issue": "15", "pages": "7460-7463" }, { "id": "authors:ve5zm-0dg23", "collection": "authors", "collection_id": "ve5zm-0dg23", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-111419990", "type": "article", "title": "Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130^(Cas)-related protein, Sin", "author": [ { "family_name": "Alexandropoulos", "given_name": "Konstantina", "clpid": "Alexandropoulos-Konstantina" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To understand how protein-protein interactions mediated by the Src-SH3 domain affect c-Src signaling, we screened for proteins that interact with the Src-SH3. We found a novel protein, Sin (Src interacting or signal integrating protein), that binds to Src-SH3 with high affinity, contains numerous tyrosine residues in configurations suggestive of SH2-binding sites, and is related to the v-Src substrate p130^(Cas). In cotransfection assays, a small fragment of Sin retaining the Src-SH3-binding site and one tyrosine-containing motif induced c-Src activation as measured by a transcriptional reporter. Phosphorylation of the peptide on tyrosine by c-Src, as a consequence of Src-SH3 binding, was necessary for its stable interaction with c-Src in vivo and for transcriptional activation. Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a signaling effector molecule for Src by binding to multiple cellular proteins.", "doi": "10.1101/gad.10.11.1341", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1996-06-01", "series_number": "11", "volume": "10", "issue": "11", "pages": "1341-1355" }, { "id": "authors:eftqk-63m75", "collection": "authors", "collection_id": "eftqk-63m75", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PEAjem96", "type": "article", "title": "Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles", "author": [ { "family_name": "Pear", "given_name": "Warren S.", "clpid": "Pear-Warren-S" }, { "family_name": "Aster", "given_name": "Jon C.", "clpid": "Aster-Jon-C" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Hasserjian", "given_name": "Robert P.", "clpid": "Hasserjian-Robert-P" }, { "family_name": "Soffer", "given_name": "Benny", "clpid": "Soffer-Benny" }, { "family_name": "Sklar", "given_name": "Jeffrey", "clpid": "Sklar-Jeffrey" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chromosomal translocation; however, its role in oncogenesis has been unclear. Using a bone marrow reconstitution assay with cells containing retrovirally transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney leukemia virus long terminal repeat drives expression in most hematopoietic cell types, retroviruses encoding either form of the TAN1 protein induced clonal leukemias of exclusively immature T cell phenotypes in approximately 50% of transplanted animals. All tumors overexpressed truncated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprotein and suggest that truncation and overexpression are important determinants of transforming activity. Moreover, the murine tumors caused by TAN1 in the bone marrow transplant model are very similar to the TAN1-associated human tumors and suggest that TAN1 may be specifically oncotropic for T cells.", "doi": "10.1084/jem.183.5.2283", "pmcid": "PMC2192581", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1996-05", "series_number": "5", "volume": "183", "issue": "5", "pages": "2283-2291" }, { "id": "authors:4k72f-yqj94", "collection": "authors", "collection_id": "4k72f-yqj94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-133625002", "type": "article", "title": "Regulation of 3' IgH enhancers by a common set of factors, including \u03baB-binding proteins", "author": [ { "family_name": "Michaelson", "given_name": "Jennifer S.", "clpid": "Michaelson-J-S" }, { "family_name": "Singh", "given_name": "Mallika", "clpid": "Singh-M" }, { "family_name": "Snapper", "given_name": "Clifford M.", "clpid": "Snapper-C-M" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Birshtein", "given_name": "Barbara K.", "clpid": "Birshtein-B-K" } ], "abstract": "Targeted disruption of the p50 subunit of NF-\u03baB resulted in isotype class switch defects resembling those observed in mice in which the downstream IgH enhancer 3'\u03b1E(hs1,2) was deleted. We postulated that \u03ba B binding proteins may regulate class switching by interacting with 3'\u03b1E(hs1,2) or with other IgH 3' enhancers with which 3'\u03b1E(hs1,2) synergizes. \u03baB binding sites were identified in 3'\u03b1E(hs1,2) and 3' \u03b1hs4, the distal 3' IgH enhancer. A \u03baB binding site within 3'\u03b1E(hs1,2) contributes to at least half the activity of the enhancer in plasma cells, while the same \u03baB binding site participates in the complex repression of the enhancer in B cells. In the case of 3'\u03b1-hs4, a \u03baB binding complex activates the enhancer in pre-B, B cells and plasma cells. Additional binding sites within 3'\u03b1-hs4 for factors known to regulate 3'\u03b1E(hs1,2), including Oct-1 and BSAP, were identified, and their contribution to 3'\u03b1-hs4 regulation during B cell development was assessed. Oct-1 positively regulates the enhancer in pre-B and B cells, while BSAP is a repressor in pre-B cells and an activator at the B cell stage. These studies identify \u03baB binding proteins as key modulators of 3'\u03b1E(hs1,2) and 3'\u03b1-hs4, and suggest coregulation of the two enhancers by a common set of factors.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "1996-04-15", "series_number": "8", "volume": "156", "issue": "8", "pages": "2828-2839" }, { "id": "authors:gyjwk-zrt97", "collection": "authors", "collection_id": "gyjwk-zrt97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-112119157", "type": "article", "title": "Deletion of the Ig\u03ba Light Chain Intronic Enhancer/Matrix Attachment Region Impairs but Does Not Abolish V\u03baJ\u03ba Rearrangement", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Davidson", "given_name": "Laurie", "clpid": "Davidson-Laurie" }, { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Roles of the \u03ba intronic enhancer (iE\u03ba) and its asssociated matrix attachment region (MAR) during B cell development were examined using mutant embryonic stem (ES) cell lines in which the entire region on both chromosomes was replaced with either a recombined LoxP site (E\u03baND) or the PGK\u2013neomycin resistance (PGK-neor) gene (E\u03baNI). B cells derived from E\u03baND ES cells had greatly impaired V\u03baJ\u03ba rearrangement, normal levels of \u03ba expression, and \u03ba:\u03bb ratios of 1:1 instead of the usual 10:1. Furthermore, \u03bb-producing hybridomas derived from E\u03baND cells displayed little \u03ba rearrangement. Thus, the MAR and iE\u03ba are quantitatively significant for \u03ba rearrangement but not necessary. In addition, little V\u03baJ\u03ba rearrangement could be detected in B cells derived from E\u03baNI ES cells, demonstrating that an inserted PGK\u2013neor gene dominantly suppresses V\u03baJ\u03ba rearrangement.", "doi": "10.1016/s1074-7613(00)80251-4", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1996-04-01", "series_number": "4", "volume": "4", "issue": "4", "pages": "377-385" }, { "id": "authors:2gvp5-8hs75", "collection": "authors", "collection_id": "2gvp5-8hs75", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROMpnas96", "type": "article", "title": "Genetic evidence that the RAG1 protein directly participates in V(D)J recombination through substrate recognition", "author": [ { "family_name": "Roman", "given_name": "Christopher A. J.", "clpid": "Roman-Christopher-A-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "RAG1 protein is essential for the activation of V(D)J recombination in developing lymphocytes (V, variable; D, diversity; J, joining). However, it has not been determined whether its role involves substrate recognition and catalysis. A single amino acid substitution mutation in the RAG1 gene has now been identified that renders its activity sensitive to the sequence of the coding region abutting the heptamer site in the recombination signal sequence. These results strongly imply that RAG1 interacts directly with DNA.", "doi": "10.1073/pnas.93.6.2333", "pmcid": "PMC39796", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1996-03-19", "series_number": "6", "volume": "93", "issue": "6", "pages": "2333-2338" }, { "id": "authors:2f1s0-ade78", "collection": "authors", "collection_id": "2f1s0-ade78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:XUYpnas96", "type": "article", "title": "Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus", "author": [ { "family_name": "Xu", "given_name": "Yang", "clpid": "Xu-Yang" }, { "family_name": "Davidson", "given_name": "Laurie", "clpid": "Davidson-Laurie" }, { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCR beta), pre-T alpha (pT alpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the early stages of T-cell development. To examine the function of the transmembrane pT alpha chain during thymocyte development, we generated pT alpha(-/-) embryonic stem cells and assayed their ability to differentiate into lymphoid cells in vivo after injection into recombination-activating gene (RAG)-2-deficient blastocysts. Thymocytes representing all stages of T-cell differentiation were detected in the thymus of pT alpha(-/-) chimeric mice, indicating that thymocyte development can occur without pT alpha. However, greatly reduced thymocyte numbers and substantially increased percentages of both CD4(-)CD8(-) thymocytes and TCR gamma delta(+) thymocytes suggest that pT alpha plays a critical role in thymocyte expansion. To investigate the role of the pT alpha chain in allelic exclusion at the TCR beta locus, a functionally rearranged TCR beta minigene was introduced into pT alpha(-/-) and pT alpha(+/-) embryonic stem cells, which were subsequently assayed by RAG-2-deficient blastocyst complementation. In the absence of pT alpha, expression of the transgenic TCR beta inhibited rearrangement of the endogenous TCR beta locus to an extent similar to that seen in normal TCR beta transgenic mice, suggesting that pT alpha may not be required for signaling allelic exclusion at the TCR beta locus.", "doi": "10.1073/pnas.93.5.2169", "pmcid": "PMC39929", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1996-03-05", "series_number": "5", "volume": "93", "issue": "5", "pages": "2169-2173" }, { "id": "authors:kk7cx-71v89", "collection": "authors", "collection_id": "kk7cx-71v89", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-135341480", "type": "article", "title": "B cells from p50/NF-\u03baB knockout mice have selective defects in proliferation, differentiation, germ-line C_H transcription, and Ig class switching", "author": [ { "family_name": "Snapper", "given_name": "Clifford M.", "clpid": "Snapper-C-M" }, { "family_name": "Zelazowski", "given_name": "Piotr", "clpid": "Zelazowski-P" }, { "family_name": "Rosas", "given_name": "Fabio R.", "clpid": "Rosas-F-R" }, { "family_name": "Kehry", "given_name": "Marilyn R.", "clpid": "Kehry-M-R" }, { "family_name": "Tian", "given_name": "Ming", "clpid": "Tian-Ming" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" } ], "abstract": "To better understand the role of NF-\u03baB in normal B cell physiology, we used a purified population of resting B cells from p50/NF-\u03ba B knockout (p50^(-/-)) mice to determine their ability to proliferate, secrete Ig, express germ-line C_H RNA, and undergo Ig isotype switching in vitro in response to a number of distinct stimuli. p50^(-/-) B cells proliferated normally in response to dextran-anti-IgD Abs (\u03b1\u03b4-dex) and membrane-bound, but not soluble, CD40 ligand (CD40), and they were virtually unresponsive to LPS when compared with control B cells. p50^(-/-) B cells secreted markedly reduced Ig in response to \u03b1\u03b4-dex or mCD40L in the presence of IL-4 + IL-5, despite their relatively normal proliferative rates, whereas normal Ig secretion was restored by the combination of \u03b1\u03b4-dex and CD40L. p50^(-/-) B cells expressed normal steady-state levels of germ-line C_H\u03b31 and C_H\u03b1 RNA but markedly reduced germ-line C_H\u03b33 and C_H\u03f5 RNA upon appropriate stimulation. Although p50^(-/-) B cells underwent substantial switching to IgG1, a marked reduction in the switch to IgG3 and IgE, as IgA, was observed. These data are the first to demonstrate key, independent roles for p50/NF-\u03baB in normal B cell maturation to Ig secretion, germ-line CH gene activation, and Ig class switching, as well as mitogenesis, and provide a powerful and well-defined in vitro model system for studying the role of p50/NF-\u03baB in a wide range of normal cellular functions.", "issn": "0022-1767", "publisher": "American Association of Immunologists", "publication": "Journal of Immunology", "publication_date": "1996-01-01", "series_number": "1", "volume": "156", "issue": "1", "pages": "183-191" }, { "id": "authors:156ja-2c740", "collection": "authors", "collection_id": "156ja-2c740", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-154456374", "type": "article", "title": "Discovery of the reverse transcriptase", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "1995 is the 20th anniversity of the award of the Nobel Prize in Physiology or Medicine to David Baltimore and Howard Temin for the discovery of the reverse transcriptase. The prize was shared with Renato Dulbecco.", "doi": "10.1096/fasebj.9.15.8529847", "issn": "0892-6638", "publisher": "Federation of American Societies for Experimental Biology", "publication": "FASEB Journal", "publication_date": "1995-12-01", "series_number": "15", "volume": "9", "issue": "15", "pages": "1660-1663" }, { "id": "authors:knh3r-5ce23", "collection": "authors", "collection_id": "knh3r-5ce23", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200507-153522640", "type": "article", "title": "Localization, interaction, and RNA binding properties of the V(D)J recombination-activating proteins RAG1 and RAG2", "author": [ { "family_name": "Spanopoulou", "given_name": "Eugenia", "clpid": "Spanopolou-Eugenia" }, { "family_name": "Cortes", "given_name": "Patricia", "clpid": "Cortes-Patricia" }, { "family_name": "Shih", "given_name": "Charles", "clpid": "Shih-Charles" }, { "family_name": "Huang", "given_name": "Chun-Ming", "clpid": "Huang-Chun-Ming" }, { "family_name": "Silver", "given_name": "Daniel P.", "clpid": "Silver-Daniel-P" }, { "family_name": "Svec", "given_name": "Pamela", "clpid": "Svec-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The RAG1 and RAG2 gene products are indispensable for activating somatic rearrangement of antigen receptor gene segments. The two proteins form a stable complex in primary thymocytes as well as when expressed in adherent cells. In both cell types, most cells localize RAG proteins at the periphery of the nucleus. However, when overexpressed in fibroblast cells, RAG1 is found largely in the nucleolus. Nucleolar localization of RAG1 is mediated by several domains containing stretches of basic amino acids, indicating that RAG1 has affinity for RNA or ssDNA. The RAG1 interacting proteins SRP1 and Rch1 directly bind to the nuclear localization signals of RAG1, which mediate the nuclear and nucleolar translocation of the protein. RAG1 appears to have a binary structure, each half containing multiple regions that can act as NLSs, binding sites for the SRP1/Rch1 family, and RNA binding domains.", "doi": "10.1016/1074-7613(95)90061-6", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1995-12", "series_number": "6", "volume": "3", "issue": "6", "pages": "715-726" }, { "id": "authors:fkwaz-rt974", "collection": "authors", "collection_id": "fkwaz-rt974", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-080705753", "type": "article", "title": "Constitutive NF-\u03baB activation, enhanced granulopoiesis, and neonatal lethality in I\u03baB\u03b1-deficient mice", "author": [ { "family_name": "Beg", "given_name": "Amer A.", "clpid": "Beg-A-A" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Bronson", "given_name": "Roderick T.", "clpid": "Bronson-R-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Transcription factors belonging to the NF-\u03baB family are controlled by inhibitory I\u03baB proteins, mainly I\u03baB\u03b1 and I\u03baB\u03b2. Apparently normal at birth, I\u03baB\u03b1^(-/-) mice exhibit severe runting, skin defects, and extensive granulopoiesis postnatally, typically dying by 8 days. Hematopoietic tissues from these mice display elevated levels of both nuclear NF-\u03baB and mRNAs of some, but not all, genes thought to be regulated by NF-\u03baB. NF-\u03baB elevation results in these phenotypic abnormalities because mice lacking both I\u03baB\u03b1 and the p50 subunit of NF-\u03baB show a dramatically delayed onset of abnormalities. In contrast to hematopoietic cells, I\u03baB\u03b1^(-/-) embryonic fibroblasts show minimal constitutive NF-\u03baB, as well as normal signal-dependent NF-\u03baB activation that is concomitant with I\u03baB\u03b2 degradation. Our results indicate that I\u03bab\u03b2, but not I\u03baB\u03b1, is required for the signal-dependent activation of NF-\u03baB in fibroblasts. However, I\u03baB\u03b1 is required for the postinduction repression of NF-\u03baB in fibroblasts. These results define distinct roles for the two forms of I\u03baB and demonstrate the necessity for stringent control of NF-\u03baB.", "doi": "10.1101/gad.9.22.2736", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1995-11-15", "series_number": "22", "volume": "9", "issue": "22", "pages": "2736-2746" }, { "id": "authors:fh1k6-vwb48", "collection": "authors", "collection_id": "fh1k6-vwb48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200424-091648599", "type": "article", "title": "HIV-1 Messenger RNA in Peripheral Blood Mononuclear Cells as an Early Marker of Risk for Progression to AIDS", "author": [ { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Stevens", "given_name": "Cladd E.", "clpid": "Stevens-C-E" }, { "family_name": "Rubinstein", "given_name": "Pablo", "clpid": "Rubinstein-Pablo" }, { "family_name": "Taylor", "given_name": "Patricia E.", "clpid": "Taylor-P-E" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Objective: To establish human immunodeficiency virus type 1 (HIV-1) messenger RNA (mRNA) expression in peripheral blood mononuclear cells as a marker of risk for progression to the acquired immunodeficiency syndrome (AIDS) in a large cohort of HIV-infected persons followed for a prolonged period. \n\nDesign: Retrospective testing of cryopreserved, coded specimens. \n\nSetting: Research laboratories at the New York Blood Center and the Rockefeller University. \n\nPatients: 150 homosexual men infected with HIV-1 who did not have an AIDS diagnosis at the time of testing. \n\nMeasurements: Multiply spliced and unspliced HIV-1 mRNAs in total peripheral blood mononuclear cell RNA were quantitated using reverse transcriptase-initiated polymerase chain reaction (PCR) and compared with other laboratory data and clinical outcome during the subsequent 8 years. \n\nResults: Although HIV-1 mRNA expression generally correlated with immunologic status, it was associated with future disease progression independently of CD4+ cell counts or their rate of decrease at the time of sampling. The association of HIV-1 mRNA with disease progression in persons with CD4+ cell counts higher than the median (> 624 cells/mm\u00b3) was particularly noteworthy; further variation in the CD4+ cell counts within this group was not prognostically significant. \n\nConclusions: The expression of HIV-1 mRNA in peripheral blood mononuclear cells is a strong independent marker for future HIV disease progression, even in persons with normal T-cell subsets.", "doi": "10.7326/0003-4819-123-9-199511010-00001", "issn": "0003-4819", "publisher": "American College of Physicians", "publication": "Annals of Internal Medicine", "publication_date": "1995-11-01", "series_number": "9", "volume": "123", "issue": "9", "pages": "641-648" }, { "id": "authors:4cy6c-9sm15", "collection": "authors", "collection_id": "4cy6c-9sm15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-082444534", "type": "article", "title": "Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor", "author": [ { "family_name": "Gurish", "given_name": "Michael F.", "clpid": "Gurish-M-F" }, { "family_name": "Pear", "given_name": "Warren S.", "clpid": "Pear-Warren-S" }, { "family_name": "Stevens", "given_name": "Richard L.", "clpid": "Stevens-R-L" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Sokol", "given_name": "Karen", "clpid": "Sokol-K" }, { "family_name": "Ghildyal", "given_name": "Namit", "clpid": "Ghildyal-N" }, { "family_name": "Webster", "given_name": "Matthew J.", "clpid": "Webster-M-J" }, { "family_name": "Hu", "given_name": "Xuzhen", "clpid": "Hu-Xuzhen" }, { "family_name": "Austen", "given_name": "K. Frank", "clpid": "Austen-K-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Friend", "given_name": "Daniel S.", "clpid": "Friend-D-S" } ], "abstract": "An immature v-abl-transformed mast cell line (V3-MC) was derived from a mouse that developed systemic mastocytosis after transplantation of v-sbl-infected bone marrow cells. V3-MCs injected intravenously into adult BALE/c mice infiltrated the liver, spleen, and intestine by day 6 and underwent progressive differentiation and maturation, eventually resembling indigenous mast cells. In terms of their protease content, the V3-MCs that localized in the liver and spleen differed from those in the intestine, and both differed from the cultured V3-MCs. The acquired expression of certain proteases and the loss of expression of other proteases in these tissue V3-MCs defines particular phenotypes and Indicates that the differentiation and maturation of mast cell-committed progenitor cells are primarily regulated by factors in the different tissue microenvironments.", "doi": "10.1016/1074-7613(95)90087-x", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1995-08", "series_number": "2", "volume": "3", "issue": "2", "pages": "175-186" }, { "id": "authors:mdmas-0ce52", "collection": "authors", "collection_id": "mdmas-0ce52", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-094722356", "type": "article", "title": "The enigma of HIV infection", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The three reviews that follow this introduction reflect contemporary knowledge of human immunodeficiency virus (HIV) infection and disease induction. Let us take a step back and reflect on why this virus infection, against which 10% of the budget of the National Institutes of Health is deployed, remains so enigmatic.", "doi": "10.1016/0092-8674(95)90303-8", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1995-07-28", "series_number": "2", "volume": "82", "issue": "2", "pages": "175-176" }, { "id": "authors:k3dns-7jt90", "collection": "authors", "collection_id": "k3dns-7jt90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-101348818", "type": "article", "title": "Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-\u03baB", "author": [ { "family_name": "Beg", "given_name": "Amer A.", "clpid": "Beg-A-A" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Bronson", "given_name": "Roderick T.", "clpid": "Bronson-R-T" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB, which consists of two polypeptides, p50 (M_r 50K) and p65/RelA (M_r 65K), is thought to be a key regulator of genes involved in responses to infection, inflammation and stress. Indeed, although developmentally normal, mice deficient in p50 display functional defects in immune responses. Here we describe the generation of mice deficient in the RelA subunit of NF-\u03baB. Disruption of the relA locus leads to embryonic lethality at 15\u201316 days of gestation, concomitant with a massive degeneration of the liver by programmed cell death or apoptosis. Embryonic fibroblasts from RelA-deficient mice are defective in the tumour necrosis factor (TNF)-mediated induction of messenger RNAs for I\u03baB\u03b1 and granulocyte/macrophage colony stimulating factor (GM-CSF), although basal levels of these transcripts are unaltered. These results indicate that RelA controls inducible, but not basal, transcription in NF-\u03baB-regulated pathways.", "doi": "10.1038/376167a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1995-07-13", "series_number": "6536", "volume": "376", "issue": "6536", "pages": "167-170" }, { "id": "authors:3bz3w-tw254", "collection": "authors", "collection_id": "3bz3w-tw254", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-102418759", "type": "article", "title": "3BP-1, an SH3 domain binding protein, has GAP activity for Rac and inhibits growth factor-induced membrane ruffling in fibroblasts", "author": [ { "family_name": "Cicchetti", "given_name": "Piera", "clpid": "Cicchetti-P" }, { "family_name": "Ridley", "given_name": "Anne J.", "clpid": "Ridley-A-J" }, { "family_name": "Zheng", "given_name": "Yi", "clpid": "Zheng-Yi" }, { "family_name": "Cerione", "given_name": "Richard A.", "clpid": "Cerione-R-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The SH3 binding protein, 3BP\u20101, was originally cloned as a partial cDNA from an expression library using the Abl SH3 domain as a probe. In addition to an SH3 binding domain, 3BP\u20101 displayed homology to a class of GTPase activating proteins (GAPs) active against Rac and Rho proteins. We report here a full length cDNA of 3BP\u20101 which extends the homology to GAP proteins previously noted. 3BP\u20101 functions in vitro as a GAP with a specificity for Rac\u2010related G proteins. Microinjection of the 3BP\u20101 protein into serum\u2010starved fibroblasts produces an inhibition of platelet\u2010derived growth factor (PDGF)\u2010induced membrane ruffling mediated by Rac. Co\u2010injection of 3BP\u20101 with an activated Rac mutant that is unresponsive to GAPs, counter\u2010acts this inhibition. 3BP\u20101 does not show in vitro activity towards Rho and, in agreement with this finding, microinjection of 3BP\u20101 into fibroblasts has no effect on lysophosphatidic acid (LPA)\u2010induced stress fiber assembly mediated by Rho. Thus 3BP\u20101 is a new and specific Rac GAP that can act in cells to counter Rac\u2010mediated membrane ruffling. How its SH3 binding site interacts with its GAP activity remains to be understood.", "doi": "10.1002/j.1460-2075.1995.tb07315.x", "pmcid": "PMC394374", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1995-07-01", "series_number": "13", "volume": "14", "issue": "13", "pages": "3127-3135" }, { "id": "authors:nvh9c-9w089", "collection": "authors", "collection_id": "nvh9c-9w089", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-144044532", "type": "article", "title": "Thinking about Howard Temin", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Twenty years after the discovery of oncogenes, we have come to Keystone to assess progress and find new pathways to discovery. To begin this homage to the power of molecular biology, I want to go back to the historic roots of this discipline. Each spring there is a gathering of scientists at Cold Spring Harbor to discuss some aspect of contemporary biology and they are published as the Cold Spring Harbor Symposia on Quantitative Biology. That phrase, \"quantitative biology\" seems quaint today--who among us could imagine non-quantitative biology? But those symposia are a record of a new and revolutionary influence on 20th century biology, the desire for quantitative measurement in a field that had been dominated by observation.", "doi": "10.1101/gad.9.11.1303", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1995-06-01", "series_number": "11", "volume": "9", "issue": "11", "pages": "1303-1307" }, { "id": "authors:jgq7t-1en22", "collection": "authors", "collection_id": "jgq7t-1en22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-142417773", "type": "article", "title": "In Memoriam: Howard Temin, the Fierce Scholar", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Howard Temin, who died on February 9, 1994, was driven by the genetic preoccupations of the \"phage group\" to an insight that was fundamental to thedevelopment of contemporary cellular biology. Howard went to Caltech in 1955 to begin graduate studies, and there developed a unique scientific style, blending the influences of Max Delbr\u00fcck and Renato Dulbecco. His work was marked by a devotion to understanding the genetic issues posed by cancer-inducing viruses. This focus on genetics put him firmly in the traditions of American science dating back to the beginning of the century, and his concern with virus-induced cancer also built on a rich past. But Howard's fierce belief in himself, his deep scholarship, and his remarkable insight allowed him to realize a synthesis that made him one of the most creative scientists of the twentieth century.", "doi": "10.1111/j.1749-6632.1995.tb24816.x", "issn": "0077-8923", "publisher": "New York Academy of Sciences", "publication": "Annals of the New York Academy of Sciences", "publication_date": "1995-06", "series_number": "1", "volume": "758", "issue": "1", "pages": "166-166" }, { "id": "authors:6b2vv-9xm60", "collection": "authors", "collection_id": "6b2vv-9xm60", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-130713713", "type": "article", "title": "A Nuclear Tyrosine Kinase Becomes a Cytoplasmic Oncogene", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Alexandropoulos", "given_name": "Konstantina", "clpid": "Alexandropoulos-Konstantina" }, { "family_name": "Cicchetti", "given_name": "Piera", "clpid": "Cicchetti-P" } ], "abstract": "It is a great pleasure to be here at this celebration. My whole scientific career has, of course, been shaped by the discovery in 1953 of the structure of DNA. At that time I was in high school, and hardly aware of it. But I do remember an incident in the late 1950s when, as a college student, I had the rare opportunity to drive Jim Watson from Cold Spring Harbor to a nearby airport on Long Island. At that time he said to me \"There's a virus that's just been discovered that has only a small amount of DNA in it.\" It had to be SV40 or polyoma virus. \"That such a virus is able to cause cancer means that a very small amount of genetic information is all that's required to cause cancer and we should be able to decipher that very quickly,\" he observed. Well, as usual, his insight was remarkable, because those viruses have played a central role in developing the notions of oncogenes; his time line, however, was a little short.", "doi": "10.1111/j.1749-6632.1995.tb24839.x", "issn": "0077-8923", "publisher": "New York Academy of Sciences", "publication": "Annals of the New York Academy of Sciences", "publication_date": "1995-06", "series_number": "1", "volume": "758", "issue": "1", "pages": "339-344" }, { "id": "authors:q6xdc-5ae09", "collection": "authors", "collection_id": "q6xdc-5ae09", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ALEpnas95", "type": "article", "title": "Proline-Rich Sequences that Bind to Src Homology 3 Domains with Individual Specificities", "author": [ { "family_name": "Alexandropoulos", "given_name": "Konstantina", "clpid": "Alexandropoulos-Konstantina" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To study the binding specificity of Src homology 3 (SH3) domains, we have screened a mouse embryonic expression library for peptide fragments that interact with them. Several clones were identified that express fragments of proteins which, through proline-rich binding sites, exhibit differential binding specificity to various SH3 domains. Src-SH3-specific binding uses a sequence of 7 aa of the consensus RPLPXXP, in which the N-terminal arginine is very important. The SH3 domains of the Src-related kinases Fyn, Lyn, and Hck bind to this sequence with the same affinity as that of the Src SH3. In contrast, a quite different proline-rich sequence from the Btk protein kinase binds to the Fyn, Lyn, and Hck SH3 domains, but not to the Src SH3. Specific binding of the Abl SH3 requires a longer, more proline-rich sequence but no arginine. One clone that binds to both Src and Abl SH3 domains through a common site exhibits reversed binding orientation, in that an arginine indispensable for binding to all tested SH3 domains occurs at the C terminus. Another clone contains overlapping yet distinct Src and Abl SH3 binding sites. Binding to the SH3 domains is mediated by a common PXXP amino acid sequence motif present on all ligands, and specificity comes about from other interactions, often ones involving arginine. The rules governing in vivo usage of particular sites by particular SH3 domains are not clear, but one binding orientation may be more specific than another.", "doi": "10.1073/pnas.92.8.3110", "pmcid": "PMC42114", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1995-04-11", "series_number": "8", "volume": "92", "issue": "8", "pages": "3110-3114" }, { "id": "authors:bjswq-tme86", "collection": "authors", "collection_id": "bjswq-tme86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-144658657", "type": "article", "title": "Involvement of CRAF1, a relative of TRAF, in CD40 signaling", "author": [ { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Cleary", "given_name": "Aileen M.", "clpid": "Cleary-A-M" }, { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Hong", "given_name": "David I.", "clpid": "Hong-David-I" }, { "family_name": "Lederman", "given_name": "Seth", "clpid": "Lederman-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "CD40 is a receptor on the surface of B lymphocytes, the activation of which leads to B cell survival, growth, and differentiation. A yeast two-hybrid screen identified a gene, CRAF1, encoding a protein that interacts directly with the CD40 cytoplasmic tail through a region of similarity to the tumor necrosis factor-alpha (TNF-alpha) receptor-associated factors. Overexpression of a truncated CRAF1 gene inhibited CD40-mediated up-regulation of CD23. A region of CRAF1 was similar to the TNF-alpha receptor-associated factors TRAF1 and TRAF2 and so defined a shared TRAF-C domain that was necessary and sufficient for CD40 binding and homodimerization. The CRAF1 sequence also predicted a long amphipathic helix, a pattern of five zinc fingers, and a zinc ring finger. It is likely that other members of the TNF receptor superfamily use CRAF-related proteins in their signal transduction processes.", "doi": "10.1126/science.7533327", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1995-03-10", "series_number": "5203", "volume": "267", "issue": "5203", "pages": "1494-1498" }, { "id": "authors:m3ftn-etk82", "collection": "authors", "collection_id": "m3ftn-etk82", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KOLpnas95", "type": "article", "title": "Reduction of caveolin and caveolae in oncogenically transformed cells", "author": [ { "family_name": "Koleske", "given_name": "Anthony J.", "clpid": "Koleske-Anthony-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Lisanti", "given_name": "Michael P.", "clpid": "Lisanti-Michael-P" } ], "abstract": "Caveolae are flask-shaped non-clathrin-coated invaginations of the plasma membrane. In addition to the demonstrated roles for caveolae in potocytosis and transcytosis, caveolae may regulate the transduction of signals from the plasma membrane. Transformation of NIH 3T3 cells by various oncogenes leads to reductions in cellular levels of caveolin, a principal component of the protein coat of caveolae. The reduction in caveolin correlates very well with the size of colonies formed by these transformed cells when groan in soft agar. Electron microscopy reveals that caveolae are morphologically absent from these transformed cell lines. These observations suggest that functional alterations in caveolae may play a critical role in oncogenic transformation, perhaps by disrupting contact inhibition in transformed cells.", "doi": "10.1073/pnas.92.5.1381", "pmcid": "PMC42523", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1995-02-28", "series_number": "5", "volume": "92", "issue": "5", "pages": "1381-1385" }, { "id": "authors:b3yat-2r007", "collection": "authors", "collection_id": "b3yat-2r007", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-145807990", "type": "article", "title": "Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef\u207a viruses but not for down-regulation of CD4", "author": [ { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Human immunodeficiency virus (HIV) and simian immunodeficiency virus Nef proteins contain a conserved motif with the minimal consensus (PxxP) site for Src homology region 3 (SH3)\u2010mediated protein\u2010protein interactions. Nef PxxP motifs show specific binding to biotinylated SH3 domains of Hck and Lyn, but not to those of other tested Src family kinases or less related proteins. A unique cooperative role of a distant proline is also observed. Endogenous Hck of monocytic U937 cells can be specifically precipitated by matrix\u2010bound HIV\u20101 Nef, but not by mutant protein lacking PxxP. Intact Nef PxxP motifs are dispensable for Nef\u2010induced CD4 down\u2010regulation, but are required for the higher in vitro replicative potential of Nef\u207a viruses. Thus, CD4 down\u2010regulation and promotion of viral growth are two distinct functions of Nef, and the latter is mediated via SH3 binding.", "doi": "10.1002/j.1460-2075.1995.tb07024.x", "pmcid": "PMC398106", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1995-02-01", "series_number": "3", "volume": "14", "issue": "3", "pages": "484-491" }, { "id": "authors:z5jgj-re745", "collection": "authors", "collection_id": "z5jgj-re745", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-152740888", "type": "article", "title": "Modular binding domains in signal transduction proteins", "author": [ { "family_name": "Cohen", "given_name": "George B.", "clpid": "Cohen-G-B" }, { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The transduction of a signal is a change in form of the signal as it is passed from one carrier to another. The root \"duce\" means \"to lead\" in Latin; thus, a signal is led through a cell by steps of transduction (the same root is in the words seduce and duct as well as II Duce). The earliest transduction steps that were elucidated involved massive release of small molecule \"second messengers\", originally cAMP, that flooded a cell with information. With the understanding that such proteins as tyrosine kinases and Ras relatives are signal transducers, came the realization that many signaling pathways are more precise, sending controlled and probably weakly amplified signals to specific targets. These intracellular signals are often maintained in macromolecular form rather than being passed to small molecules.", "doi": "10.1016/0092-8674(95)90406-9", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1995-01-27", "series_number": "2", "volume": "80", "issue": "2", "pages": "237-248" }, { "id": "authors:mpk4d-cqn56", "collection": "authors", "collection_id": "mpk4d-cqn56", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-151210636", "type": "article", "title": "Targeted disruption of the p50 subunit of NF-\u03baB leads to multifocal defects in immune responses", "author": [ { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Tuomanen", "given_name": "Elaine I.", "clpid": "Tuomanen-E-I" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "NF-\u03baB, a heterodimeric transcription factor composed of p50 and p65 subunits, can be activated in many cell types and is thought to regulate a wide variety of genes involved in immune function and development. Mice lacking the p50 subunit of NF-\u03baB show no developmental abnormalities, but exhibit multifocal defects in immune responses involving B lymphocytes and nonspecific responses to infection. B cells do not proliferate in response to bacterial lipopolysaccharide and are defective in basal and specific antibody production. Mice lacking p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. pneumoniae, but are more resistant to infection with murine encephalomyocarditis virus. These data support the role of NF-\u03baB as a vital transcription factor for both specific and nonspecific immune responses, but do not indicate a developmental role for the factor.", "doi": "10.1016/0092-8674(95)90415-8", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1995-01-27", "series_number": "2", "volume": "80", "issue": "2", "pages": "321-330" }, { "id": "authors:yd537-8zc18", "collection": "authors", "collection_id": "yd537-8zc18", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-095145975", "type": "article", "title": "Lessons from People with Nonprogressive HIV Infection", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Infectious diseases can be extremely variable in their manifestations, but human immunodeficiency virus (HIV) infection is notorious for its protean manifestations. One of these, the absence of any apparent progression of disease over a decade or more, is particularly intriguing. The average time from HIV infection to death is 10 years, but clinical and immunologic decline is generally evident much earlier. About 5 percent of infected people are characterized as having nonprogressive infection because they remain healthy and do not have the declining CD4+ lymphocyte counts that are evident in people with progressive disease.1 Although we remain uncertain of their eventual fate, people with long-term nonprogressive infection nonetheless have especially favorable outcomes of an otherwise fatal disease. From these patients we may be able to learn important lessons that could improve the treatment of those with progressive disease. In this issue of the Journal there are three reports of investigations into the possibility that people with long-term nonprogressive infection represent some special circumstance of the virus\u2013host interaction.", "doi": "10.1056/nejm199501263320410", "issn": "0028-4793", "publisher": "Massachusetts Medical Society", "publication": "New England Journal of Medicine", "publication_date": "1995-01-26", "series_number": "4", "volume": "332", "issue": "4", "pages": "259-260" }, { "id": "authors:edqv5-vys14", "collection": "authors", "collection_id": "edqv5-vys14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-154017090", "type": "article", "title": "A butterfly flutters by", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Beg", "given_name": "Amer A.", "clpid": "Beg-A-A" } ], "abstract": "The miracle of X-ray crystallography has brought forth from the chrysalis of NF-\u03baB a butterfly that grips DNA by enveloping it. Two laboratories have solved the biggest DNA-binding domain yet to yield to the combined power of modern X-ray sources, detectors and computers, that of a dimer of the p50 subunit of NF-\u03baB.", "doi": "10.1038/373287a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1995-01-26", "series_number": "6512", "volume": "373", "issue": "6512", "pages": "287-288" }, { "id": "authors:pcyph-cfh07", "collection": "authors", "collection_id": "pcyph-cfh07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200512-154625286", "type": "book_section", "title": "Identification of 3BP-1 in cDNA expression library by SH3 domain screening", "book_title": "Small GTPases and Their Regulators Part B: Rho Family", "author": [ { "family_name": "Cicchetti", "given_name": "Piera", "clpid": "Cicchetti-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "contributor": [ { "family_name": "Hall", "given_name": "Alan", "clpid": "Hall-Alan" }, { "family_name": "Balch", "given_name": "W. E.", "clpid": "Balch-W-E" }, { "family_name": "Der", "given_name": "Channing J.", "clpid": "Der-C-J" } ], "abstract": "This chapter describes a screening procedure to assay for protein\u2013protein interactions using a biotinylated glutathione S-transferase (GST) fusion protein probe to screen cDNA expression libraries. This method is developed to allow nonradioactive probing, which has the additional advantages of a very low background signal and a low incidence of false positives. Because neither the fusion protein probe nor the protein in the expression library is denatured, this assay allows the structural components of the binding reaction to remain intact. This screening procedure offers a practical and highly efficient method of identifying protein\u2013protein interactions. Using this procedure to detect proteins that bound to the Abl SH3 domain, five cDNA clones were isolated out of 7 million cDNA containing plaques that were screened. Of these five, three contained the identical cDNA clone termed \"3BP-1,\" while the other two were identical for a different clone termed \"3BP-2.\" On sequencing these clones, only a short stretch of approximately 40 amino acids was found where sequence similarity existed between these proteins.", "doi": "10.1016/0076-6879(95)56019-x", "isbn": "978-0-12-182157-9", "publisher": "Academic Press", "place_of_publication": "San Diego, CA", "publication_date": "1995", "pages": "140-148" }, { "id": "authors:3jey8-zhr07", "collection": "authors", "collection_id": "3jey8-zhr07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:YEZpnas94", "type": "article", "title": "Binding of Vav to Grb2 through dimerization of Src homology 3 domains", "author": [ { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The protooncogenic protein Vav has the structure of an intracellular signal transducer. It is exclusively expressed in cells of hematopoietic lineage and plays a crucial role in hematopoietic cell differentiation. Here we report that both in cell extracts and within intact mammalian cells Vav binds to Grb2 (Sem-5/ASH/Drk), an adaptor molecule which plays a key role in Ras activation. The interaction became evident from a yeast two-hybrid screen and its specificity was demonstrated by in vitro binding assays. It is mediated by an unusual protein-protein binding reaction: dimerization of specific intact Src homology 3 domains of each of the partners. Signaling during hematopoietic lineage differentiation may therefore involve the tissue-specific signal transducer Vav linking into the ubiquitous pathway involving Grb2 and ultimately Ras.", "doi": "10.1073/pnas.91.26.12629", "pmcid": "PMC45492", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1994-12-20", "series_number": "26", "volume": "91", "issue": "26", "pages": "12629-12633" }, { "id": "authors:3pg02-da395", "collection": "authors", "collection_id": "3pg02-da395", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BARpnas94", "type": "article", "title": "Molecular evolution of the vertebrate immune system", "author": [ { "family_name": "Bartl", "given_name": "Simona", "clpid": "Bartl-Simona" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Weissman", "given_name": "Irving L.", "clpid": "Weissman-Irving-L" } ], "abstract": "An understanding of the evolution of vertebrate immunity is slowly emerging from studies of chordates that share distant\nancestors with mammals. In higher vertebrates, such as birds and mammals, we know that two receptor systems are operative. B cells use immunoglobulins to bind foreign agents (the functionally defined antigens). T cells use T-cell receptors (TCRs) to respond to antigen in the form of processed peptides bound to cell surface proteins encoded in the major histocompatibility complex (MHC). Thus, for T cells, two receptor molecules are required for recognition of antigen. First, the MHC molecule on the infected cell binds the processed antigenic peptide; second, the TCR binds the MHC molecule-antigenic peptide complex.", "doi": "10.1073/pnas.91.23.10769", "pmcid": "PMC45107", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1994-11-08", "series_number": "23", "volume": "91", "issue": "23", "pages": "10769-10770" }, { "id": "authors:t2x5p-n4v06", "collection": "authors", "collection_id": "t2x5p-n4v06", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-074221409", "type": "article", "title": "SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl", "author": [ { "family_name": "Feller", "given_name": "Stephan M.", "clpid": "Feller-S-M" }, { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Hanafusa", "given_name": "Hidesaburo", "clpid": "Hanafusa-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Src homology domains SH2 and SH3 are modular components present in many signal transduction proteins. They allow rapid formation of stable protein complexes and may also regulate protein function through intramolecular binding events. SH2 domains recognize phosphotyrosyl residues in a specific sequence context, while SH3 domains recognize a PxxP motif and additional residues that mediate binding specificity.", "doi": "10.1016/0968-0004(94)90129-5", "issn": "0968-0004", "publisher": "Elsevier", "publication": "Trends in Biochemical Sciences", "publication_date": "1994-11", "series_number": "11", "volume": "19", "issue": "11", "pages": "453-458" }, { "id": "authors:ry3jx-cvb43", "collection": "authors", "collection_id": "ry3jx-cvb43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-075723383", "type": "article", "title": "Engineering poliovirus as a vaccine vector for the expression of diverse antigens", "author": [ { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Silvera", "given_name": "Deborah", "clpid": "Silvera-D" }, { "family_name": "Suggett", "given_name": "Shelley D.", "clpid": "Suggett-S-D" }, { "family_name": "Achacoso", "given_name": "Philip L.", "clpid": "Achacoso-P-L" }, { "family_name": "Miller", "given_name": "Christopher J.", "clpid": "Miller-C-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" } ], "abstract": "As a step toward developing poliovirus as a vaccine vector, poliovirus recombinants were constructed by fusing exogenous peptides (up to 400 amino acids) and an artificial cleavage site for viral protease 3Cpro to the amino terminus of the viral polyprotein. Viral replication proceeded normally. An extended polyprotein was produced in infected cells and proteolytically processed into the complete array of viral proteins plus the foreign peptide, which was excluded from mature virions. The recombinants retained exogenous sequences through successive rounds of replication in culture and in vivo. Infection of animals with recombinants elicited a humoral immune response to the foreign peptides.", "doi": "10.1126/science.8073288", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1994-09-02", "series_number": "5177", "volume": "265", "issue": "5177", "pages": "1448-1451" }, { "id": "authors:0swqw-76089", "collection": "authors", "collection_id": "0swqw-76089", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEpnas94", "type": "article", "title": "Binding of Bruton's Tyrosine Kinase to Fyn, Lyn, or Hck Through a Src Homology 3 Domain-Mediated Interaction", "author": [ { "family_name": "Cheng", "given_name": "Genhong", "clpid": "Cheng-Genhong" }, { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Bruton's tyrosine kinase (Btk) is a recently described B-cell-specific tyrosine kinase. Mutations in this gene lead to human X chromosome-linked agammaglobulinemia and murine X-linked immunodeficiency. Although genetic evidence strongly suggests that Btk plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remains unknown, primarily because the proteins that it interacts with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-aa motifs in Btk. An analogous site with the same specificity is also present in Itk, the T-cell-specific homologue of Btk. Our data extend the range of interactions mediated by Src homology 3 domains and provide an indication of a link between Btk and established signaling pathways in B lymphocytes.", "doi": "10.1073/pnas.91.17.8152", "pmcid": "PMC44563", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1994-08-16", "series_number": "17", "volume": "91", "issue": "17", "pages": "8152-8155" }, { "id": "authors:6ab0v-1h685", "collection": "authors", "collection_id": "6ab0v-1h685", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CORpnas94", "type": "article", "title": "RAG-1 Interacts with the Repeated Amino Acid Motif of the Human Homologue of the Yeast Protein SRP1", "author": [ { "family_name": "Cortes", "given_name": "Patricia", "clpid": "Cortes-Patricia" }, { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Genes for immunoglobulins and T-cell receptor are generated by a process known as V(D)J recombination. This process is highly regulated and mediated by the recombination activating proteins RAG-1 and RAG-2. By the use of the two-hybrid protein interaction system, we isolated a human protein that specifically interacts with RAG-1. This protein is the human homologue of the yeast SRP1 (suppressor of a temperature-sensitive RNA polymerase I mutation). The SRP1-1 mutation is an allele-specific dominant suppressor of a temperature-sensitive mutation in the zinc binding domain of the 190-kDa subunit of Saccharomyces cerevisiae RNA polymerase I. The human SRP cDNA clone was used to screen a mouse cDNA library. We obtained a 3.9-kbp cDNA clone encoding the mouse SRP1. The open reading frame of this cDNA encodes a 538-amino acid protein with eight degenerate repeats of 40-45 amino acids each. The mouse and human SRP1 are 98% identical, while the mouse and yeast SRP1 have 48% identity. After cotransfection of the genes encoding RAG-1 and human SRP1 into 293T cells, a stable complex was evident. Deletion analysis indicated that the region of the SRP1 protein interacting with RAG-1 involved four repeats. The domain of RAG-1 that associates with SRP1 mapped N-terminal to the zinc finger domain. Because this region of RAG-1 is not required for recombination and SRP1 appears to be bound to the nuclear envelope, we suggest that this interaction helps to localize RAG-1.", "doi": "10.1073/pnas.91.16.7633", "pmcid": "PMC44456", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1994-08-02", "series_number": "16", "volume": "91", "issue": "16", "pages": "7633-7637" }, { "id": "authors:kzhch-ks936", "collection": "authors", "collection_id": "kzhch-ks936", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LIOmcb94", "type": "article", "title": "Sequential induction of NF-\u03baB/Rel family proteins during B-cell terminal differentiation", "author": [ { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Sha", "given_name": "William C.", "clpid": "Sha-William-C" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The NF-kappa B/Rel family of at least five transcription factor polypeptides is thought to function both as a developmental regulator in B cells and as a rapid response system in all cells. To examine this notion in more detail, we determined the protein contents of both the inducible and constitutive NF-kappa B/Rel activities in a pre-B-cell line, 70Z/3, and a mature B-cell line, WEHI 231. NF-kappa B p50/p65 is the major inducible nuclear complex after lipopolysaccharide or phorbol myristate acetate treatment of 70Z/3 cells. The constitutive and inducible complexes in WEHI 231 cells are mainly composed of p50 and Rel. The constitutive or induced activities are all sensitive to I kappa B-alpha, but this inhibitor is very short-lived in WEHI 231 cells, suggesting that the balance between synthesis and degradation of I kappa B-alpha determines whether a particular cell lineage has constitutive activity. A patterned expression of the NF-kappa B/Rel activator proteins emerges from an analysis of other B-lineage cell lines and splenic B cells: mainly p50 and p65 in pre-B (and non-B) cells, a predominance of Rel and p50 in mature B cells, and expression of p52 and RelB in plasmacytoma lines. This ordered pattern of regulators may reflect the requirement for expression of different genes during terminal B-cell differentiation because different combinations of NF-kappa B/Rel family members preferentially activate distinct kappa B sites in reporter constructs.", "doi": "10.1128/mcb.14.8.5349", "pmcid": "PMC359054", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1994-08", "series_number": "8", "volume": "14", "issue": "8", "pages": "5349-5359" }, { "id": "authors:a91sr-6wv43", "collection": "authors", "collection_id": "a91sr-6wv43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-080630337", "type": "article", "title": "Functional commitment to helper T cell lineage precedes positive selection and is independent of T cell receptor MHC specificity", "author": [ { "family_name": "Corbella", "given_name": "Paola", "clpid": "Corbella-P" }, { "family_name": "Moskophidis", "given_name": "Demetrius", "clpid": "Moskophidis-D" }, { "family_name": "Spanopoulou", "given_name": "Eugenia", "clpid": "Spanopolou-Eugenia" }, { "family_name": "Mamalaki", "given_name": "Clio", "clpid": "Mamalaki-C" }, { "family_name": "Tolaini", "given_name": "Mauro", "clpid": "Tolaini-M" }, { "family_name": "Itano", "given_name": "Andrea", "clpid": "Itano-A" }, { "family_name": "Lans", "given_name": "Deborah", "clpid": "Lans-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Robeyj", "given_name": "Ellen", "clpid": "Robeyj-E" }, { "family_name": "Kioussis", "given_name": "Dimitris", "clpid": "Kioussis-D" } ], "abstract": "Thymocyte differentiation proceeds from double positive CD4\u207aCD8\u207a to single positive T cells. It has been proposed that this process occurs by an instructive or a stochastic mechanism. In this report, we show that in recombination-deficient mice (RAG-1^(-/-)) constitutive expression of a CD8 transgene allows maturation of CD4\u207a (CD8tg\u207a) cells, which express mature levels of a transgenic class I-restricted T cell receptor, F5. Rescued F5\u207aCD4\u207a (CD8tg\u207a) cells have equivalent levels of T cell receptor expression as CD8end\u207a cells, respond to cognate antigen and, upon stimulation, they exhibit a phenotype characteristic of CD4\u207a helper T cells. These data are consistent with a model of differentiation that predicts that thymocytes become functionally committed to a helper or cytotoxic lineage before the final step of positive selection and independently of MHC specificity of their T cell receptor.", "doi": "10.1016/1074-7613(94)90078-7", "issn": "1074-7613", "publisher": "Elsevier", "publication": "Immunity", "publication_date": "1994-07", "series_number": "4", "volume": "1", "issue": "4", "pages": "269-276" }, { "id": "authors:wavb5-1dc81", "collection": "authors", "collection_id": "wavb5-1dc81", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-081507377", "type": "article", "title": "Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice", "author": [ { "family_name": "Spanopoulou", "given_name": "Eugenia", "clpid": "Spanopolou-Eugenia" }, { "family_name": "Roman", "given_name": "Christopher A. J.", "clpid": "Roman-Christopher-A-J" }, { "family_name": "Corcoran", "given_name": "Lynn M.", "clpid": "Corcoran-Lynn-M" }, { "family_name": "Schlissel", "given_name": "Mark S.", "clpid": "Schlissel-Mark-S" }, { "family_name": "Silver", "given_name": "Daniel P.", "clpid": "Silver-Daniel-P" }, { "family_name": "Nemazee", "given_name": "David", "clpid": "Nemazee-D" }, { "family_name": "Nussenzweig", "given_name": "Michel C.", "orcid": "0000-0003-0592-8564", "clpid": "Nussenzweig-M-C" }, { "family_name": "Shinton", "given_name": "Susan A.", "clpid": "Shinton-S-A" }, { "family_name": "Hardy", "given_name": "Richard R.", "clpid": "Hardy-R-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have examined the regulatory role of the individual components of the immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1\u207b) mice. Complementation with a membrane \u00b5 heavy chain (\u00b5HC) gene allows progression of developmentally arrested Rag-1\u207b pro-B-cells to the small pre-B cell stage, whereas the introduction of independently integrated \u00b5HC and \u03ba light chain (\u03baLC) transgenes promotes the appearance of peripheral lymphocytes which, however, remain unresponsive to external stimuli. Complete reconstitution of the B-cell lineage and the emergence of functionally nature Rag-1\u207b peripheral B cells is achieved by the introduction of cointegrated heavy and light chain transgenes encoding an anti-H-2^k antibody. This experimental system demonstrates the competence of the \u00b5HC and \u03baLC to direct and regulate the sequential stages of B-cell differentiation, defines the time at which negative selection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its presence. These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process.", "doi": "10.1101/gad.8.9.1030", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1994-05-01", "series_number": "9", "volume": "8", "issue": "9", "pages": "1030-1042" }, { "id": "authors:w2xm4-xnz61", "collection": "authors", "collection_id": "w2xm4-xnz61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MAYmcb94", "type": "article", "title": "Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase", "author": [ { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.", "pmcid": "PMC358656", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1994-05", "series_number": "5", "volume": "14", "issue": "5", "pages": "2883-2894" }, { "id": "authors:s6mwm-6rd38", "collection": "authors", "collection_id": "s6mwm-6rd38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-093834948", "type": "article", "title": "Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites", "author": [ { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To understand the normal and oncogenic functions of the protein-tyrosine kinase Abl, the yeast two-hybrid system has been used for identifying proteins that interact with it. One interacting protein is Crk-I, an SH3/SH2-containing adapter protein that was originally identified as the oncogenic element in the avian sarcoma virus CT10. Direct interaction between the Crk-I SH3 and Abl at novel, ~10 amino acid sites just carboxy-terminal to the Abl kinase domain occurs in vitro and in mammalian cells. There is a nearby site specific for binding another adapter, Nck, and these sites also bind Grb-2. When bound to Abl, Crk-I was phosphorylated on tyrosine. Thus, the SH3-binding sites on Abl serve as substrate recognition sites for the relatively nonspecific kinase of Abl. In Crk-I-transformed cells, Crk-I associates with endogenous c-Abl and is phosphorylated on tyrosine. The association of Crk and Abl suggests that Abl could play a role in v-Crk and Crk-I transformation and that normal Abl function may be partly mediated through bound adapter molecules.", "doi": "10.1101/gad.8.7.783", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1994-04-01", "series_number": "7", "volume": "8", "issue": "7", "pages": "783-795" }, { "id": "authors:9b9cm-mdd62", "collection": "authors", "collection_id": "9b9cm-mdd62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ETTjcb94", "type": "article", "title": "The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity", "author": [ { "family_name": "Van Etten", "given_name": "Richard A.", "clpid": "Van-Etten-Richard-A" }, { "family_name": "Jackson", "given_name": "Peter K.", "clpid": "Jackson-Peter-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Sanders", "given_name": "Mitchell C.", "clpid": "Sanders-Mitchell-C" }, { "family_name": "Matsudaira", "given_name": "Paul T.", "clpid": "Matsudaira-Paul-T" }, { "family_name": "Janmey", "given_name": "Paul A.", "clpid": "Janmey-Paul-A" } ], "abstract": "The myristoylated form of c-Abl protein, as well as the P210bcr/abl protein, have been shown by indirect immunofluorescence to associate with F-actin stress fibers in fibroblasts. Analysis of deletion mutants of c-Abl stably expressed in fibroblasts maps the domain responsible for this interaction to the extreme COOH-terminus of Abl. This domain mediates the association of a heterologous protein with F-actin filaments after microinjection into NIH 3T3 cells, and directly binds to F-actin in a cosedimentation assay. Microinjection and cosedimentation assays localize the actin-binding domain to a 58 amino acid region, including a charged motif at the extreme COOH-terminus that is important for efficient binding. F-actin binding by Abl is calcium independent, and Abl competes with gelsolin for binding to F- actin. In addition to the F-actin binding domain, the COOH-terminus of Abl contains a proline-rich region that mediates binding and sequestration of G-actin, and the Abl F- and G-actin binding domains cooperate to bundle F-actin filaments in vitro. The COOH terminus of Abl thus confers several novel localizing functions upon the protein, including actin binding, nuclear localization, and DNA binding. Abl may modify and receive signals from the F-actin cytoskeleton in vivo, and is an ideal candidate to mediate signal transduction from the cell surface and cytoskeleton to the nucleus.", "doi": "10.1083/jcb.124.3.325", "pmcid": "PMC2119935", "issn": "0021-9525", "publisher": "Rockefeller University Press", "publication": "Journal of Cell Biology", "publication_date": "1994-02-01", "series_number": "3", "volume": "124", "issue": "3", "pages": "325-340" }, { "id": "authors:c178x-9tv55", "collection": "authors", "collection_id": "c178x-9tv55", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SAKpnas94", "type": "article", "title": "Human Immunodeficiency Virus Type 1 mRNA Expression in Peripheral Blood Cells Predicts Disease Progression Independently of the Numbers of CD4+ Lymphocytes", "author": [ { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Stevens", "given_name": "Cladd", "clpid": "Stevens-Cladd" }, { "family_name": "Rubinstein", "given_name": "Pablo", "clpid": "Rubinstein-Pablo" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To address the significance of human immunodeficiency virus (HIV) replication in peripheral blood mononuclear cells (PBMCs), we have used reverse transcriptase-initiated PCR to measure HIV-1 mRNA expression in PBMC specimens collected from a cohort of HIV-infected individuals during a long-term prospective study. We found dramatic differences in HIV mRNA expression among individuals with very similar clinical and laboratory indices, and this variation strongly correlated with the future course of the disease. No evidence of viral replication was detected in PBMCs from asymptomatic individuals who, thereafter, had normal levels of CD4+ cells for at least 5 years. Irrespective of whether the CD4+ cell numbers were normal at the time of sampling, abundant expression of HIV-1 mRNA in PBMCs predicted accelerated disease progression within the next 2 years. Thus, independently of what may be the rate of HIV replication in other viral reservoirs, such as lymphatic tissue, the amount of HIV mRNA in PBMCs appears to reflect the subsequent development of HIV disease. We have also used the reverse transcriptase-initiated PCR assay to demonstrate a transient response to 3'-azido-3'-deoxythymidine treatment. Determination of HIV-1 mRNA expression in the PBMCs of infected individuals could, therefore, have significant clinical utility as a prognostic indicator and as a means to guiding and monitoring antiviral therapies.", "doi": "10.1073/pnas.91.3.1104", "pmcid": "PMC521462", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1994-02-01", "series_number": "3", "volume": "91", "issue": "3", "pages": "1104-1108" }, { "id": "authors:094es-p4x77", "collection": "authors", "collection_id": "094es-p4x77", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHEjvir94", "type": "article", "title": "Distinct modes of human immunodeficiency virus type 1 proviral latency revealed by superinfection of nonproductively infected cell lines with recombinant luciferase-encoding viruses", "author": [ { "family_name": "Chen", "given_name": "Benjamin K.", "clpid": "Chen-Benjamin-K" }, { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To study the basis of cellular latency of human immunodeficiency virus (HIV), we have used a recombinant luciferase-encoding HIV (HXB-Luc) to superinfect nonproductively HIV-1-infected human leukemic cell lines. HXB-Luc contains the Photinus pyralis luciferase gene in place of the nef gene and provides a highly sensitive, simple assay for HIV infection and expression. To circumvent any superinfection block in latently infected cells, we also generated viruses pseudotyped with murine leukemia virus amphotropic envelope (HXB-Luc:ampho). The parental uninfected lines, U937 and A3.01, from which the latently infected cell lines U1 and ACH-2, respectively, were derived could be readily infected with pseudotyped or nonpseudotyped reporter viruses. However, superinfection of U1 cells with either HXB-Luc or HXB-Luc:ampho resulted in only low levels of luciferase activity. Like the endogenous provirus, HXB-Luc provirus could be efficiently activated by phorbol ester treatment of HXB-Luc:ampho-superinfected U1 cells. In contrast, superinfection of ACH-2 cells resulted in active expression of the secondarily introduced virus even in unstimulated cells and luciferase production higher than in the parental cell line A3.01. Thus, the proviral latency in U1 cells appears to result from a defect in the cellular environment (a trans effect), whereas the latency in ACH-2 is specific to the integrated provirus and is probably a cis effect due to the site of integration. These results demonstrate distinct modes of proviral latency in these two cell line models and may have implications in our understanding of the regulation and significance of cellular latency in HIV infection.", "pmcid": "PMC236499", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1994-02", "series_number": "2", "volume": "68", "issue": "2", "pages": "654-660" }, { "id": "authors:5ynpr-9nr11", "collection": "authors", "collection_id": "5ynpr-9nr11", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-131711374", "type": "article", "title": "Functional Analysis of the TAN-1 Gene, a Human Homolog of Drosophila Notch", "author": [ { "family_name": "Aster", "given_name": "J.", "clpid": "Aster-J" }, { "family_name": "Pear", "given_name": "W.", "clpid": "Pear-W" }, { "family_name": "Hasserjian", "given_name": "R.", "clpid": "Hasserjian-R" }, { "family_name": "Erba", "given_name": "H.", "clpid": "Erba-H" }, { "family_name": "Davi", "given_name": "F.", "clpid": "Davi-F" }, { "family_name": "Luo", "given_name": "B.", "clpid": "Luo-B" }, { "family_name": "Scott", "given_name": "M.", "clpid": "Scott-M" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Sklar", "given_name": "J.", "clpid": "Sklar-J" } ], "abstract": "The TAN-1 gene was originally discovered at the breakpoint of a recurrent (7;9)(q34;q34.3) chromosomal translocation found in a subset of human T-lymphoblastic leukemias (Reynolds et al. 1987; Smith et al. 1988; Ellisen et al. 1991). This translocation joins roughly the 3\u2032 half of TAN-1 head-to-head with the 3\u2032 portion of the \u03b2 T-cell-receptor gene (TCRB) beginning at the 5\u2032 boundary of one or the other J segment. Intact TAN-1 is normally transcribed into an 8.2-kb transcript that is present in many tissues, most abundantly in developing thymus and spleen (Ellisen et al. 1991). This tissue distribution and the apparent involvement of an altered version of the gene in T-cell cancers have suggested that TAN-1 normally has some special function in lymphocytes or their precursors.", "doi": "10.1101/sqb.1994.059.01.016", "issn": "0091-7451", "publisher": "Cold Spring Harbor Laboratory", "publication": "Cold Spring Harbor Symposia on Quantitative Biology", "publication_date": "1994-01-01", "volume": "59", "pages": "125-136" }, { "id": "authors:cqbwz-yy346", "collection": "authors", "collection_id": "cqbwz-yy346", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SAKjvir93", "type": "article", "title": "High viral load in lymph nodes and latent human immunodeficiency virus (HIV) in peripheral blood cells of HIV-1-infected chimpanzees", "author": [ { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Muchmore", "given_name": "Elizabeth", "clpid": "Muchmore-E" }, { "family_name": "Girard", "given_name": "Marc", "clpid": "Girard-Marc" }, { "family_name": "Fultz", "given_name": "Patricia", "clpid": "Fultz-Patricia" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have examined human immunodeficiency virus type 1 (HIV-1) infection in chimpanzees by analyzing HIV-1 DNA and RNA in lymph nodes and peripheral mononuclear cells (PBMCs). Like certain asymptomatic HIV-infected persons, these chimpanzees had no detectable viral replication in their PBMCs. However, viral replication and a high viral load were observed in the lymphatic tissue. Despite the absence of viral replication in PBMCs, 1/1,000 to 1/10,000 of the PBMCs contained HIV-1 proviral DNA, and HIV transcription could be rapidly induced in these cells in vitro. These results provide direct evidence of cellular latency of HIV in vivo and suggest that HIV infection in chimpanzees may be a useful model for clinical latency of HIV infection in humans.", "pmcid": "PMC238207", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1993-12", "series_number": "12", "volume": "67", "issue": "12", "pages": "7423-7427" }, { "id": "authors:rm15k-64x58", "collection": "authors", "collection_id": "rm15k-64x58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120307-141507389", "type": "article", "title": "\u03c0, a Pre-B-Cell-Specific Enhancer Element in the Immunoglobulin Heavy-Chain Enhancer", "author": [ { "family_name": "Libermann", "given_name": "Towia A.", "clpid": "Libermann-Towia-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have identified a new immunoglobulin heavy-chain enhancer element, designated \u03c0, between the \u00b5E2 and \u00b5E3 elements. The \u03c0 enhancer element is transcriptionally active primarily during early stages of B-cell development but becomes virtually inactive during B-cell maturation at about the stage of immunoglobulin K light-chain gene rearrangement. Mutational analysis suggests that the \u03c0 element is crucial for immunoglobulin heavy-chain enhancer activity at the pre-B-cell stage but is almost irrelevant for enhancer activity at the mature B-cell or plasma-cell stage. The activity of the \u03c0 enhancer element correlates with the presence of an apparently pre-B-cell-specific protein-DNA complex. The similarity of the \u03c0 site to recognition sequences for members of the ets gene family suggests that the protein(s) interacting with the \u03c0 site most likely are ets-related transcription factors.", "doi": "10.1128/MCB.13.10.5957", "pmcid": "PMC364640", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-10", "series_number": "10", "volume": "13", "issue": "10", "pages": "5957-5969" }, { "id": "authors:avb0f-ddz34", "collection": "authors", "collection_id": "avb0f-ddz34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120308-093523110", "type": "article", "title": "Production of high-titer helper-free retroviruses by transient transfection", "author": [ { "family_name": "Pear", "given_name": "Warren S.", "clpid": "Pear-Warren-S" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The generation of high-titer, helper-free retroviruses by transient transfection has been achieved by using the highly transfectable 293T cell line into which are stably introduced constructs that express retroviral packaging functions. The resulting ecotropic virus packaging cell line BOSC 23 produces infectious retrovirus at > 10^(6) infectious units/ml of supernatant within 72 hr after CaPO_(4)-mediated transfection. A stringent assay for replication-competent virus showed that no helper virus was present. The system can produce high titers of retroviral vectors expressing genes that are extremely difficult to propagate at high titer in stable producer lines. This method should facilitate and extend the use of helper-free retroviral gene transfer, as well as be useful for gene therapy.", "doi": "10.1073/pnas.90.18.8392", "pmcid": "PMC47362", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1993-09-15", "series_number": "18", "volume": "90", "issue": "18", "pages": "8392-8396" }, { "id": "authors:qj83r-dxn68", "collection": "authors", "collection_id": "qj83r-dxn68", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-095146080", "type": "article", "title": "Shattuck Lecture -- Misconduct in Medical Research", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In his Shattuck Lecture as published in the Journal (June 3 issue), Congressman John Dingell says that the Subcommittee on Oversight and Investigations of the U.S. House of Representatives, which he chairs, has \"looked only at clear-cut cases involving fabrication, falsification, or plagiarism.\" He then includes among these cases the investigation by his subcommittee of a 1986 paper published in Cell, by Dr. Thereza Imanishi-Kari and others, including myself. Congressman Dingell's lecture is replete with suggestions that it is an established fact that fabrication was involved in the writing of the paper. He is incorrect, as shown by the published record as well as the statements of the U.S. Attorney for Maryland.", "doi": "10.1056/nejm199309023291012", "issn": "0028-4793", "publisher": "Massachusetts Medical Society", "publication": "New England Journal of Medicine", "publication_date": "1993-09-02", "series_number": "10", "volume": "329", "issue": "10", "pages": "732-734" }, { "id": "authors:6hgxq-qf665", "collection": "authors", "collection_id": "6hgxq-qf665", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-132321186", "type": "article", "title": "Poliovirus RNA synthesis utilizes an RNP complex formed around the 5\u2032-end of viral RNA", "author": [ { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Rieckhof", "given_name": "Gabrielle E.", "clpid": "Rieckhof-Gabrielle-E" }, { "family_name": "Achacoso", "given_name": "Philip L.", "clpid": "Achacoso-P-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The structure of a ribonucleoprotein complex formed at the 5\u2032\u2010end of poliovirus RNA was investigated. This complex involves the first 90 nucleotides of poliovirus genome which fold into a cloverleaf\u2010like structure and interact with both uncleaved 3CD, the viral protease\u2010polymerase precursor, and a 36 kDa ribosome\u2010associated cellular protein. The cellular protein is required for complex formation and interacts with unpaired bases in one stem\u2010loop of the cloverleaf RNA. Amino acids within the 3C protease which are important for RNA binding were identified by site\u2010directed mutagenesis and the crystal structure of a related protease was used to model the RNA binding domain within the viral 3CD protein. The physiologic importance of the ribonucleic\u2010protein complex is suggested by the finding that mutations that disrupt complex formation abolish RNA replication but do not affect RNA translation or stability. Based on these structural and functional findings we propose a model for the initiation of poliovirus RNA synthesis where an initiation complex consisting of 3CD, a cellular protein, and the 5\u2032\u2010end of the positive strand RNA catalyzes in trans the initiation of synthesis of new positive stranded RNA.", "doi": "10.1002/j.1460-2075.1993.tb06032.x", "pmcid": "PMC413634", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1993-09-01", "series_number": "9", "volume": "12", "issue": "9", "pages": "3587-3598" }, { "id": "authors:xspbp-eq658", "collection": "authors", "collection_id": "xspbp-eq658", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120308-110917005", "type": "article", "title": "Stimulation of \u03ba Light-Chain Gene Rearrangement by the\n Immunoglobulin, \u00b5 Heavy Chain in a Pre-B-Cell Line", "author": [ { "family_name": "Shapiro", "given_name": "Alan M.", "clpid": "Shapiro-Alan-M" }, { "family_name": "Schlissel", "given_name": "Mark S.", "clpid": "Schlissel-Mark-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "DeFranco", "given_name": "Anthony L.", "clpid": "DeFranco-Anthony-L" } ], "abstract": "B-lymphocyte development exhibits a characteristic order of immunoglobulin gene rearrangements. Previous work has led to the hypothesis that expression of the immunoglobulin \u00b5 heavy chain induces rearrangement activity at the K light-chain locus. To examine this issue in more detail, we isolated five matched pairs of \u00b5^- and endogenously rearranged \u00b5^+ cell lines from the Abelson murine leukemia virus-transformed pro-B-cell line K.40. In four of the five \u00b5^+ cell lines, substantial expression of \u00b5 protein on the cell surface was observed, and this correlated with an enhanced frequency of K immunoglobulin gene rearrangement compared with that in the matched \u00b5^- cell lines. This increased K gene rearrangement frequency was not due to a general increase in the amount of V(D)J recombinase activity in the \u00b5^+ cells. Consistently, introduction of a functionally rearranged \u00b5 gene into one of the \u00b5^- pre-B-cell lines resulted in a fivefold increase in K gene rearrangements. In three of the four clonally matched pairs with increased K gene rearrangements, the increase in rearrangement frequency was not accompanied by a significant increase in germ line transcripts from the C_K locus. However, in the fourth pair, K.40D, we observed an increase in germ line transcription of the kappa locus after expression of \u00b5 protein encoded by either an endogenously rearranged or a transfected functional heavy-chain allele. In these cells, the amount of the germ line C_K transcript correlated with the measured frequency of rearranged K genes. These results support a regulated model of B-cell development in which \u00b5 protein expression in some way targets the V(D)J recombinase to the K gene locus.", "doi": "10.1128/MCB.13.9.5679", "pmcid": "PMC360301", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-09", "series_number": "9", "volume": "13", "issue": "9", "pages": "5679-5690" }, { "id": "authors:men8s-84a61", "collection": "authors", "collection_id": "men8s-84a61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-135823678", "type": "article", "title": "The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-\u03baB p50 homodimers", "author": [ { "family_name": "Fujita", "given_name": "Takashi", "clpid": "Fujita-Takashi" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The candidate proto-oncogene bcl-3 encodes a protein that shares structural features with I\u03baB-\u03b1 and other proteins that bind to members of the Rel protein family. Here, we show that in contrast to the inhibitory activity of I\u03baB-\u03b1, the bcl-3 gene product superactivates NF-\u03baB p50 homodimer-mediated gene expression both in vivo and in vitro. BCL-3 protein can, as well, selectively associate with p50 homodimers in the presence of DNA containing a \u03baB motif. These results strongly suggest that BCL-3 can act as a transcriptional coactivator, acting through DNA-bound p50 homodimers.", "doi": "10.1101/gad.7.7b.1354", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1993-07-01", "series_number": "7b", "volume": "7", "issue": "7b", "pages": "1354-1363" }, { "id": "authors:g2b2r-dvk06", "collection": "authors", "collection_id": "g2b2r-dvk06", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-140848808", "type": "article", "title": "The p65 subunit of NF-\u03baB regulates I\u03baB by two distinct mechanisms", "author": [ { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Fujita", "given_name": "Takashi", "clpid": "Fujita-Takashi" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Transcription factor NF-\u03baB (p50/p65) is generally localized to the cytoplasm by its inhibitor I\u03baB. Overproduced I\u03baB, free from NF-\u03baB, is rapidly degraded. Overexpression of p65 increases endogenous I\u03baB protein in both carcinoma and lymphoid cells by two mechanisms: protein stabilization and increased transcription of I\u03baB mRNA. In contrast, p65\u0394, a naturally occurring splice variant, fails to markedly augment I\u03baB protein levels. Both overexpressed p65 and coexpressed p50 are cytoplasmic, whereas p65\u0394 is partly nuclear, indicating that the I\u03baB induced by p65 can maintain NF-\u03baB in the cytoplasm. Thus, p65 and I\u03baB are linked in an autoregulatory loop, ensuring that NF-\u03baB is held in the cytoplasm until cells are specifically induced to translocate it to the nucleus.", "doi": "10.1101/gad.7.7a.1266", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1993-07-01", "series_number": "7a", "volume": "7", "issue": "7a", "pages": "1266-1276" }, { "id": "authors:pakfd-nde53", "collection": "authors", "collection_id": "pakfd-nde53", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-133107304", "type": "article", "title": "Hormone-conditional transformation by fusion proteins of c-Abl and its transforming variants", "author": [ { "family_name": "Jackson", "given_name": "Peter", "clpid": "Jackson-Peter-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Picard", "given_name": "Didier", "clpid": "Picard-D" } ], "abstract": "Fusion of the hormone binding domain (HBD) of steroid receptors to transcription factors renders them hormone\u2010dependent. We show here that an SH3\u2010deleted, oncogenic variant of the Abl tyrosine kinase becomes hormone\u2010dependent for transformation by fusion to the estrogen receptor (ER) HBD, extending the phenomenon to tyrosine kinases. Surprisingly, fusion of the HBD to the normal, non\u2010transforming c\u2010Abl (IV) protein activated transforming activity in a hormone\u2010dependent fashion. In the presence of hormone, the c\u2010Abl:ER fusion protein was transforming, cytoplasmic and tyrosine phosphorylated, whereas it was non\u2010transforming, nuclear and hypophosphorylated without hormone. We have examined the kinetics of activation of the c\u2010Abl:ER protein and found that protein synthesis is required both for kinase activation and for redistribution of the c\u2010Abl:ER protein from the nucleus to the cytoplasm. We suggest that the activation of c\u2010Abl could be due to HBD\u2010mediated dimerization and/or to the ability to overexpress conditionally the normally toxic c\u2010Abl protein. This novel approach may be applicable to a wide variety of proteins, particularly when activating mutations or physiological inducers are unknown or when the protein is toxic to cells.", "doi": "10.1002/j.1460-2075.1993.tb05942.x", "pmcid": "PMC413531", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1993-07-01", "series_number": "7", "volume": "12", "issue": "7", "pages": "2809-2819" }, { "id": "authors:yd14c-3pt35", "collection": "authors", "collection_id": "yd14c-3pt35", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120307-154008004", "type": "article", "title": "Dispensable sequence motifs in the RAG-1 and RAG-2 genes for\n plasmid V(D)J recombination", "author": [ { "family_name": "Silver", "given_name": "Daniel P.", "clpid": "Silver-Daniel-P" }, { "family_name": "Spanopoulou", "given_name": "Eugenia", "clpid": "Spanopolou-Eugenia" }, { "family_name": "Mulligan", "given_name": "Richard C.", "clpid": "Mulligan-Richard-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "As a probe of whether RAG-1 and RAG-2 gene products activate other genes or form part of the recombinase itself, certain mutants of the RAG genes were assayed for their ability to activate variable-diversity-joining region [V(D)J] recombination in a plasmid substrate in fibroblasts. The results indicate that the N-terminal one-third of RAG-1, including a zinc-finger-like domain, and an acidic domain of RAG-2 are dispensable for activating V(D)J recombination in a fibroblast, although they contribute quantitatively. In contrast, deletion of the C-terminal segment of RAG-1, which has homology to a topoisomerase-like protein from yeast, abolished recombination activation. These results do not support the hypothesis that the RAG gene products are transcription factors and suggest the possibility that they are parts of the recombination machinery.", "doi": "10.1073/pnas.90.13.6100", "pmcid": "PMC46875", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1993-07-01", "series_number": "13", "volume": "90", "issue": "13", "pages": "6100-6104" }, { "id": "authors:y1w4q-ve489", "collection": "authors", "collection_id": "y1w4q-ve489", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200424-113155449", "type": "article", "title": "Mutation of a phenylalanine conserved in SH3-containing tyrosine kinases activates the transforming ability of c-Abl", "author": [ { "family_name": "Jackson", "given_name": "P. K.", "clpid": "Jackson-P-K" }, { "family_name": "Paskind", "given_name": "M.", "clpid": "Paskind-Michael" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "c-abl is the normal cellular homolog of the v-abl transforming gene of Abelson murine leukemia virus. By constructing recombinants between c- and v-abl retroviruses, we show that a point mutation in c-Abl is sufficient to change the myristoylated form of c-Abl into a protein able to transform fibroblasts, but not capable of transforming bone marrow or inducing Abelson disease. This activating mutation, which changes the phenylalanine at amino acid 420 to valine (F420V) found in the homologous position of v-Abl, is positioned outside of the SH3 domain, a region typically modified in transforming alleles of abl. Phenylalanine 420 is perfectly conserved among tyrosine kinases with N-terminal SH3 domains (the Src and Abl families). The equivalent position in other protein tyrosine kinases is a conserved hydrophobic residue that predicts the specific family to which that kinase belongs. Mutation of phenylalanine 420 to other hydrophobic residues activates c-Abl. Unlike other transforming variants of Abl, the F420V mutant protein is not highly phosphorylated on tyrosine. Mutation of the nearby proposed autophosphorylation site, tyrosine 412, shows that this tyrosine is not strictly required for fibroblast transformation in either F420V or SH3-deleted variants of c-Abl (IV).", "issn": "0950-9232", "publisher": "Oncogene", "publication": "Oncogene", "publication_date": "1993-07", "series_number": "7", "volume": "8", "issue": "7", "pages": "1943-1956" }, { "id": "authors:z0h11-8dt92", "collection": "authors", "collection_id": "z0h11-8dt92", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-144023678", "type": "article", "title": "Regulation of the NF-\u03b7B/rel transcription factor and I\u03b7B inhibitor system", "author": [ { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The interplay between proteins of the NF-\u03b7B/rel and I\u03b7B families is a tightly regulated process that ensures appropriate responses to specific environmental and developmental signals. Various mechanisms are utilized in regulating NF-\u03b7B/rel and IxB activities, some unique to this transcription factor system. All of these regulatory strategies converge towards one purpose, namely the controlled nuclear translocation of activated NF-\u03b7B/rel protein complexes. The variety of rel-related and ankyrin repeat containing subunits makes regulation of this system both rich and complicated.", "doi": "10.1016/0955-0674(93)90014-h", "issn": "0955-0674", "publisher": "Elsevier", "publication": "Current Opinion in Cell Biology", "publication_date": "1993-06", "series_number": "3", "volume": "5", "issue": "3", "pages": "477-487" }, { "id": "authors:6pcxh-6y554", "collection": "authors", "collection_id": "6pcxh-6y554", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-142724228", "type": "article", "title": "Gerhard Domagk Lecture", "author": [ { "family_name": "Domagk", "given_name": "Gerhard", "clpid": "Domagk-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Gerhard Domagk (1895-1964) was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery of the antibacterial effects of Prontosil, the first of the sulfonamide drugs.\n\nDavid Baltimore shared, with Renato Dulbecco and Howard Temin, the Nobel Prize for Physiology or Medicine in 1975 for discoveries concerning the interaction between tumor viruses and genetic material of host cells and the role of reverse transcriptase.", "doi": "10.1111/j.1749-6632.1993.tb35900.x", "issn": "0077-8923", "publisher": "New York Academy of Sciences", "publication": "Annals of the New York Academy of Sciences", "publication_date": "1993-06", "series_number": "1", "volume": "685", "issue": "1", "pages": "420-420" }, { "id": "authors:w1snz-av291", "collection": "authors", "collection_id": "w1snz-av291", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:NOLmcb93", "type": "article", "title": "The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner", "author": [ { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Fujita", "given_name": "Takashi", "clpid": "Fujita-Takashi" }, { "family_name": "Bhatia", "given_name": "Kishor", "clpid": "Bhatia-Kishor" }, { "family_name": "Huppi", "given_name": "Conrad", "clpid": "Huppi-Conrad" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The product of the putative proto-oncogene bcl-3 is an I kappa B-like molecule with novel binding properties specific for a subset of the rel family of transcriptional regulators. In vitro, Bcl-3 protein specifically inhibited the DNA binding of both the homodimeric NF-kappa B p50 subunit and a closely related homolog, p52 (previously p49), to immunoglobulin kappa NF-kappa B DNA motifs. Bcl-3 could catalyze the removal of these proteins from DNA. At concentrations that significantly inhibited DNA binding by homodimeric p50, Bcl-3 did not inhibit binding of reconstituted heterodimeric NF-kappa B (p50:p65), a DNA-binding homodimeric form of p65, or homodimers of c-Rel. Phosphatase treatment of Bcl-3 partially inactivated its inhibitory properties, implicating a role for phosphorylation in the regulation of Bcl-3 activity. Bcl-3, like p50, localizes to the cell nucleus. In cells cotransduced with Bcl-3 and p50, both molecules could be found in the nucleus of the same cells. Interestingly, coexpression of Bcl-3 with a p50 mutant deleted for its nuclear-localizing signal resulted in the relocalization of Bcl-3 to the cytoplasm, showing that the proteins interact in the cell. These properties contrast Bcl-3 to classically defined I kappa B, which maintains heterodimeric NF-kappa B p50:p65 in the cytoplasm through specific interactions with the p65 subunit. Bcl-3 appears to be a nuclear, I kappa B-related molecule that regulates the activity of homodimeric nuclear p50 and its homolog p52.", "doi": "10.1128/mcb.13.6.3557", "pmcid": "PMC359825", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-06", "series_number": "6", "volume": "13", "issue": "6", "pages": "3557-3566" }, { "id": "authors:31ytb-0h906", "collection": "authors", "collection_id": "31ytb-0h906", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SAKmcb93", "type": "article", "title": "Negative regulation of immunoglobulin kappa light-chain gene transcription by a short sequence homologous to the murine B1 repetitive element", "author": [ { "family_name": "Saksela", "given_name": "Kalle", "clpid": "Saksela-Kalle" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "B-cell-specific expression of the immunoglobulin kappa light-chain (Ig kappa) gene is in part accomplished by negative regulatory influences. Here we describe a new negatively acting element (termed kappa NE) immediately upstream of the NF-kappa B-binding site in the Ig kappa intronic enhancer. The 27-bp kappa NE sequence is conserved in the corresponding positions in the rabbit and human Ig kappa genes, and the human kappa NE homolog was shown to have a similar negative regulatory activity. Data base searches using the mouse kappa NE sequence revealed a striking homology to murine B1 repetitive sequences. A sequence homologous to kappa NE and B1 was also noted in a previously identified silencer element in the murine T-cell receptor alpha locus. The homologous T-cell receptor alpha locus sequence, but notably not a corresponding 27-bp B1 consensus sequence, showed a negative regulatory potential similar to that of kappa NE. The negative effect of kappa NE by itself was not cell type specific but became so when paired with its 5'-flanking sequence in the Ig kappa enhancer. A short (30-bp) fragment upstream of kappa NE (termed kappa BS) was found to be necessary and sufficient for abolishing the negative effect of kappa NE in B cells. Point mutations in a T-rich motif within the kappa BS sequence allowed the transcriptional repression by kappa NE to be evident in B cells as well as other cells. As suggested by this cell-independent negative activity, proteins binding to the mouse and human kappa NE sequences were identified in all cell types tested.", "doi": "10.1128/mcb.13.6.3698", "pmcid": "PMC359843", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-06", "series_number": "6", "volume": "13", "issue": "6", "pages": "3698-3705" }, { "id": "authors:xbb82-02x08", "collection": "authors", "collection_id": "xbb82-02x08", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-144502804", "type": "article", "title": "A putative modular domain present in diverse signaling proteins", "author": [ { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Clark", "given_name": "Kirk L.", "clpid": "Clark-K-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Proteins involved in signal transduction consist of one or more modular domains. These modules can confer catalytic or structural functions or mediate protein-protein interactions. Src homology 3 (SH3) domains are presumed to mediate associations between signaling proteins (Mayer and Baltimore, 1993; Pawson and Gish, 1992), and several SH3-binding proteins have been isolated (Cicchetti et al., 1992). We have noticed that one of these SH3-binding proteins, termed 3BP2 (Cicchetti et al., 1992; Ren et al., 1993), contains a 100 amino acid region with sequence similarity to several other proteins. The presence of this putative domain in a variety of contexts in proteins implicated in signaling suggests that it might function, like SH2 and SH3 domains, to mediate protein associations. Since this region was first noted (as a duplicated region) in the platelet protein pleckstrin (Tyers et al., 1988), we propose that this putative domain be termed the pleckstrin homology, or PH, domain.", "doi": "10.1016/0092-8674(93)90244-k", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1993-05-21", "series_number": "4", "volume": "73", "issue": "4", "pages": "629-630" }, { "id": "authors:1atv2-rq195", "collection": "authors", "collection_id": "1atv2-rq195", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-145713907", "type": "article", "title": "Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival", "author": [ { "family_name": "Corcoran", "given_name": "Lynn M.", "clpid": "Corcoran-Lynn-M" }, { "family_name": "Karvelas", "given_name": "Maria", "clpid": "Karvelas-M" }, { "family_name": "Nossal", "given_name": "G. J. V.", "clpid": "Nossal-G-J-V" }, { "family_name": "Ye", "given_name": "Zheng-Sheng", "clpid": "Ye-Zheng-Sheng" }, { "family_name": "Jacks", "given_name": "Tyler", "clpid": "Jacks-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Oct-2, a POU homeo domain transcription factor, is believed to stimulate B-cell-restricted expression of immunoglobulin genes through binding sites in immunoglobulin gene promoters and enhancers. To determine whether Oct-2 is required for B-cell development or function, or has other developmental roles, the gene was disrupted by homologous recombination. Oct-2^(-/-) mice develop normally but die within hours of birth for undetermined reasons. Mutants contain normal numbers of B-cell precursors but are somewhat deficient in IgM+ B cells. These B cells have a marked defect in their capacity to secrete immunoglobulin upon mitogenic stimulation in vitro. Thus, Oct-2 is not required for the generation of immunoglobulin-bearing B cells but is crucial for their maturation to immunoglobulin-secreting cells and for another undetermined organismal function.", "doi": "10.1101/gad.7.4.570", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1993-04-01", "series_number": "4", "volume": "7", "issue": "4", "pages": "570-582" }, { "id": "authors:30s8a-ve263", "collection": "authors", "collection_id": "30s8a-ve263", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120308-110427034", "type": "article", "title": "The Immunoglobulin Heavy Chain Locus Contains Another\n B-Cell-Specific 3' Enhancer Close to the \u03b1 Constant Region", "author": [ { "family_name": "Matthias", "given_name": "Patrick", "clpid": "Matthias-Patrick" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The transcription of immunoglobulin genes is controlled by variable region promoters and by enhancers, both of which are lymphoid specific. Because immunoglobulin genes are subject to an extremely complex regulation, we anticipated that there might be additional control elements for these genes. We therefore sought additional enhancers and demonstrate here that there is indeed another weak transcriptional enhancer just 3' to the mouse alpha constant region. This novel immunoglobulin enhancer is lymphoid specific and at two positions can bind members of the Oct family of transcription factors.", "doi": "10.1128/MCB.13.3.1547", "pmcid": "PMC359466", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-03", "series_number": "3", "volume": "13", "issue": "3", "pages": "1547-1553" }, { "id": "authors:efw7f-yne90", "collection": "authors", "collection_id": "efw7f-yne90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-151928911", "type": "article", "title": "Identification of a ten-amino acid proline-rich SH3 binding site", "author": [ { "family_name": "Ren", "given_name": "Ruibao", "clpid": "Ren-Ruibao" }, { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Cicchetti", "given_name": "Piera", "clpid": "Cicchetti-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Src homology 3 (SH3) region is a small protein domain present in a very large group of proteins, including cytoskeletal elements and signaling proteins. It is believed that SH3 domains serve as modules that mediate protein-protein associations and, along with Src homology 2 (SH2) domains, regulate cytoplasmic signaling. The SH3 binding sites of two SH3 binding proteins were localized to a nine- or ten-amino acid stretch very rich in proline residues. Similar SH3 binding motifs exist in the formins, proteins that function in pattern formation in embryonic limbs of the mouse, and one subtype of the muscarinic acetylcholine receptor. Identification of the SH3 binding site provides a basis for understanding the interaction between the SH3 domains and their targets.", "doi": "10.1126/science.8438166", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1993-02-19", "series_number": "5098", "volume": "259", "issue": "5098", "pages": "1157-1161" }, { "id": "authors:bvj7s-hej12", "collection": "authors", "collection_id": "bvj7s-hej12", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-152803250", "type": "article", "title": "Signalling through SH2 and SH3 domains", "author": [ { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In 1986, Pawson's group recognized a region of homology between two oncogenic tyrosine kinases that lay outside the catalytic domain. They termed this the Src homology 2, or SH2, domain. In the ensuing years, SH2 domains have been found in an impressive variety of proteins, as has a second region of homology, inevitably termed SH3. These domains appear to mediate controlled protein-protein interactions. Many proteins that contain SH2 and SH3 domains are involved in signal transduction, suggesting a new paradigm for regulation of intracellular signalling pathways.", "doi": "10.1016/0962-8924(93)90194-6", "issn": "0962-8924", "publisher": "Elsevier", "publication": "Trends in Cell Biology", "publication_date": "1993-01", "series_number": "1", "volume": "3", "issue": "1", "pages": "8-13" }, { "id": "authors:7thhj-yfz84", "collection": "authors", "collection_id": "7thhj-yfz84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KAMmcb93", "type": "article", "title": "E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice", "author": [ { "family_name": "Kamps", "given_name": "Mark P.", "clpid": "Kamps-Mark-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "One-quarter of pediatric pre-B-cell leukemias contain the t(1;19) chromosomal translocation, which fuses 5' exons encoding the transactivation domain of the E2A transcription factor gene to 3' exons ecoding the putative DNA-binding region of the unusual homeobox gene, PBX1. To test the leukemic potential of this fused gene, a cDNA encoding its major protein product, p85E2A-Pbx1, was incorporated into a retrovirus construct and introduced into normal mouse marrow progenitors by infection. The cells were used in a bone marrow transplantation protocol to reconstitute the hematopoietic compartments of lethally irradiated recipients. After 3 to 8 months, reconstituted mice developed acute myeloid leukemias that expressed high levels of p85E2A-Pbx1 and were readily transmissible to immunocompetent mice. Most acute myeloid leukemias also grew as granulocytic sarcomas and exhibited some neutrophilic differentiation. These results demonstrate a causative role for p85E2A-Pbx1 in human acute leukemia and indicate that the oncogenic potential of Pbx1 is not limited to pre-B-cell malignancies.", "doi": "10.1128/mcb.13.1.351", "pmcid": "PMC358914", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1993-01", "series_number": "1", "volume": "13", "issue": "1", "pages": "351-357" }, { "id": "authors:cvxfh-h3q91", "collection": "authors", "collection_id": "cvxfh-h3q91", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:OVEpnas92", "type": "article", "title": "Secondary structure of Src homology 2 domain of c-Abl by heteronouclear NMR spectroscopy in solution", "author": [ { "family_name": "Overduin", "given_name": "Michael", "clpid": "Overduin-Michael" }, { "family_name": "Mayer", "given_name": "Bruce", "clpid": "Mayer-Bruce-J" }, { "family_name": "Rios", "given_name": "Carlos B.", "clpid": "Rios-Carlos-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cowburn", "given_name": "David", "clpid": "Cowburn-David" } ], "abstract": "The Src homology 2 (SH2) domain is a recognition motif thought to mediate the association of the cytoplasmic proteins involved in signal transduction by binding to phosphotyrosyl-containing sequences in proteins. Assignments of nearly all 1H and 15N resonances of the SH2 domain from the c-Abl protein-tyrosine kinase have been obtained from homonuclear and heteronuclear NMR experiments. The secondary structure has been elucidated from the pattern of nuclear Overhauser effects, from vicinal coupling constants, and from observation of slowly exchanging amino hydrogens. The secondary structure contains two \u03b1-helices and eight \u03b2-strands, six of which are arranged in two contiguous, antiparallel \u03b2-sheets. Residues believed to be involved in phosphotyrosyl ligand binding are on a face of one \u03b2-sheet. The alignment of homologous sequences on the basis of secondary structure suggests a conserved global fold in a family of SH2 domains.", "doi": "10.1073/pnas.89.24.11673", "pmcid": "PMC50618", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1992-12-15", "series_number": "24", "volume": "89", "issue": "24", "pages": "11673-11677" }, { "id": "authors:vtyb8-sw821", "collection": "authors", "collection_id": "vtyb8-sw821", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SESpnas92", "type": "article", "title": "Blocked early-stage latency in the peripheral blood cells of certain individuals infected with human immunodeficiency virus type 1", "author": [ { "family_name": "Seshamma", "given_name": "Thikkavarapu", "clpid": "Seshamma-Thikkavarapu" }, { "family_name": "Bagasra", "given_name": "Omar", "clpid": "Bagasra-Omar" }, { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Pomerantz", "given_name": "Roger J.", "clpid": "Pomerantz-Roger-J" } ], "abstract": "Human immunodeficiency virus type 1 (HIV-1) infections of humans have a natural history characterized by a variable but usually slow progression to an immunodeficient state. We have described a molecular model of HIV-1 proviral latency in certain cell lines, characterized by extremely low or undetectable levels of unspliced genomic HIV-1-specific RNA but significant levels of multiply spliced HIV-1-specific RNA. We have utilized a quantitative reverse transcriptase-initiated polymerase chain reaction to measure the levels of various HIV-1 RNA species in peripheral blood mononuclear cells. The median level of multiply spliced HIV-1 RNA was dramatically higher than the median level of unspliced viral RNA in asymptomatic individuals. In addition, HIV-1 RNA patterns characterized by at least a 10-fold excess of multiply spliced to unspliced viral RNA were significantly more common in asymptomatic individuals than in patients with the acquired immunodeficiency syndrome. We suggest that asymptomatic clinical HIV-1 infection is characterized by a preponderance of HIV-1-infected peripheral blood cells blocked at an early stage of HIV-1 infection. This viral expression pattern, which we have called blocked early-stage latency, may constitute a reservoir of latently infected cells in certain HIV-1-infected persons.", "doi": "10.1073/pnas.89.22.10663", "pmcid": "PMC50401", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1992-11-15", "series_number": "22", "volume": "89", "issue": "22", "pages": "10663-10667" }, { "id": "authors:zpb77-a0z70", "collection": "authors", "collection_id": "zpb77-a0z70", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-104032929", "type": "article", "title": "Three-dimensional solution structure of the src homology 2 domain of c-abl", "author": [ { "family_name": "Overduin", "given_name": "Michael", "clpid": "Overduin-M" }, { "family_name": "Rios", "given_name": "Carlos B.", "clpid": "Rios-Carlos-B" }, { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cowburn", "given_name": "David", "clpid": "Cowburn-D" } ], "abstract": "SH2 regions are protein motifs capable of binding target protein sequences that contain a phosphotyrosine. The solution structure of the abl SH2 product, a protein of 109 residues and 12.1 kd, has been determined by multidimensional nuclear magnetic resonance spectroscopy. It is a compact spherical domain with a pair of three-stranded antiparallel \u03b2 sheets and a C-terminal \u03b1 helix enclosing the hydrophobic core. Three arginines project from a short N-terminal \u03b1 helix and one \u03b2 sheet into the putative phosphotyrosine-binding site, which lies on a face distal from the termini. Comparison with other SH2 sequences supports a common global fold and mode of phosphotyrosine binding for this family.", "doi": "10.1016/0092-8674(92)90437-h", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1992-08-21", "series_number": "4", "volume": "70", "issue": "4", "pages": "697-704" }, { "id": "authors:nwvmy-42d17", "collection": "authors", "collection_id": "nwvmy-42d17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-153340587", "type": "article", "title": "Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides", "author": [ { "family_name": "Waksman", "given_name": "Gabriel", "clpid": "Waksman-G" }, { "family_name": "Kominos", "given_name": "Dorothea", "clpid": "Kominos-D" }, { "family_name": "Robertson", "given_name": "Scott C.", "clpid": "Robertson-S-C" }, { "family_name": "Pant", "given_name": "Nalin", "clpid": "Pant-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Birge", "given_name": "Raymond B.", "clpid": "Birge-R-B" }, { "family_name": "Cowburn", "given_name": "David", "clpid": "Cowburn-David" }, { "family_name": "Hanafusa", "given_name": "Hidesaburo", "clpid": "Hanafusa-H" }, { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Overduin", "given_name": "Michael", "clpid": "Overduin-Michael" }, { "family_name": "Resh", "given_name": "Marilyn D.", "clpid": "Resh-M-D" }, { "family_name": "Rios", "given_name": "Carlos B.", "clpid": "Rios-Carlos-B" }, { "family_name": "Silverman", "given_name": "Lauren", "clpid": "Silverman-L" }, { "family_name": "Kuriyan", "given_name": "John", "clpid": "Kuriyan-J" } ], "abstract": "Three-dimensional structures of complexes of the SH2 domain of the v-src oncogene product with two phosphotyrosyl peptides have been determined by X-ray crystallography at resolutions of 1.5 and 2.0 \u00c5, respectively. A central antiparallel \u03b2-sheet in the structure is flanked by two \u03b1-helices, with peptide binding mediated by the sheet, intervening loops and one of the helices. The specific recognition of phosphotyrosine involves amino\u2013aromatic interactions between lysine and arginine side chains and the ring system in addition to hydrogen-bonding interactions with the phosphate.", "doi": "10.1038/358646a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1992-08-20", "series_number": "6388", "volume": "358", "issue": "6388", "pages": "646-653" }, { "id": "authors:7dykq-m5y95", "collection": "authors", "collection_id": "7dykq-m5y95", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-150240015", "type": "article", "title": "Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho", "author": [ { "family_name": "Cicchetti", "given_name": "Piera", "clpid": "Cicchetti-P" }, { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Thiel", "given_name": "Gerald", "clpid": "Thiel-G" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A Src homology 3 (SH3) region is a sequence of approximately 50 amino acids found in many nonreceptor tyrosine kinases and other proteins. Deletion of the SH3 region from the protein encoded by the c-abl proto-oncogene activates the protein's transforming capacity, thereby suggesting the participation of the SH3 region in the negative regulation of transformation. A complementary DNA was isolated that encoded a protein, 3BP-1, to which the SH3 region of Abl bound with high specificity and to which SH3 regions from other proteins bound differentially. The sequence of the 3BP-1 protein is similar to that of a COOH-terminal segment of Bcr and to guanosine triphosphatase-activating protein (GAP)-rho, which suggests that it might have GAP activity for Ras-related proteins. The 3BP-1 protein may therefore be a mediator of SH3 function in transformation inhibition and may link tyrosine kinases to Ras-related proteins.", "doi": "10.1126/science.1379745", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1992-08-07", "series_number": "5071", "volume": "257", "issue": "5071", "pages": "803-806" }, { "id": "authors:5twx2-5bh85", "collection": "authors", "collection_id": "5twx2-5bh85", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-151613822", "type": "article", "title": "NF-\u03baB p50 precursor, p105, contains an internal I\u03baB-like inhibitor that preferentially inhibits p50", "author": [ { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Fujita", "given_name": "Takashi", "clpid": "Fujita-Takashi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The p50 subunit of NF\u2010\u03baB is apparently synthesized as a precursor molecule of 105 kDa (p105); subsequent processing releases the amino\u2010terminal p50 polypeptide with rel homology, DNA binding activity and transcriptional activation potential. The carboxy\u2010terminal region of p105 contains seven copies of an ankyrin\u2010related sequence previously found in several genes involved in differentiation and cell cycle control. Two proteins with I\u03baB activity, MAD\u20103 and pp40, have been cloned and found to contain five obvious ankyrin repeats that align with those in the carboxy\u2010terminus of p105. Both proteins target their inhibitory activity to the p65 subunit of NF\u2010\u03baB and to c\u2010rel. Here we show that the bacterially expressed and purified carboxy\u2010terminal region (CTR) of p105 abolishes the binding of p50 homodimers to a \u03baB motif but minimally affects the binding of p65 homodimers and NF\u2010\u03baB. By contrast, MAD\u20103 inhibits the binding of p65 and NF\u2010\u03baB but not p50. Both the CTR and MAD\u20103 interact with their respective targets through physical association both in vitro and in vivo. The CTR can be expressed as an independent entity and thus may play two roles, as a cis inhibitor built into the p105 molecule and as a trans regulator of p50.", "doi": "10.1002/j.1460-2075.1992.tb05370.x", "pmcid": "PMC556782", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1992-08", "series_number": "8", "volume": "11", "issue": "8", "pages": "3003-3009" }, { "id": "authors:pdy49-36e94", "collection": "authors", "collection_id": "pdy49-36e94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-154625749", "type": "article", "title": "Independent modes of transcriptional activation by the p50 and p65 subunits of NF-\u03baB", "author": [ { "family_name": "Fujita", "given_name": "Takashi", "clpid": "Fujita-Takashi" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Recombinant subunits of the transcription factor NF-\u03baB, p50 and p65, were analyzed both for binding to various \u03baB motifs and in vitro activation. The subunits preferentially form a heterodimer that activates transcription. Although p50 and p65 bind DNA individually as homodimers and are structurally related, their activation mechanisms are distinct. p65 activates transcription by its unique carboxy-terminal activation domain. (p50)\u2082 displays higher affinity DNA binding than (p65)\u2082 for many distinct \u03baB motifs and provides strong transcriptional activation only when adopting a chymotrypsin-resistant conformation induced by certain \u03baB motifs but not others. Thus, (p50)\u2082 acts as a positive regulator in vitro, consistent with its isolation as a putative constitutive regulator of MHC class I genes. Both subunits of NF-\u03baB, therefore, contribute independently to provide regulation at given \u03baB motifs.", "doi": "10.1101/gad.6.5.775", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1992-05-01", "series_number": "5", "volume": "6", "issue": "5", "pages": "775-787" }, { "id": "authors:5rbej-bnt35", "collection": "authors", "collection_id": "5rbej-bnt35", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120328-134128939", "type": "article", "title": "Different molecular consequences of the 1;19 chromosomal translocation in childhood B-cell precursor acute lymphoblastic leukemia", "author": [ { "family_name": "Privitera", "given_name": "Enrica", "clpid": "Privitera-Enrica" }, { "family_name": "Kamps", "given_name": "Mark P.", "clpid": "Kamps-Mark-P" }, { "family_name": "Hayashi", "given_name": "Yasuhide", "clpid": "Hayashi-Yasuhide" }, { "family_name": "Inaba", "given_name": "Toshiya", "clpid": "Inaba-Toshiya" }, { "family_name": "Shapiro", "given_name": "Linda H.", "clpid": "Shapiro-Linda-H" }, { "family_name": "Raimondi", "given_name": "Susana C.", "clpid": "Raimondi-Susana-C" }, { "family_name": "Behm", "given_name": "Frederic", "clpid": "Behm-Frederic" }, { "family_name": "Hendershot", "given_name": "Linda", "clpid": "Hendershot-Linda" }, { "family_name": "Carroll", "given_name": "Andrew J.", "clpid": "Carroll-Andrew-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Look", "given_name": "A. Thomas", "clpid": "Look-A-Thomas" } ], "abstract": "The prognostically important 1;19 chromosomal translocation can alter the E2A gene on chromosome 19p13 in childhood B-cell precursor acute lymphoblastic leukemia (ALL), leading to formation of a fusion gene (E2A-PBX1) that encodes a hybrid transcription factor with oncogenic potential. It is not known whether this molecular alteration is a uniform consequence of the t(1;19) or is restricted to translocation events within specific immunologic subtypes of the disease. Therefore, we studied leukemic cells from 25 cases of B-cell precursor ALL, with or without evidence of cytoplasmic Ig mu heavy chains (cIg); 17 cases had the t(1;19) by cytogenetic analysis. Leukemic cell DNA samples were analyzed by Southern blotting to detect alterations within the E2A genomic locus; a polymerase chain reaction assay was used to identify expression of chimeric E2A-pbx1 transcripts in leukemic cell RNA; and immunoblotting with anti-Pbx1 antibodies was used to detect hybrid E2A- Pbx1 proteins. Of 11 cases of cIg+ ALL with the t(1;19), 10 had E2A- pbx1 chimeric transcripts with identical junctions and a characteristic set of E2A-Pbx1 hybrid proteins. Each of these cases had E2A gene rearrangements, including the one in which fusion transcripts were not detected. By contrast, none of the six cases of t(1;19)-positive, cIg- ALL had evidence of rearranged E2A genomic restriction fragments, detectable E2A-pbx1 chimeric transcripts, or hybrid E2A-Pbx1 proteins. Typical chimeric E2A-pbx1 transcripts and proteins were detected in one of eight cIg+ leukemias in which the t(1;19) was not identified by cytogenetic analysis, emphasizing the increased sensitivity of molecular analysis for detection of this abnormality. We conclude that the molecular breakpoints in cases of cIg- B-cell precursor ALL with the t(1;19) differ from those in cIg+ cases with this translocation. Leukemias that express hybrid oncoproteins such as E2A-Pbx1 or Bcr-Abl have had a poor prognosis in most studies. Thus, molecular techniques to detect fusion genes and their aberrant products should allow more timely and appropriate treatment of these aggressive subtypes of the disease.", "doi": "10.1182/blood.V79.7.1781.1781", "issn": "0006-4971", "publisher": "American Society of Hematology", "publication": "Blood", "publication_date": "1992-04-01", "series_number": "7", "volume": "79", "issue": "7", "pages": "1781-1788" }, { "id": "authors:40zk5-kkh47", "collection": "authors", "collection_id": "40zk5-kkh47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DALmcb92", "type": "article", "title": "Nonmyristoylated Abl proteins transform a factor-dependent hematopoietic cell line", "author": [ { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Van Etten", "given_name": "Richard A.", "clpid": "Van-Etten-Richard-A" }, { "family_name": "Jackson", "given_name": "Peter K.", "clpid": "Jackson-Peter-K" }, { "family_name": "Bernards", "given_name": "Andre", "clpid": "Bernards-Andre" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "N-terminal myristoylation can promote the association of proteins with the plasma membrane, a property that is required for oncogenic variants of Src and Abl to transform fibroblastic cell types. The P210bcr/abl protein of chronic myelogenous leukemia cells is not myristoylated and does not stably transform NIH 3T3 fibroblasts; however, it will transform lymphoid and myeloid cell types in vitro and in vivo, suggesting that myristoylation is not required for Abl variants to transform hematopoietic cells. To test this hypothesis, we introduced point mutations that disrupt myristoylation into two activated Abl proteins, v-Abl and a deletion mutant of c-Abl (delta XB), and examined their ability to transform an interleukin-3-dependent lymphoblastoid cell line, Ba/F3. Neither of the nonmyristoylated Abl proteins transformed NIH 3T3 fibroblasts, but like P210bcr/abl, both were capable of transforming the Ba/F3 cells to factor independence and tumorigenicity. Nonmyristoylated Abl variants did not associate with the plasma membrane in the transformed Ba/F3 cells. These results demonstrate that Abl proteins can transform hematopoietic cells in the absence of membrane association and suggest that distinct functions of Abl are required for transformation of fibroblast and hematopoietic cell types.", "doi": "10.1128/mcb.12.4.1864", "pmcid": "PMC369630", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1992-04", "series_number": "4", "volume": "12", "issue": "4", "pages": "1864-1871" }, { "id": "authors:brr9a-9ry90", "collection": "authors", "collection_id": "brr9a-9ry90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MAYmcb92", "type": "article", "title": "Point mutations in the abl SH2 domain coordinately impair phosphotyrosine binding in vitro and transforming activity in vivo", "author": [ { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Jackson", "given_name": "Peter K.", "clpid": "Jackson-Peter-K" }, { "family_name": "Van Etten", "given_name": "Richard A.", "clpid": "Van-Etten-Richard-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have constructed a series of point mutations in the highly conserved FLVRES motif of the src homology 2 (SH2) domain of the abl tyrosine kinase. Mutant SH2 domains were expressed in bacteria, and their ability to bind to tyrosine-phosphorylated proteins was examined in vitro. Three mutants were greatly reduced in their ability to bind both phosphotyrosine itself and tyrosine-phosphorylated cellular proteins. All of the mutants that retained activity bound to the same set of tyrosine-phosphorylated proteins as did the wild type, suggesting that binding specificity was unaffected. These results implicate the FLVRES motif in direct binding to phosphotyrosine. When the mutant SH2 domains were inserted into an activated abl kinase and expressed in murine fibroblasts, decreased in vitro phosphotyrosine binding correlated with decreased transforming ability. This finding implies that SH2-phosphotyrosine interactions are involved in transmission of positive growth signals by the nonreceptor tyrosine kinases, most likely via the assembly of multiprotein complexes with other tyrosine-phosphorylated proteins.", "doi": "10.1128/mcb.12.2.609", "pmcid": "PMC364250", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1992-02", "series_number": "2", "volume": "12", "issue": "2", "pages": "609-618" }, { "id": "authors:e4yka-3a260", "collection": "authors", "collection_id": "e4yka-3a260", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200513-155012262", "type": "article", "title": "Cellular latency of human immunodeficiency virus type 1", "author": [ { "family_name": "Pomerantz", "given_name": "Roger J.", "clpid": "Pomerantz-Roger-J" }, { "family_name": "Bagasra", "given_name": "Omar", "clpid": "Bagasra-Omar" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The infection of humans by human immunodeficiency virus type 1 is characterized by a prolonged stage of clinical quiescence. This clinically asymptomatic period may be based, in part, on the development of cell populations within the body that maintain human immunodeficiency virus type 1 in a state of latency. Recent advances in the understanding of the molecular mechanisms involved in various forms of cellular latency of human immunodeficiency virus type 1 have begun to shed light on the variable period of asymptomatic infection. The elucidation of cellular retroviral latency, in vivo, will also be critical to the design of novel therapeutic approaches with which to combat human immunodeficiency virus type 1 infections.", "doi": "10.1016/s0952-7915(06)80042-7", "issn": "0952-7915", "publisher": "Elsevier", "publication": "Current Opinion in Immunology", "publication_date": "1992-01", "series_number": "4", "volume": "4", "issue": "4", "pages": "475-480" }, { "id": "authors:g11f3-62a07", "collection": "authors", "collection_id": "g11f3-62a07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200427-082038556", "type": "article", "title": "The recombination activating genes, RAG 1 and RAG 2, are on chromosome 11p in humans and chromosome 2p in mice", "author": [ { "family_name": "Oettinger", "given_name": "Marjorie A.", "clpid": "Oettinger-M-A" }, { "family_name": "Stanger", "given_name": "Ben", "clpid": "Stanger-B" }, { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Glaser", "given_name": "Tom", "clpid": "Glaser-T" }, { "family_name": "Call", "given_name": "Kathy", "clpid": "Call-K" }, { "family_name": "Housman", "given_name": "David", "clpid": "Housman-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The recombination activating genes RAG-1 and RAG-2 are adjacent genes that act synergistically to activate variable-diversity-joining (V(D)J) recombination. Southern analysis of hybrid cell lines derived from patients with the Wilms tumor-aniridia-genitourinary defects-mental retardation (WAGR) syndrome and from mutagenized cell hybrids selected for deletions in chromosome 11 has allowed us to map the chromosomal location of the human RAG locus. The RAG locus defines a new interval of human chromosome 11p, but is not associated with any genetically mapped human disease. Guided by the chromosomal localization of the human recombination activating genes, we have also mapped the location of the mouse Rag locus.", "doi": "10.1007/bf00189518", "issn": "0093-7711", "publisher": "Springer", "publication": "Immunogenetics", "publication_date": "1992-01", "series_number": "2", "volume": "35", "issue": "2", "pages": "97-101" }, { "id": "authors:z9vs7-van64", "collection": "authors", "collection_id": "z9vs7-van64", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-155839664", "type": "article", "title": "The inhibitory ankyrin and activator Rel proteins", "author": [ { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The gene families encoding the proteins NF-\u03baB, c-Rel and Dorsal, in conjunction with their respective inhibitors I\u03baB, pp40, and Cactus, achieve specificity in gene regulation by means of common principles. The related activities of NF-\u03baB and Dorsal are mediated by heterodimeric or homodimeric complexes of proteins containing the conserved dimerization and DNA-binding domain termed Rel. The I\u03baBs and Cactus, which share a core series of structural repeats termed ankyrin, inhibit cognate activators through differential interactions with the Rel-homology domain. Together, the inhibitory ankyrin proteins and their cognate Rel dimers probably define specific signalling pathways able to activate specific gene expression. Both gene families include proto-oncogenes, thus broadly implicating Rel/I\u03baB in the control of both normal gene expression and the abberant gene expression that makes cells cancerous.", "doi": "10.1016/s0959-437x(05)80276-x", "issn": "0959-437X", "publisher": "Current Biology Ltd", "publication": "Current Opinion in Genetics and Development", "publication_date": "1992-01", "series_number": "2", "volume": "2", "issue": "2", "pages": "211-220" }, { "id": "authors:yabff-hc678", "collection": "authors", "collection_id": "yabff-hc678", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DALpnas91", "type": "article", "title": "Blast Crisis in a Murine Model of Chronic Myelogenous Leukemia", "author": [ { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Van Etten", "given_name": "Richard A.", "clpid": "Van-Etten-Richard-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The P210bcr/abl protein is produced in cells from patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Retroviral transfer of the gene encoding P210bcr/abl into murine bone marrow induces a granulocytic leukemia that models the chronic phase of human CML. We have transferred the leukemic clone to syngeneic animals, albeit with surprising inefficiency, and have observed CML and clonally related acute leukemias of lymphoid or myeloid phenotype in some transplant recipients. These data show that murine CML can result from retroviral transfer of the bcr/abl gene into pluripotent hematopoietic stem cells, that infected clones repopulate poorly after adoptive transfer, and that these clones can give rise to acute leukemia, reflecting evolution to a phase resembling blast crisis in the human disease.", "doi": "10.1073/pnas.88.24.11335", "pmcid": "PMC53129", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1991-12-15", "series_number": "24", "volume": "88", "issue": "24", "pages": "11335-11338" }, { "id": "authors:ezhmk-yey16", "collection": "authors", "collection_id": "ezhmk-yey16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120420-071424839", "type": "article", "title": "Id Proteins Id1 and Id2 Selectively Inhibit DNA Binding by One Class of Helix-Loop-Helix Proteins", "author": [ { "family_name": "Sun", "given_name": "Xiao-Hong", "clpid": "Sun-Xiao-Hong" }, { "family_name": "Copeland", "given_name": "Neal G.", "clpid": "Copeland-Neal-G" }, { "family_name": "Jenkins", "given_name": "Nancy A.", "clpid": "Jenkins-Nancy-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The DNA binding activities of some basic region and putative helix-loop-helix (bHLH)-containing transcriptional\nfactors can be inhibited by the Id protein. Because Id contains the HLH motif for dimerization but not\nthe basic amino acid region for DNA binding, heterodimers of Id with bHLH transcriptional factors may not\nbind to DNA. We have isolated and characterized the gene and cDNA clones for a new Id protein, designated\nId2. The Id2 protein contains a helix-loop-helix motif similar to that of the previously described Id protein\n(referred to here as Idl), but the two proteins are different elsewhere. Idl and Id2 are encoded by two unlinked\ngenes, as shown by chromosome mapping. The two Id proteins have similar inhibitory activities. They\nselectively bind to and inhibit the function of one set of bHLH proteins, typified by E2A.E47 and E2B.m3, but\nnot that of the other set, including TFE3, USF, and AP4. The Id proteins also homodimerize poorly. Expression\nof both Id genes is down-regulated during differentiation in a variety of cell types.", "doi": "10.1128/MCB.11.11.5603", "pmcid": "PMC361931", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1991-11", "series_number": "11", "volume": "11", "issue": "11", "pages": "5603-5611" }, { "id": "authors:92xas-f9d51", "collection": "authors", "collection_id": "92xas-f9d51", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-161356013", "type": "article", "title": "Rel-associated pp40: an inhibitor of the rel family of transcription factors", "author": [ { "family_name": "Davis", "given_name": "Nathan", "clpid": "Davis-Nathan" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Simmons", "given_name": "Daniel L.", "clpid": "Simmons-D-L" }, { "family_name": "Tempst", "given_name": "Paul", "clpid": "Tempst-P" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Bose", "given_name": "Henry R., Jr.", "clpid": "Bose-H-R-Jr" } ], "abstract": "The Rel-associated protein pp40 is functionally related to I\u03baB, an inhibitor of the transcription factor NF-\u03baB. Purified pp40 inhibits the DNA binding activity of the NF-\u03baB protein complex (p50:p65 heterodimers), p50:c-Rel heteromers, and c-Rel homodimers. The sequence of the complementary DNA encoding pp40 revealed similarity to the gene encoding MAD-3, a protein with mammalian I\u03baB-like activity. Protein sequencing of I\u03baB purified from rabbit lung confirmed that MAD-3 encodes a protein similar to I\u03baB. The sequence similarity between MAD-3 and pp40 includes a casein kinase II and consensus tyrosine phosphorylation site, as well as five repeats of a sequence found in the human erythrocyte protein ankyrin. These results suggest that rel-related transcription factors, which are capable of cytosolic to nuclear translocation, may be held in the cytosol by interaction with related cytoplasmic anchor molecules.", "doi": "10.1126/science.1891714", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1991-09-13", "series_number": "5025", "volume": "253", "issue": "5025", "pages": "1268-1271" }, { "id": "authors:jx2a5-nxc43", "collection": "authors", "collection_id": "jx2a5-nxc43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200515-074204649", "type": "article", "title": "Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line", "author": [ { "family_name": "Schlissel", "given_name": "Mark", "clpid": "Schlissel-Mark-S" }, { "family_name": "Voronova", "given_name": "Anna", "clpid": "Voronova-Anna" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "E47 is a helix-loop-helix transcription factor that binds to sites in the immunoglobulin heavy-chain and \u03ba light-chain gene enhancers. Other proteins of this type are involved in cell-type determination. A possible role for E47 in B-cell development was tested by overexpressing a cDNA encoding E47 in the pre-T-cell line 2017. We found a dramatic activation of a germ-line heavy-chain gene transcript in these stable transfectants and an equally large induction of immunoglobulin D-to-J rearrangement, the first recognized step in B-cell development. Germ-line \u03ba light-chain gene transcription and rearrangement were unaffected, but transcription of the recombination-activating genes RAG-1 and RAG-2 and the lymphoid-specific transcription factor Oct-2 was increased. These T cells did not transcribe their rearranged DJ alleles, however, and failed to progress to the next stage of heavy-chain gene assembly, V-to-DJ rearrangement. Because transcription factor E47 can induce pre-T cells to carry out events of B-cell differentiation, it may be a crucial determinant of the earliest stages of B-cell development.", "doi": "10.1101/gad.5.8.1367", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1991-08-01", "series_number": "8", "volume": "5", "issue": "8", "pages": "1367-1376" }, { "id": "authors:tjy7g-vp590", "collection": "authors", "collection_id": "tjy7g-vp590", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SCOpnas91", "type": "article", "title": "v-abl causes hematopoietic disease distinct from that caused by bcr-abl", "author": [ { "family_name": "Scott", "given_name": "Martin L.", "clpid": "Scott-Martin-L" }, { "family_name": "Van Etten", "given_name": "Richard A.", "clpid": "Van-Etten-Richard-A" }, { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "v-abl, the oncogene transduced by Abelson murine leukemia virus, was first characterized by its ability to transform lymphoid cells. bcr-abl, the oncogene formed by a t(9;22) translocation thought to occur in human hematopoietic stem cells, is detectable in almost all cases of chronic myelogenous leukemia (CML), a malignancy of granulocytic cells. bcr-abl also causes a CML-like syndrome in mice whose bone-marrow cells are infected with a retrovirus transducing the gene. More recent reports have suggested that v-abl can, however, cause a disease similar to CML. We demonstrate here that v-abl, when transduced in a helper virus-containing system, causes disease similar to, but distinct from, the CML-like syndrome induced by bcr-abl. Animals whose bone marrow has been infected by v-abl virus develop modest splenomegaly, marked granulocytosis, and malignant disease of several hematopoietic cell types. Unlike animals with CML-like disease resulting from bcr-abl, the polymorphonuclear leukocytes from animals infected with a v-abl construct do not contain the v-abl provirus at a significant frequency. Histopathologic analysis also shows significant differences between the diseases caused by v-abl and bcr-abl.", "doi": "10.1073/pnas.88.15.6506", "pmcid": "PMC52114", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1991-08-01", "series_number": "15", "volume": "88", "issue": "15", "pages": "6506-6510" }, { "id": "authors:k5d43-vnv38", "collection": "authors", "collection_id": "k5d43-vnv38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-163038774", "type": "article", "title": "Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo", "author": [ { "family_name": "Lassar", "given_name": "Andrew B.", "clpid": "Lassar-A-B" }, { "family_name": "Davis", "given_name": "Robert L.", "clpid": "Davis-R-L" }, { "family_name": "Wright", "given_name": "Woodring E.", "clpid": "Wright-W-E" }, { "family_name": "Kadesch", "given_name": "Tom", "clpid": "Kadesch-T" }, { "family_name": "Murre", "given_name": "Cornelis", "clpid": "Murre-C" }, { "family_name": "Voronova", "given_name": "Anna", "clpid": "Voronova-Anna" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Weintraub", "given_name": "Harold", "clpid": "Weintraub-H" } ], "abstract": "In this report we provide four lines of evidence indicating that E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin. First, cotransfection of MyoD and E47 in COS cells indicates that these factors synergistically enhance transcription of a reporter gene containing an oligomerized MyoD-binding site. Second, mobility-shift assays of muscle cell nuclear extracts, \"double shifted\" with specific antisera, have identified complexes binding to the MEF1 site that contain either MyoD or myogenin in association with E12/E47-like proteins. Third, association with E47 alters the phosphorylation state of MyoD. Fourth, C3H10T1/2 cells expressing antisense E2A transcripts contain low levels of E2A gene products and display less terminal muscle differentiation when infected with retroviral MyoD or when challenged to differentiate with 5-azacytidine treatment. In addition we demonstrate that MyoD, in conjunction with E12/E47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators.", "doi": "10.1016/0092-8674(91)90620-e", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1991-07-26", "series_number": "2", "volume": "66", "issue": "2", "pages": "305-315" }, { "id": "authors:tj9hd-6zc05", "collection": "authors", "collection_id": "tj9hd-6zc05", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KLOpnas91", "type": "article", "title": "Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes", "author": [ { "family_name": "Klotman", "given_name": "Mary E.", "clpid": "Klotman-Mary-E" }, { "family_name": "Kim", "given_name": "Sunyoung", "clpid": "Kim-Sunyoung" }, { "family_name": "Buchbinder", "given_name": "Aby", "clpid": "Buchbinder-Aby" }, { "family_name": "DeRossi", "given_name": "Anita", "clpid": "DeRossi-Anita" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Wong-Staal", "given_name": "Flossie", "clpid": "Wong-Staal-Flossie" } ], "abstract": "The genome of human immunodeficiency virus type 1 (HIV-1) encodes at least six proteins involved in regulation as well as the structural proteins Gag, Pol, and Env. The interplay of the various regulators generates early and late transcriptional phases in the HIV-1 life cycle; the earliest RNA is enriched in subgenomic species, and the genomic transcript appears at the later stage of infection. We investigated the nature of the mRNAs expressed in the early stages of infection when the 2 kilobase subgenomic species predominate. RNA was analyzed in the early phase of a one-step growth cycle of HIV-1 infection in T-lymphoid and monocytic cell lines by using PCR amplification of in vitro-synthesized viral cDNAs. In both cell lines, expression of Tat-, Rev-, and Nef-specific messages appeared simultaneously and could be detected within 8-12 hr of infection but in different amounts with a predominance of Nef-specific message. The Env-specific message could be detected as early as the Rev-specific message, indicating that expression of at least small amounts of the singly spliced message could occur before the accumulation of Rev.", "doi": "10.1073/pnas.88.11.5011", "pmcid": "PMC51797", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1991-06-01", "series_number": "11", "volume": "88", "issue": "11", "pages": "5011-5015" }, { "id": "authors:sj6vd-0hf44", "collection": "authors", "collection_id": "sj6vd-0hf44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FEIpnas91", "type": "article", "title": "The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation", "author": [ { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Frankel", "given_name": "Alan D.", "clpid": "Frankel-Alan-D" } ], "abstract": "The mechanism of Tat transactivation was studied by treating cell lines containing Tat-defective viruses with purified Tat protein. These cell lines constitutively produce very low levels of virus in the absence of Tat, as measured by p24 antigen levels. Virus production can be increased >30,000-fold by adding exogenous Tat. Tat addition increases mRNA levels early in the viral life cycle, and Tat is required for Rev function to become evident. There is no evidence for a translational effect of Tat. Nuclear run-on experiments show that the increase in mRNA levels is due to an increased efficiency of elongation of nascent transcripts. These results suggest that Tat may be a gene-specific elongation factor.", "doi": "10.1073/pnas.88.9.4045", "pmcid": "PMC51590", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1991-05-01", "series_number": "9", "volume": "88", "issue": "9", "pages": "4045-4049" }, { "id": "authors:xhee9-p7595", "collection": "authors", "collection_id": "xhee9-p7595", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LIVjvir91", "type": "article", "title": "Mechanism of leukemogenesis induced by mink cell focus-forming murine leukemia viruses", "author": [ { "family_name": "Li", "given_name": "Jing-Po", "clpid": "Li-Jing-Po" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The Friend or Moloney mink cell focus-forming (MCF) virus encodes a recombinant-type envelope glycoprotein, gp 70, that is closely related to the membrane glycoprotein, gp55, of Friend spleen focus-forming virus (SFFV). We have shown previously that gp55 has the ability to activate cell growth by binding to the cellular receptor for erythropoietin. Here we show that gp70 encoded by either the Friend of Moloney MCF virus also binds to the erythropoietin receptor and that coexpression of the receptor and gp70 in an interleukin-3 (IL-3)-dependent cell line can activate IL-3-independent growth. Furthermore, when the cDNA for the human IL-2 receptor beta chain, which is related by sequence to the erythropoietin receptor, was introduced into this cell line, it became growth factor independent after infection either with SFFV or with one of the two MCF viruses but not with an ecotropic virus. Based on these observations, we propose a mechanism for the early stage of luekemogenesis induced by the MCF-type murine leukemia viruses.", "pmcid": "PMC240593", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1991-05", "series_number": "5", "volume": "65", "issue": "5", "pages": "2408-2414" }, { "id": "authors:efsqm-z3h59", "collection": "authors", "collection_id": "efsqm-z3h59", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200518-071259231", "type": "article", "title": "DNA binding and I\u03baB inhibition of the cloned p65 subunit of NF-\u03baB, a rel-related polypeptide", "author": [ { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Liou", "given_name": "Hsiou-Chi", "clpid": "Liou-Hsiou-Chi" }, { "family_name": "Tempst", "given_name": "Paul", "clpid": "Tempst-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The sequence and biochemical properties of the product of the cloned cDNA for the p65 subunit of nuclear factor \u03baB (NF-\u03baB) have been determined. The cDNA has an open reading frame of 549 amino acids capable of encoding a 60 kd protein. NF-\u03baB p65 contains an amino-terminal region of 320 amino acids with extensive similarity to the oncogene c-rel and lesser similarity to NF-\u03baB p50. In vitro translated p65 forms a DNA-binding complex with NF-\u03baB p50, and the binding of this complex can be specifically inhibited by purified I\u03baB. Progressive carboxy-terminal deletions of p65 show that, contrary to previous assumptions, p65 does include a DNA-binding domain that in vivo might become activated only through hetero-oligomerization with p50. DNA binding by truncated p65 is inhibited by I\u03baB, thus mapping the I\u03baB interaction domain to the rel-homologous region and suggesting that I\u03baB exerts its inhibitory effect upon NF-\u03baB primarily through interaction with p65.", "doi": "10.1016/0092-8674(91)90320-x", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1991-03-08", "series_number": "5", "volume": "64", "issue": "5", "pages": "961-969" }, { "id": "authors:bm6cm-m4k65", "collection": "authors", "collection_id": "bm6cm-m4k65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200518-073943504", "type": "article", "title": "The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials", "author": [ { "family_name": "Kamps", "given_name": "Mark P.", "clpid": "Kamps-Mark-P" }, { "family_name": "Look", "given_name": "A. Thomas", "clpid": "Look-A-Thomas" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The t(1;19) translocation that characterizes 25% of pediatric pre-B cell acute lymphoblastic leukemias (pre-B ALL) produces a chimeric gene, joining 5' sequences that encode a transcriptional activator domain of E2A with 3' sequences that, in part, encode a homeo box domain of a new gene called pbx1. Two E2A-pbx1 transcripts have been cloned. They encode the putative fusion proteins, p85^(E2A-Pbx1) and p77^(E2A-Pbx1), which differ in Pbx1 sequences alone, containing unique carboxyl termini whose sequences diverge after the Pbx1 homeo box. In this study, an antiserum to Pbx1 was used to investigate the identity and abundance of E2A-Pbx1 fusion proteins in both the pre-B ALL cell line, 697, and in cryopreserved leukemic bone marrow cells, obtained from six children with t(1;19)-positive pre-B ALL. Five species of E2A-Pbx1 proteins were identified in all cells containing t(1;19), two of which were indistinguishable from in vitro-translated p85^(E2A-Pbx1) and p77^(E2A-Pbx1). To assess the biological properties of p85^(E2A-Pbx1) and p77^(E2A-Pbx1) in fibroblasts, the cDNAs encoding these proteins were cloned into retroviral vectors, and each was introduced into NIH-3T3 cells. Both p85^(E2A-Pbx1) and p77^(E2A-Pbx1) are localized in the nucleus, and expression of either resulted in malignant conversion of NIH-3T3 cells as assayed by tumor formation in nude mice. When scored by focus formation, density-independent growth, and growth in agar assays, p77^(E2A-Pbx1) was a much more potent transforming protein than was p85^(E2A-Pbx1). Because subtle mutations in p85^(E2A-Pbx1) converted its transforming activity into that of p77^(E2A-Pbx1), we suggest that a sequence within the unique carboxyl terminus of p85^(E2A-Pbx1) serves to negatively regulate its biochemical activity.", "doi": "10.1101/gad.5.3.358", "issn": "0890-9369", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "Genes and Development", "publication_date": "1991-03-01", "series_number": "3", "volume": "5", "issue": "3", "pages": "358-368" }, { "id": "authors:449je-t0667", "collection": "authors", "collection_id": "449je-t0667", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SCHLjem91", "type": "article", "title": "Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription", "author": [ { "family_name": "Schlissel", "given_name": "Mark S.", "clpid": "Schlissel-Mark-S" }, { "family_name": "Corcoran", "given_name": "Lynn M.", "clpid": "Corcoran-Lynn-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Virus-transformed pre-B cells undergo ordered immunoglobulin (Ig) gene rearrangements during culture. We devised a series of highly sensitive polymerase chain reaction assays for Ig gene rearrangement and unrearranged Ig gene segment transcription to study both the possible relationship between these processes in cultured pre-B cells and the role played by heavy (H) chain (mu) protein in regulating gene rearrangement. Our analysis of pre-B cell cultures representing various stages of maturity revealed that transcription of each germline Ig locus precedes or is coincident with its rearrangement. Cell lines containing one functional rearranged H chain allele, however, continue to transcribe and to rearrange the allelic, unrearranged H chain locus. These cell lines appear to initiate but not terminate rearrangement events and therefore provide information about the requirements for activating rearrangement but not about allelic exclusion mechanisms.", "doi": "10.1084/jem.173.3.711", "pmcid": "PMC2118835", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1991-03", "series_number": "3", "volume": "173", "issue": "3", "pages": "711-720" }, { "id": "authors:k55t9-bfg15", "collection": "authors", "collection_id": "k55t9-bfg15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120418-142805707", "type": "article", "title": "Differentiation Requires Continuous Regulation", "author": [ { "family_name": "Blau", "given_name": "Helen M.", "clpid": "Blau-Helen-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "An abstract for this item is not available.", "doi": "10.1083/jcb.112.5.781", "pmcid": "PMC2288865", "issn": "0021-9525", "publisher": "Rockefeller University Press", "publication": "Journal of Cell Biology", "publication_date": "1991-03", "series_number": "5", "volume": "112", "issue": "5", "pages": "781-783" }, { "id": "authors:p33as-qng96", "collection": "authors", "collection_id": "p33as-qng96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120419-081351781", "type": "article", "title": "Silencing of the Expression of the Immunoglobulin Kappa Gene in Non-B Cells", "author": [ { "family_name": "Pierce", "given_name": "Jacqueline W.", "clpid": "Pierce-Jacqueline-W" }, { "family_name": "Gifford", "given_name": "Ann M.", "clpid": "Gifford-Ann-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Although the activating factor NF-_K B can be present in the nucleus of many cell types, transcription and rearrangement of the immunoglobulin kappa chain gene is restricted to cells of the B lineage. Part of this specificity is determined by sequences within the major intron of the kappa gene that specifically silence gene expression in non-B cells (T cells and HeLa cells). These sequences are found in a 232-bp fragment located 5' of the NF-K B binding sequence of the enhancer. When this fragment is added back upstream of an active NF-_K B site, it specifically decreases the expression of a linked gene by more than 10-fold in activated T cells but it has no effect on expression in B cells. The kappa silencer region acts in an orientation- and distance-independent manner and appears to be composed of multiple negative elements. The kappa silencer may act to restrict transcription and rearrangement of the C_K locus to cells of the B lineage.", "doi": "10.1128/mcb.11.3.1431", "pmcid": "PMC369419", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1991-03", "series_number": "3", "volume": "11", "issue": "3", "pages": "1431-1437" }, { "id": "authors:j0hap-e0795", "collection": "authors", "collection_id": "j0hap-e0795", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MURmcb91", "type": "article", "title": "B-cell- and myocyte-specific E2-box-binding factors contain E12/E47-like subunits", "author": [ { "family_name": "Murre", "given_name": "Cornelis", "clpid": "Murre-Cornelis" }, { "family_name": "Voronova", "given_name": "Anna", "clpid": "Voronova-Anna" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Recent studies have identified a family of DNA-binding proteins that share a common DNA-binding and dimerization domain with the potential to form a helix-loop-helix (HLH) structure. Various HLH proteins can form heterodimers that bind to a common DNA sequence, termed the E2-box. We demonstrate here that E2-box-binding B-cell- and myocyte-specific nuclear factors contain subunits which are identical or closely related to ubiquitously expressed (E12/E47) HLH proteins. These biochemical function for E12/E47-like molecules in mammalian differentiation, similar to the genetically defined function of daughterless in Drosophila development.", "doi": "10.1128/mcb.11.2.1156", "pmcid": "PMC359799", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1991-02", "series_number": "2", "volume": "11", "issue": "2", "pages": "1156-1160" }, { "id": "authors:1gptd-a6c76", "collection": "authors", "collection_id": "1gptd-a6c76", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120420-071528647", "type": "article", "title": "Activation of Phosphatidylinositol 3-Kinase in Cells Expressing abl Oncogene Variants", "author": [ { "family_name": "Varticovski", "given_name": "Lyuba", "clpid": "Varticovski-Lyuba" }, { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Jackson", "given_name": "Peter", "clpid": "Jackson-Peter-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Cantley", "given_name": "Lewis C.", "clpid": "Cantley-Lewis-C" } ], "abstract": "A phosphoinositide kinase specific for the D-3 position of the inositol ring, phosphatidylinositol (PI) 3-kinase, associates with activated receptors for platelet-derived growth factor, insulin, and colony-stimulating factor 1, with products of the oncogenes src, fms, yes, crk, and with polyomavirus middle T antigen. Efficient fibroblast transformation by proteins of the abl and src oncogene families requires activation of their protein-tyrosine kinase activity and membrane association via an amino-terminal myristoylation. We have demonstrated that the PI 3-kinase directly associates with autophosphorylated, activated protein-tyrosine kinase variants of the abl protein. In vivo, this association leads to accumulation of the highly phosphorylated products of PI 3-kinase, PI-3,4-bisphosphate and PI-3,4,5-trisphosphate, only in myristoylated, transforming abl protein variants. Myristoylation thus appears to be required to recruit PI 3-kinase activity to the plasma membrane for in vivo activation and correlates with the mitogenicity of the abl protein variants.", "doi": "10.1128/MCB.11.2.1107", "pmcid": "PMC359788", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1991-02", "series_number": "2", "volume": "11", "issue": "2", "pages": "1107-1113" }, { "id": "authors:wgwfq-hnf31", "collection": "authors", "collection_id": "wgwfq-hnf31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:POMjvir91", "type": "article", "title": "The long terminal repeat is not a major determinant of the cellular tropism of human immunodeficiency virus type 1", "author": [ { "family_name": "Pomerantz", "given_name": "Roger J.", "clpid": "Pomerantz-Roger-J" }, { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" }, { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The long terminal repeats (LTRs) of human immunodeficiency virus type 1 (HIV-1) strains from the central nervous systems of four patients with AIDS and of an HIV-1 isolate which is highly macrophage-tropic were isolated by using the polymerase chain reaction. In transient transfection assays, these LTRs demonstrated no significant difference in basal or stimulated levels of transcription in any of a variety of cell lines tested, compared with expression directed from the LTR of a T-lymphocyte-tropic strain of HIV-1. Chimeric viruses were created with the LTRs of the macrophage-tropic and brain-derived viruses ligated to the viral backbone from a T-lymphocyte-tropic strain. No change in cellular tropism was demonstrated with these chimeric viruses. Thus, unlike the LTRs of some murine retroviruses, the LTR of HIV-1 does not appear to play a major role in determining cellular tropism.", "pmcid": "PMC239855", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1991-02", "series_number": "2", "volume": "65", "issue": "2", "pages": "1041-1045" }, { "id": "authors:hyr1z-qan75", "collection": "authors", "collection_id": "hyr1z-qan75", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200518-075320939", "type": "article", "title": "An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers", "author": [ { "family_name": "Sun", "given_name": "Xiao-Hong", "clpid": "Sun-Xiao-Hong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The \u03baE2 sequence binding proteins, E12 and E47, are generated by alternative splicing of the E2A gene, giving closely related basic and helix-loop-helix structures crucial for DNA binding and dimerization. Measurements of dimerization constants and binding strengths to the optimal DNA sequence (the \u03baE2 site or its near relatives) showed that E47 homodimers and MyoD heterodimers with E12 or E47 dimerized and bound avidly, but E12 homodimerized efficiently and bound to DNA poorly; MyoD homodimerized poorly and bound strongly. An inhibitory domain N-terminal to the basic region of E12 prevents E12 homodimers but not E12/MyoD heterodimers from binding to DNA. Thus, E47 binds to DNA both as a heterodimer with MyoD and as a homodimer, while E12 and MyoD bind to DNA efficiently only as heterodimers.", "doi": "10.1016/0092-8674(91)90653-g", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1991-01-25", "series_number": "2", "volume": "64", "issue": "2", "pages": "459-470" }, { "id": "authors:ec8y5-eqs31", "collection": "authors", "collection_id": "ec8y5-eqs31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MAYpnas91", "type": "article", "title": "The noncatalytic src homology region 2 segment of abl tyrosine kinase binds to tyrosine-phosphorylated cellular proteins with high affinity", "author": [ { "family_name": "Mayer", "given_name": "Bruce J.", "clpid": "Mayer-Bruce-J" }, { "family_name": "Jackson", "given_name": "Peter K.", "clpid": "Jackson-Peter-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Several proteins implicated in the regulation of cell proliferation contain a common noncatalytic domain, src homology region 2 (SH2). We have used the bacterially expressed SH2 domain of abl protein-tyrosine kinase to evaluate the ability of this domain to bind to cellular proteins. abl SH2 specifically bound to a number of tyrosine-phosphorylated proteins from cells transformed by tyrosine kinase oncogenes in a filter-binding assay and to a subset of those proteins in solution. The SH2 probe bound almost exclusively to tyrosine-phosphorylated proteins, and binding was eliminated by dephosphorylation of cell proteins. Free phosphotyrosine could partially disrupt SH2 binding, suggesting that phosphotyrosine is directly involved in the binding interaction. These results demonstrate that an SH2 domain is sufficient to confer direct, high-affinity phosphotyrosine-dependant binding to proteins and suggest a general role for SH2 domains in cellular signaling pathways.", "doi": "10.1073/pnas.88.2.627", "pmcid": "PMC50865", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1991-01-15", "series_number": "2", "volume": "88", "issue": "2", "pages": "627-631" }, { "id": "authors:trsz9-tkh40", "collection": "authors", "collection_id": "trsz9-tkh40", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-135406275", "type": "article", "title": "The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system", "author": [ { "family_name": "Chun", "given_name": "Jerold J. M.", "clpid": "Chun-Jerold-J-M" }, { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Oettinger", "given_name": "Marjorie A.", "clpid": "Oettinger-M-A" }, { "family_name": "Jaenisch", "given_name": "Rudolf", "clpid": "Jaenisch-Rudolf" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The recombination activating genes, RAG-1 and RAG-2, are likely to encode components of the V(D)J site-specific recombination machinery. We report here the detection of low levels of the RAG-1 transcrlpt in the murlne central nervous system by polymerase chain reaction, In situ hybridization, and Northern blot analyses. In contrast, an authentic RAG-2 transcript could not be detected reproduclbly in the central nervous system. The RAG-1 transcript was found to be wide-spread in embryonic and postnatal neurons, with transcription being most apparent in regions of the postnatal brain with a high neuronal cell denslty (the cerebellum and the hippocampal formation). The results suggest that RAG-1 functions in neurons, where its role might be to recombine elements of the neuronal genome site-specifically, or to prevent detrimental alterations of the genome in these long-lived cells.", "doi": "10.1016/0092-8674(91)90220-s", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1991-01-11", "series_number": "1", "volume": "64", "issue": "1", "pages": "189-200" }, { "id": "authors:b46ja-qfw14", "collection": "authors", "collection_id": "b46ja-qfw14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-135406177", "type": "article", "title": "Selective expression of RAG-2 in chicken B cells undergoing immunoglobulin gene conversion", "author": [ { "family_name": "Carlson", "given_name": "Louise M.", "clpid": "Carlson-Louise-M" }, { "family_name": "Oettinger", "given_name": "Marjorie A.", "clpid": "Oettinger-M-A" }, { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Masteller", "given_name": "Emma L.", "clpid": "Masteller-E-L" }, { "family_name": "Hurley", "given_name": "Elizabeth A.", "clpid": "Hurley-E-A" }, { "family_name": "McCormack", "given_name": "Wayne T.", "clpid": "McCormack-W-T" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Thompson", "given_name": "Craig B.", "clpid": "Thompson-Craig-B" } ], "abstract": "Chickens create their immunoglobulin (Ig) repertoires during B cell development in the bursa of Fabriclus by intrachromosomal gene conversion. Recent evidence has suggested that Ig gene conversion may involve cis-acting DNA elements related to those involved in V(D)J recombination. Therefore, we have examined the potential role of the V(D)J recombination activating genes, RAG-1 and RAG-2, in regulating chicken Ig gene conversion. In contrast to the coexpression of RAG-1 and RAG-2 observed in mammalian B cells that undergo V(D)J recombination, chicken B cells isolated from the bursa of Fabricius express high levels of the RAG-2 mRNA but do not express RAG-1 mRNA. The developmental and phenotypic characteristics of the bursal lymphocytes and chicken B cell lines that express RAG-2 mRNA demonstrate that selective RAG-2 expression occurs specifically in B cells undergoing Ig diversification by gene conversion. These data suggest that RAG-2 plays a fundamental role in Ig-specific gene conversion.", "doi": "10.1016/0092-8674(91)90221-j", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1991-01-11", "series_number": "1", "volume": "64", "issue": "1", "pages": "201-208" }, { "id": "authors:dvbj8-sta85", "collection": "authors", "collection_id": "dvbj8-sta85", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-135406350", "type": "article", "title": "A human cell factor is essential for HIV-1 Rev action", "author": [ { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To examine the restriction of HIV growth in murine cells, we infected NIH 3T3 cells with HIV pseudotyped by Moloney murine leukemia virus. The virus, which carried a dominant selectable marker under the control of the HIV LTR, gave large numbers of resistant clones, showing that murine cells are permissive for HIV uncoating, reverse transcription, nuclear transport and integration. However, we found that several murine cell lines, as well as CHO cells, could not support the function of rev, the viral regulatory gene which, in human cells, induces the cytoplasmic expression of the incompletely spliced class of HIV mRNAs that encode the viral structural proteins. Transfection of the HIV\u2010infected murine cells with a HTLV\u20101 rex\u2010expressing vector failed to rescue the rev\u2010 phenotype, indicating that the block extended to rex function. Most importantly, we could complement the rev defect by fusing the infected murine with uninfected human cells. We conclude that HIV tropism is partly a consequence of a trans\u2010acting cellular factor critical for Rev function.", "doi": "10.1002/j.1460-2075.1990.tb07638.x", "pmcid": "PMC552190", "issn": "0261-4189", "publisher": "European Molecular Biology Organization", "publication": "EMBO Journal", "publication_date": "1990-12", "series_number": "12", "volume": "9", "issue": "12", "pages": "4155-4160" }, { "id": "authors:yrpte-pvw70", "collection": "authors", "collection_id": "yrpte-pvw70", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KIMjvir90", "type": "article", "title": "Factors affecting cellular tropism of human immunodeficiency virus", "author": [ { "family_name": "Kim", "given_name": "Sunyoung", "clpid": "Kim-Sunyoung" }, { "family_name": "Ikeuchi", "given_name": "Kenji", "clpid": "Ikeuchi-Kenji" }, { "family_name": "Groopman", "given_name": "Jerome", "clpid": "Groopman-Jerome" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To evaluate the basis of the slow growth of many human immunodeficiency virus strains in monocytes/macrophages, various stages of the virus life cycle have been studied for their possible contribution to viral tropism. Although we found that monocytic U937 cells had a higher percentage of CD4-positive cells than T-lymphoid H9 cells, the human immunodeficiency virus strain grew much less efficiently in the monocytic line. Viral tropism was primarily determined during the early stages of the virus cycle, that is, sometime between binding of the virus to the cell surface and reverse transcription of viral genomic RNA. Once the virus entered the host cell, reverse transcription, use of the long terminal repeat, RNA expression, and production of virus particles was about as efficient in monocytes as in T cells. Thus, during viral entry into the host cell cytoplasm there is a major limiting event that is particularly inefficient in U937 cells and possibly in all monocytes/macrophages.", "pmcid": "PMC248613", "issn": "0021-8979", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1990-11", "series_number": "11", "volume": "64", "issue": "11", "pages": "5600-5604" }, { "id": "authors:mzk97-a2f42", "collection": "authors", "collection_id": "mzk97-a2f42", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-135406435", "type": "article", "title": "A functional ribonucleoprotein complex forms around the 5\u2032 end of poliovirus RNA", "author": [ { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Rieckhof", "given_name": "Gabrielle E.", "clpid": "Rieckhof-Gabrielle-E" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The existence of a computer-predicted cloverleaf structure for the first 100 nucleotides at the 5\u2032 end of poliovirus RNA was verified by site-directed mutagenesis and by chemical and RNAase probing. Mutations that modified the cloverleaf in the positive strand but not the negative strand were lethal to the virus. This RNA cloverleaf structure binds a cellular protein and the viral proteins 3C\u1d56\u02b3\u1d52 and 3D\u1d56\u1d52\u2071. Mutations in specific regions of the RNA cloverleaf prevented this binding. Mutations in either 3C\u1d56\u02b3\u1d52 or the RNA that disrupted ribonucleoprotein complex formation inhibited virus growth and selectively affected positive strand RNA accumulation. Phenotypic reversion of these mutations restored the ability to form the complex. Thus, a cloverleaf structure in poliovirus RNA plays a central role in organizing viral and cellular proteins involved in positive strand production.", "doi": "10.1016/0092-8674(90)90170-j", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1990-10-19", "series_number": "2", "volume": "63", "issue": "2", "pages": "369-380" }, { "id": "authors:ws03y-s0h86", "collection": "authors", "collection_id": "ws03y-s0h86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KAMmcb90", "type": "article", "title": "The promoter of the human interleukin-2 gene contains two octamer-binding sites and is partially activated by the expression of Oct-2", "author": [ { "family_name": "Kamps", "given_name": "Mark P.", "clpid": "Kamps-Mark-P" }, { "family_name": "Corcoran", "given_name": "Lynn", "clpid": "Corcoran-Lynn-M" }, { "family_name": "LeBowitz", "given_name": "Jonathan H.", "clpid": "LeBowitz-Jonathan-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The gene encoding interleukin-2 (IL-2) contains a sequence 52 to 326 nucleotides upstream of its transcriptional initiation site that promotes transcription in T cells that have been activated by costimulation with tetradecanoyl phorbol myristyl acetate (TPA) and phytohemagglutinin (PHA). We found that the ubiquitous transcription factor, Oct-1, bound to two previously identified motifs within the human IL-2 enhancer, centered at nucleotides -74 and -251. Each site in the IL-2 enhancer that bound Oct-1 in vitro was also required to achieve a maximal transcriptional response to TPA plus PHA in vivo. Point mutations within either the proximal or distal octamer sequences reduced the response of the enhancer to activation by 54 and 34%, respectively. Because the murine T-cell line EL4 constitutively expresses Oct-2 and requires only TPA to induce transcription of the IL-2 gene, the effect of Oct-2 expression on activation of the IL-2 promoter in Jurkat T cells was determined. Expression of Oct-2 potentiated transcription 13-fold in response to TPA plus PHA and permitted the enhancer to respond to the single stimulus of TPA. Therefore, both the signal requirements and the magnitude of the transcription response of the IL-2 promoter can be modulated by Oct-2.", "doi": "10.1128/mcb.10.10.5464", "pmcid": "PMC361254", "issn": "1098-5549", "publisher": "American Society for Microbiology", "publication": "Molecular And Cellular Biology", "publication_date": "1990-10", "series_number": "10", "volume": "10", "issue": "10", "pages": "5464-5472" }, { "id": "authors:65vdm-qvk60", "collection": "authors", "collection_id": "65vdm-qvk60", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-145542160", "type": "article", "title": "Cloning of the p50 DNA binding subunit of NF-\u03baB: Homology to rel and dorsal", "author": [ { "family_name": "Ghosh", "given_name": "Sankar", "clpid": "Ghosh-Sankar" }, { "family_name": "Gifford", "given_name": "Ann M.", "clpid": "Gifford-Ann-M" }, { "family_name": "Riviere", "given_name": "Lise R.", "clpid": "Riviere-L-R" }, { "family_name": "Tempst", "given_name": "Paul", "clpid": "Tempst-P" }, { "family_name": "Nolan", "given_name": "Garry P.", "clpid": "Nolan-Garry-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The DNA binding subunit of the transcription factor NF-\u03baB, p50, has been cloned. p50 appears to be synthesized as a larger protein that is then processed to its functional size. Sequence analysis reveals remarkable homology for over 300 amino acids at the amino-terminal end to the oncogene v-rel, its cellular homolog c-rel, and the Drosophila maternal effect gene dorsal. This establishes NF-\u03baB as a member of the rel family of proteins, all of which display nuclear-cytosolic translocation. Protein sequence from the p65 polypeptide has established that it is not encoded in the same mRNA as p50. However, p65 appears homologous to c-rel, suggesting that c-rel may form heterodimers with p50 and rel may include a homodimerization motif.", "doi": "10.1016/0092-8674(90)90276-k", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1990-09-07", "series_number": "5", "volume": "62", "issue": "5", "pages": "1019-1029" }, { "id": "authors:9aba3-dpr13", "collection": "authors", "collection_id": "9aba3-dpr13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120509-133826978", "type": "article", "title": "Lipopolysaccharide Is a Potent Monocyte/Macrophage-specific Stimulator of Human Immunodeficiency Virus Type 1 Expression", "author": [ { "family_name": "Pomerantz", "given_name": "Roger J.", "clpid": "Pomerantz-Roger-J" }, { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" }, { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Lipopolysaccharide (LPS) potently stimulates human immunodeficiency virus type 1-long terminal repeat (HIV-1-LTR) CAT constructs transfected into monocyte/macrophage-like cell lines but not a T cell line. This effect appears to be mediated through the induction of nuclear factor kappa B (NF-kappa B). Electrophoretic mobility shift assays demonstrate that LPS induces a DNA binding activity indistinguishable from NF-kappa B in U937 and THP-1 cells. LPS is also shown to dramatically increase HIV-1 production from a chronically infected monocyte/macrophage-like cloned cell line, U1, which produces very low levels of HIV-1 at baseline. The stimulation of viral production from this cell line occurs only if these cells are treated with granulocyte/macrophage colony-stimulating factor (GM-CSF) before treatment with LPS. This stimulation of HIV-1 production is correlated with an increase in the level of HIV-1 RNA and and activation of NF-kappa B. LPS is not able to induce HIV-1 production in a cloned T cell line. The effect of LPS on HIV-1 replication occurs at picogram per milliliter concentrations and may be clinically significant in understanding the variability of the natural history of HIV-1 infection.", "doi": "10.1084/jem.172.1.253", "pmcid": "PMC2188186", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1990-07-01", "series_number": "1", "volume": "172", "issue": "1", "pages": "253-261" }, { "id": "authors:6ye3j-r7b40", "collection": "authors", "collection_id": "6ye3j-r7b40", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200612-145542290", "type": "article", "title": "Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: A molecular model for latency", "author": [ { "family_name": "Pomerantz", "given_name": "Roger J.", "clpid": "Pomerantz-Roger-J" }, { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Feinberg", "given_name": "Mark B.", "clpid": "Feinberg-Mark-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "U1 and ACH-2 cells are subclones of HIV-1-infected monocyte/macrophage-like and T lymphocyte cell lines, respectively, which express the HIV-1 genome at very low levels. We have examined whether they might provide a model of HIV-1 latency. The patterns of HIV-1-specific RNA expressed in these cells consisted of singly and multiply spliced RNA species, with little or no full-length genomic RNA. Upon stimulation with agents that activate the HIV-1 long terminal repeat in these cells, a marked rise in the amount of small mRNAs, encoding the viral regulatory proteins, preceded the increase in the unspliced RNA. Thus, U1 and ACH-2 cells maintain HIV-1 in a state equivalent to the early phase of a lytic infection and, after stimulation, recapitulate the events of a single cycle infection of highly susceptible target cells.", "doi": "10.1016/0092-8674(90)90691-7", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1990-06-29", "series_number": "7", "volume": "61", "issue": "7", "pages": "1271-1276" }, { "id": "authors:8xdja-skp90", "collection": "authors", "collection_id": "8xdja-skp90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200626-123754898", "type": "article", "title": "RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination", "author": [ { "family_name": "Oettinger", "given_name": "Marjorie A.", "clpid": "Oettinger-M-A" }, { "family_name": "Schatz", "given_name": "David G.", "orcid": "0000-0002-5669-1176", "clpid": "Schatz-D-G" }, { "family_name": "Gorka", "given_name": "Carolyn", "clpid": "Gorka-Carolyn" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The vast repertoire of immunoglobulins and T cell receptors is generated, in part, by V(D)J recombination, a series of genomic rearrangements that occur specifically in developing lymphocytes. The recombination activating gene, RAG-1, which is a gene expressed exclusively in maturing lymphoid cells, was previously isolated. RAG-1 inefficiently induced V(D)J recombinase activity when transfected into fibroblasts, but cotransfection with an adjacent gene, RAG-2, has resulted in at least a 1000-fold increase in the frequency of recombination. The 2.1-kilobase RAG-2 complementary DNA encodes a putative protein of 527 amino acids whose sequence is unrelated to that of RAG-1. Like RAG-1, RAG-2 is conserved between species that carry out V(D)J recombination, and its expression pattern correlates precisely with that of V(D)J recombinase activity. In addition to being located just 8 kilobases apart, these convergently transcribed genes are unusual in that most, if not all, of their coding and 3' untranslated sequences are contained in single exons. RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction.", "doi": "10.1126/science.2360047", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "1990-06-22", "series_number": "4962", "volume": "248", "issue": "4962", "pages": "1517-1523" }, { "id": "authors:8dy87-ydm14", "collection": "authors", "collection_id": "8dy87-ydm14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SMApnas90", "type": "article", "title": "Transcriptional activation by SP1 as directed through TATA or initiator: Specific requirement for mammalian transcription factor IID", "author": [ { "family_name": "Smale", "given_name": "Stephen T.", "clpid": "Smale-Stephen-T" }, { "family_name": "Schmidt", "given_name": "Martin C.", "clpid": "Schmidt-Martin-C" }, { "family_name": "Berk", "given_name": "Arnold J.", "clpid": "Berk-Arnold-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Transcription of mammalian genes by RNA polymerase II often begins at a specific nucleotide, whose location is determined either by an upstream DNA element known as a TATA box or by an element positioned at the transcription start site called an initiator (Inr). By in vitro analysis of synthetic promoters, we demonstrate here that the TATA and Inr elements are functionally similar and that the Inr is contained between nucleotides -3 and +5 relative to the initiation site. Moreover, we found that a mammalian transcription factor IID (TFIID) protein fraction is required for transcriptional stimulation by an Sp1-dependent activating element placed upstream of either TATA or Inr elements. However, in these assays, the yeast TATA-binding protein, which previously was shown to function similarly to mammalian TFIID, could not efficiently substitute for the mammalian TFIID fraction. These results demonstrate that mammalian TFIID is functionally distinct from the yeast TATA-binding protein and may contain additional subunits or domains that are important for transcriptional activation from some promoters.", "doi": "10.1073/pnas.87.12.4509", "pmcid": "PMC54145", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1990-06-15", "series_number": "12", "volume": "87", "issue": "12", "pages": "4509-4513" }, { "id": "authors:32yf4-ngr62", "collection": "authors", "collection_id": "32yf4-ngr62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120425-134250382", "type": "article", "title": "Mutations that disrupt DNA binding and dimer formation in the E47 helix-loop-helix protein map to distinct domains", "author": [ { "family_name": "Voronova", "given_name": "Anna", "clpid": "Voronova-Anna" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A common DNA binding and dimerization domain containing an apparent \"helix-loop-helix\" (HLH) structure was recognized recently in a number of regulatory proteins, including the E47 and E12 proteins that bind to the kappa E2 motif in immunoglobulin kappa gene enhancer. The effect of site-directed mutagenesis on E47 protein multimerization and DNA binding was examined. Mutations in either putative helix domain disrupted protein dimerization and DNA binding. No DNA binding was observed when mutations were introduced in the basic region, but these mutants were able to dimerize. These basic region mutants were not able to bind to DNA as heterodimers with the wild-type E47 proteins, demonstrating that two functional basic regions are required for binding to DNA. Therefore the basic region mutants are \"transdominant.\"", "doi": "10.1073/pnas.87.12.4722", "pmcid": "PMC54189", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1990-06-01", "series_number": "12", "volume": "87", "issue": "12", "pages": "4722-4726" }, { "id": "authors:t2aj7-11h78", "collection": "authors", "collection_id": "t2aj7-11h78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120509-104303031", "type": "article", "title": "Involvement of a second lymphoid-specific enhancer element in the regulation of immunoglobulin heavy-chain gene expression", "author": [ { "family_name": "Libermann", "given_name": "Towia Aron", "clpid": "Libermann-Towia-Aron" }, { "family_name": "Lenardo", "given_name": "Michael", "clpid": "Lenardo-Michael-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To determine whether enhancer elements in addition to the highly conserved octamer (OCTA)-nucleotide motif are important for lymphoid-specific expression of the immunoglobulin heavy-chain (IgH) gene, we have investigated the effect of mutating the binding site for a putative additional lymphoid-specific transcription factor, designated NF-microB, in the murine IgH enhancer. We demonstrate that the NF-microB-binding site plays a critical role in the IgH enhancer, because mutation of the microB DNA motif decreased transcriptional activity of the IgH enhancer in cells of the B-cell lineage but not in nonlymphoid cells. This effect was comparable to or even stronger than the effect of a mutation in the OCTA site. Moreover, combined mutation of both microB and OCTA sites further reduced enhancer activity in lymphoid cells. Interestingly, alteration of either the microB or E3 site in a 70-base-pair fragment of the IgH enhancer that lacks the binding site for OCTA abolished enhancer activity in lymphoid cells completely. Nevertheless, a multimer of the microB motif alone showed no enhancer activity. DNase footprinting analysis corroborated the functional data showing that a lymphoid-specific protein binds to the microB DNA motif. Our results suggest that the microB element is a new crucial element important for lymphoid-specific expression of the IgH gene but that interaction with another enhancer element is essential for its activity.", "pmcid": "PMC360680", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1990-06", "series_number": "6", "volume": "10", "issue": "6", "pages": "3155-3162" }, { "id": "authors:taggn-2nz27", "collection": "authors", "collection_id": "taggn-2nz27", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200626-135308824", "type": "article", "title": "Activation of interleukin-6 gene expression through the NF-\u03baB transcription factor", "author": [ { "family_name": "Libermann", "given_name": "Towia A.", "clpid": "Libermann-Towia-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The promoter region of the interleukin-6 (IL-6) gene has a putative NF-\u03baB-binding site. We found that a fragment of the IL-6 promoter containing the site specifically binds highly purified NF-\u03baB protein and the NF-\u03baB protein in nuclear extracts of phorbol ester-induced Jurkat cells. Mutations of the NF-\u03baB site abolished complex formation with both purified NF-\u03baB and the nuclear extract protein. Transient expression of chloramphenicol acetyltransferase (CAT) plasmids containing the IL-6 promoter revealed very little activity of the promoter in U-937 monocytic cells and in HeLa cells before stimulation. However, stimulation of U-937 and HeLa cells by inducers of NF-\u03baB led to a dramatic increase in CAT activity. Mutations in the NF-\u03baB-binding site abolished inducibility of IL-6 promoter-cat constructs in U-937 cells by lipopolysaccharide, tumor necrosis factor \u03b1, the double-stranded RNA poly(IC), or phytohemagglutinin and in HeLa cells by tumor necrosis factor alpha and drastically reduced but did not completely eliminate inducibility in HeLa cells stimulated by double-stranded RNA poly(IC) or phorbol 12-myristate 13-acetate. These results suggest that NF-\u03baB is an important mediator for activation of the IL-6 gene by a variety of IL-6 inducers in both U-937 and HeLa cells and that alternative inducible enhancer elements contribute in a cell-specific manner to IL-6 gene induction. Because NF-\u03baB is involved in the control of a variety of genes activated upon inflammation, NF-\u03baB may play a central role in the inflammatory response to infection and tissue injury.", "doi": "10.1128/mcb.10.5.2327", "pmcid": "PMC360580", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1990-05", "series_number": "5", "volume": "10", "issue": "5", "pages": "2327-2334" }, { "id": "authors:4sd2k-c8282", "collection": "authors", "collection_id": "4sd2k-c8282", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LIJjvir90", "type": "article", "title": "An intragenic revertant of a poliovirus 2C mutant has an uncoating defect", "author": [ { "family_name": "Li", "given_name": "Jing-Po", "clpid": "Li-Jing-Po" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A revertant was isolated from a temperature-sensitive poliovirus 2C mutant, 2C-31, which is defective in viral RNA synthesis. This revertant, called 2C-31R1, grew well at 39 degrees C and was not defective in RNA synthesis. However, in contrast to its parental mutant, 2C-31R1 was cold sensitive and could hardly grow at all at 32 degrees C. Analysis of a single-cycle growth revealed that 2C-31R1 was defective in virion uncoating at 32 degrees C, and a substantial amount (more than 30%) of input viruses could be recovered as infectious particles from an infected cell lysate up to 6 h postinfection. The uncoating defect and the inability to grow at cold temperatures could be overcome by a brief incubation at the permissive temperature (39 degrees C) before the infection was continued at 32 degrees C. cDNA cloning and mix-and-match recombination experiments indicated that the defect in uncoating was the result of two secondary point mutations, seven nucleotides apart, in the 2C-coding sequence downstream of the inserted linker which is the original mutation in the parental 2C-31 genome. Another revertant, 2C-31R3, isolated from the same 2C-31 stock, was not defective in uncoating and appeared to be a secondary revertant that contained an intragenic suppressor for the uncoating defect. The uncoating defect of 2C-31R1 could be complemented by type 2 poliovirus. These results suggested that protein 2C, in addition to its role in viral RNA synthesis, has a function in determining virion structure.", "pmcid": "PMC249223", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1990-03", "series_number": "3", "volume": "64", "issue": "3", "pages": "1102-1107" }, { "id": "authors:5ybf7-bwf33", "collection": "authors", "collection_id": "5ybf7-bwf33", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ANDjvir90", "type": "article", "title": "Substitutions in the protease (3Cpro) gene of poliovirus can suppress a mutation in the 5' noncoding region", "author": [ { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Rieckhof", "given_name": "Gabrielle E.", "clpid": "Rieckhof-Gabrielle-E" }, { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The poliovirus mutant 5NC-11 has a 4-base insertion at position 70 within the 5' untranslated region and is deficient in RNA synthesis. Revertants from 5NC-11 were isolated, showing a partial recovery of wild-type levels of RNA synthesis. The 5' noncoding region of those revertants contained the mutation intact; mix-and-match experiments with the cDNA from these revertants revealed that a restricted region within the 3C gene was the site of the suppressing mutations in the revertants. The suppressors were point mutations, confirmed by introducing them into the 3C gene by site-directed mutagenesis. Although complementation studies indicated that the suppressors were cis active, we believe that protein changes rather than RNA sequence alterations are responsible for the suppression because RNA changes that did not alter protein sequence had no effect, whereas various protein alterations were suppressive. The results therefore imply that protein 3C interacts with the 5' end of the RNA and may play a role in RNA replication.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1990-02", "series_number": "2", "volume": "64", "issue": "2", "pages": "607-612" }, { "id": "authors:p9q4c-tyk94", "collection": "authors", "collection_id": "p9q4c-tyk94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KIMjvir89", "type": "article", "title": "Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression", "author": [ { "family_name": "Kim", "given_name": "Sunyoung", "clpid": "Kim-Sunyoung" }, { "family_name": "Byrn", "given_name": "Randal", "clpid": "Byrn-Randal-A" }, { "family_name": "Groopman", "given_name": "Jerome", "clpid": "Groopman-Jerome" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The kinetics of retroviral DNA and RNA synthesis are parameters vital to understanding viral growth, especially for human immunodeficiency virus (HIV), which encodes several of its own regulatory genes. We have established a single-cycle growth condition for HIV in H9 cells, a human CD4+ lymphocyte line. The full-length viral linear DNA is first detectable by 4 h postinfection. During a one-step growth of HIV, amounts of viral DNA gradually increase until 8 to 12 h postinfection and then decrease. The copy number of unintegrated viral DNA is not extraordinarily high even at its peak. Most strikingly, there is a temporal program of RNA accumulation: the earliest RNA is greatly enriched in the 2-kilobase subgenomic mRNA species, while the level of 9.2-kilobase RNA which is both genomic RNA and mRNA remains low until after 24 h of infection. Virus production begins at about 24 h postinfection. Thus, viral DNA synthesis is as rapid as for other retroviruses, but viral RNA synthesis involves temporal alteration in the species that accumulate, presumably as a consequence of viral regulatory genes.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1989-09", "series_number": "9", "volume": "63", "issue": "9", "pages": "3708-3713" }, { "id": "authors:krs77-13338", "collection": "authors", "collection_id": "krs77-13338", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SUNpnas89", "type": "article", "title": "Human immunodeficiency virus tat-activated expression of poliovirus protein 2A inhibits mRNA translation", "author": [ { "family_name": "Sun", "given_name": "Xiao-Hong", "clpid": "Sun-Xiao-Hong" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To study the effect of poliovirus protein 2A on cellular RNA translation, the tat control system of human immunodeficiency virus (HIV) was used. Protein 2A was expressed from a plasmid construct (pHIV/2A) incorporating the HIV long terminal repeat. Protein synthesis was measured by using chloramphenicol acetyltransferase as a reporter gene driven by the Rous sarcoma virus long terminal repeat. When HIV/2A was contransfected with the reporter, addition of a tat-producing plasmid caused at least a 50-fold drop in chloramphenicol acetyltransferase synthesis. A HeLa cell line carrying HIV/2A was established. In it, tat expression caused more than a 10-fold drop in chloramphenicol acetyltransferase synthesis from the reporter plasmid. Furthermore, 2A induction by tat caused cleavage of the cellular translation factor P220, a part of eukaryotic translation initiation factor 4F. Thus protein 2A can, by itself, carry out the inhibition of cellular protein synthesis characteristic of a poliovirus infection. Also, the HIV tat activation provides a very effective method to control gene expression in mammalian cells.", "doi": "10.1073/pnas.86.7.2143", "pmcid": "PMC286867", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1989-04-01", "series_number": "7", "volume": "86", "issue": "7", "pages": "2143-2146" }, { "id": "authors:kdpkr-36x54", "collection": "authors", "collection_id": "kdpkr-36x54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DALpnas88", "type": "article", "title": "Transformation of an Interleukin 3-Dependent Hematopoietic Cell Line by the Chronic Myelogenous Leukemia-Specific P210bcr/abl Protein", "author": [ { "family_name": "Daley", "given_name": "George Q.", "clpid": "Daley-George-Q" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The P210bcr/abl protein is associated with virtually every case of human chronic myelogenous leukemia. Unlike the related P160gag/v-abl oncogene product of Abelson murine leukemia virus, P210bcr/abl does not transform NIH 3T3 fibroblasts. To assess whether P210bcr/abl might transform hematopoietic cell types, retroviral constructs encoding P210bcr/abl were used to infect the bone marrow-derived interleukin 3-dependent Ba/F3 cell line. As for P160gag/v-abl, cell lines expressing P210bcr/abl were growth factor independent and tumorigenic in nude mice. No evidence for autocrine production of interleukin 3 by factor-independent cell lines was found. These experiments establish that P210bcr/abl can transform hematopoietic cell types to tumorigenicity.", "doi": "10.1073/pnas.85.23.9312", "pmcid": "PMC282729", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1988-12-01", "series_number": "23", "volume": "85", "issue": "23", "pages": "9312-9316" }, { "id": "authors:xjvzp-z1p22", "collection": "authors", "collection_id": "xjvzp-z1p22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LENpnas88", "type": "article", "title": "NF-KB protein purification from bovine spleen: Nucleotide stimulation and binding site specificity", "author": [ { "family_name": "Lenardo", "given_name": "Michael J.", "clpid": "Lenardo-Michael-J" }, { "family_name": "Kuang", "given_name": "Anna", "clpid": "Kuang-Anna" }, { "family_name": "Gifford", "given_name": "Ann", "clpid": "Gifford-Ann" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The activity of the enhancer for the \u03ba immunoglobulin light chain gene critically depends on the presence in the nucleus of the NF-\u03baB protein. We purified NF-\u03baB over 50,000-fold and identified two protein species, 42 and 44 kDa, that could be eluted and renatured from a sodium dodecyl sulfate/polyacrylamide gel to give specific DNA-binding activity. Binding of the purified bovine NF-\u03baB as well as that from human and murine B- or T-lymphoid cell extracts was dramatically stimulated by nucleoside triphosphates. This effect distinguished NF-\u03baB from a related factor, H2-TF1. Purified NF-\u03baB interacted efficiently with regulatory sequences that function during either B- or T-lymphocyte activation, including the human immunodeficiency virus enhancer and a NF-\u03baB binding site we detected in the interleukin 2 enhancer.", "doi": "10.1073/pnas.85.23.8825", "pmcid": "PMC282599", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1988-12-01", "series_number": "23", "volume": "85", "issue": "23", "pages": "8825-8829" }, { "id": "authors:xmrnh-39y65", "collection": "authors", "collection_id": "xmrnh-39y65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120605-082210846", "type": "article", "title": "Isolation of poliovirus 2C mutants defective in viral RNA synthesis", "author": [ { "family_name": "Li", "given_name": "Jing-Po", "clpid": "Li-Jing-Po" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Two poliovirus mutants were isolated that contain an oligonucleotide linker insertion in the 2C-coding region of the viral genome. One, 2C-31, has a strongly temperature-sensitive phenotype and the other, 2C-32, forms small plaques on HeLa cell monolayers at all temperatures. Both mutants have a severe temperature-sensitive defect in viral RNA synthesis but little effect on the types of viral protein that are made. Temperature shift experiments showed that the 2C function is continuously required for viral RNA synthesis to proceed. The 2C mutants could be complemented in trans by mutants with mutations in other viral proteins. Protein 2C is also the locus of the guanidine resistance and dependence mutants, a drug whose action also affects viral RNA synthesis. Thus, protein 2C is one that is needed continually for viral RNA synthesis and, at least with these temperature-sensitive alleles, can be provided in trans.", "pmcid": "PMC253830", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1988-11", "series_number": "11", "volume": "62", "issue": "11", "pages": "4016-4021" }, { "id": "authors:z2y44-mq843", "collection": "authors", "collection_id": "z2y44-mq843", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BERjvir88", "type": "article", "title": "Poliovirus mutant that contains a cold-sensitive defect in viral RNA synthesis", "author": [ { "family_name": "Bernstein", "given_name": "Harris D.", "clpid": "Bernstein-Harris-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "By manipulating an infectious cDNA clone of poliovirus, we have introduced a single-codon insertion into the 3A region of the viral genome which has been proposed to encode a functional precursor of the virion-linked protein VPg. The resulting mutant was cold sensitive in monkey kidney cells. Viral RNA synthesis was poor at 32.5 degrees C, although no other function of the virus was obviously affected. The synthesis of both positive and negative strands was severely depressed. Temperature shift experiments suggest that a normal level of production of the affected function was required only during the early (exponential) phase of RNA synthesis. Analysis of viral polyprotein processing at the nonpermissive temperature revealed that some of the normal cleavages were not made, most likely as a consequence of the defect in RNA synthesis or as a result of the concomitant reduction in the level of virally encoded proteases.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1988-08", "series_number": "8", "volume": "62", "issue": "8", "pages": "2922-2928" }, { "id": "authors:3cta5-8gy19", "collection": "authors", "collection_id": "3cta5-8gy19", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:TROjvir88", "type": "article", "title": "An RNA sequence of hundreds of nucleotides at the 5' end of poliovirus RNA is involved in allowing viral protein synthesis", "author": [ { "family_name": "Trono", "given_name": "Didier", "clpid": "Trono-Didier" }, { "family_name": "Andino", "given_name": "Raul", "clpid": "Andino-Raul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Twenty-one mutations were engineered in the 5' noncoding region of poliovirus type 1 RNA, using an infectious cDNA copy of the viral genome. RNA was made from these constructs and used to transfect HeLa cells. Viable virus was recovered from 12 of these transfection experiments, including six strains with a recognizable phenotype, mapping in four different regions. One mutant of each site was studied in more detail. Mutant 5NC-11, having a 4-base insertion at nucleotide 70, was dramatically deficient in RNA synthesis, suggesting that the far 5' end of the genome is primarily involved in one or more steps of RNA replication. Mutants 5NC-13, 5NC-114, and 5NC-116, mapping at nucleotides 224, 270, and 392, respectively, showed a similar behavior; they made very little viral protein, they did not inhibit host cell translation, and they synthesized a significant amount of viral RNA, although with some delay compared with wild type. These three mutants were efficiently complemented by all other poliovirus mutants tested, except those with lesions in protein 2A. Our results imply that these three mutants map in a region (region P) primarily involved in viral protein synthesis and that their inability to shut off host cell translation is secondary to a quantitative defect in protein 2A. The exact function of region P is still to be determined, but our data supports the hypothesis of a single functional module allowing viral protein synthesis and extending over several hundred nucleotides.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1988-07", "series_number": "7", "volume": "62", "issue": "7", "pages": "2291-2299" }, { "id": "authors:rw9m8-2rg30", "collection": "authors", "collection_id": "rw9m8-2rg30", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:NABpnas88", "type": "article", "title": "T-cell-specific expression of interleukin 2: evidence for a negative regulatory site", "author": [ { "family_name": "Nabel", "given_name": "Gary J.", "clpid": "Nabel-Gary-J" }, { "family_name": "Gorka", "given_name": "Carolyn", "clpid": "Gorka-Carolyn" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To understand the basis for T-cell-specific induction of interleukin 2 (IL-2), we have analyzed nuclear factors from the Jurkat T-lymphoid leukemia cell, which can be induced to secrete IL-2. We have used an electrophoretic mobility shift assay to examine binding of proteins to the upstream regulatory region, before and after activation with mitogens. We find two types of binding sites. One resembles an inducible enhancer element, but the protein that recognizes it is found in non-T cells and is unlikely to determine T-cell-specific expression of IL-2. A second site negatively regulates expression in resting T cells. A complex that binds to a DNA fragment containing this site is modified only when IL-2 is expressed, and it lies near a specific inducible DNase hypersensitive region. We suggest that negative regulation at this site, mediated by its associated protein(s), may contribute to the cell-specific expression of IL-2.", "doi": "10.1073/pnas.85.9.2934", "pmcid": "PMC280117", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1988-05-01", "series_number": "9", "volume": "85", "issue": "9", "pages": "2934-2938" }, { "id": "authors:7ch17-qnt88", "collection": "authors", "collection_id": "7ch17-qnt88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120604-141212468", "type": "article", "title": "Standardized and simplified nomenclature for proteins common to all retroviruses", "author": [ { "family_name": "Leis", "given_name": "J.", "clpid": "Leis-J" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Bishop", "given_name": "J. M.", "clpid": "Bishop-J-M" }, { "family_name": "Coffin", "given_name": "J.", "clpid": "Coffin-J" }, { "family_name": "Fleissner", "given_name": "E.", "clpid": "Fleissner-E" }, { "family_name": "Goff", "given_name": "S. P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Oroszlan", "given_name": "S.", "clpid": "Oroszlan-S" }, { "family_name": "Robinson", "given_name": "H.", "clpid": "Robinson-H" }, { "family_name": "Skalka", "given_name": "A. M.", "clpid": "Skalka-A-M" }, { "family_name": "Temin", "given_name": "H. M.", "clpid": "Temin-H-M" }, { "family_name": "Vogt", "given_name": "V.", "clpid": "Vogt-V" } ], "abstract": "We propose a revised standardized nomenclature for the proteins common to all retroviruses on the basis of biological function, enzymatic activity, and/or virion location data. (We do not discuss proteins specific for subfamilies or only some retroviruses.)", "pmcid": "PMC253234", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1988-05", "series_number": "5", "volume": "62", "issue": "5", "pages": "1808-1809" }, { "id": "authors:rp6xc-gtt13", "collection": "authors", "collection_id": "rp6xc-gtt13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PIEpnas88", "type": "article", "title": "Oligonucleotide that binds nuclear factor NF-kappa-B acts as a lymphoid-specific and inducible enhancer element", "author": [ { "family_name": "Pierce", "given_name": "Jacqueline W.", "clpid": "Pierce-Jacqueline-W" }, { "family_name": "Lenardo", "given_name": "Michael", "clpid": "Lenardo-Michael-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The immunoglobulin kappa light chain gene contains a lymphoid-specific enhancer that includes several short protein-binding sequences. The sequence that binds the nuclear factor NF-kappa B was tested for its ability to act independently as an enhancer element by inserting it into test plasmids containing the chloramphenicol acetyltransferase gene. When analyzed for activity by transient transfection into lymphoid and nonlymphoid cells, a single copy of the NF-kappa B binding site could act as a tissue-specific upstream activating element. Two copies (dimer) showed 10-fold higher activity than did one copy and could act as an enhancer element 2.5 kilobases downstream of the transcriptional start site. The enhancer activity of this sequence was correlated with the presence of the cognate binding protein, NF-kappa B. This sequence acted as an inducible enhancer under conditions that induce NF-kappa B binding activity. Thus, the NF-kappa B binding site acts by itself as a tissue-specific and inducible enhancer element, and two copies show cooperative interaction.", "doi": "10.1073/pnas.85.5.1482", "pmcid": "PMC279795", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1988-03-01", "series_number": "5", "volume": "85", "issue": "5", "pages": "1482-1486" }, { "id": "authors:c0tsx-xyp39", "collection": "authors", "collection_id": "c0tsx-xyp39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MATmcb88", "type": "article", "title": "Recombinants within the tyrosine kinase region of v-abl and v-src identify a v-abl segment that confers lymphoid specificity", "author": [ { "family_name": "Mathey-Prevot", "given_name": "Bernard", "clpid": "Mathey-Prevot-Bernard" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The v-abl and v-src oncogenes encode protein-tyrosine kinases that possess different biological properties in spite of their high degree of amino acid conservation. To correlate functional differences with structural domains of the two oncogenes, we recombined v-abl and v-src just downstream of the lysines in their ATP-binding sites, within the kinase domain. The biological activity of the chimeric genes was studied and compared with that of v-src and v-abl. The v-src/v-abl recombinant shared with v-src and v-abl the ability to transform fibroblasts. In addition, like v-abl, it transformed lymphoid cells and relieved a hematopoietic cell line of its interleukin 3 requirement. In contrast, the reciprocal construct, v-abl/v-src, was transformation defective. Lack of biological activity correlated with formation of a stable complex between the chimeric protein and two cellular proteins and with low kinase activity. We conclude that the specificity within the kinase domain determines the particular biological behavior of protein-tyrosine kinase oncogenes.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1988-01", "series_number": "1", "volume": "8", "issue": "1", "pages": "234-240" }, { "id": "authors:hgc0r-m2p49", "collection": "authors", "collection_id": "hgc0r-m2p49", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PILpnas87", "type": "article", "title": "Myristoylation and the post-translational acquisition of hydrophobicity by the membrane immunoglobulin heavy-chain polypeptide in B lymphocytes", "author": [ { "family_name": "Pillai", "given_name": "Shiv", "clpid": "Pillai-Shiv" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Membrane immunoglobulin heavy chain in pre-B and in B cells is initially synthesized as a relatively hydrophilic protein that is nonetheless stably anchored in the endoplasmic reticulum membrane. In B cells, but not in pre-B cells, the membrane immunoglobulin heavy chain is post-translationally converted to a relatively hydrophobic form that partitions into the oil phase when solubilized with the phase-separating detergent Triton X-114. Covalent myristoylation of the membrane and secretory forms of immunoglobulin heavy chains as well as of light chains was observed in B cells. Myristoylation of the membrane immunoglobulin heavy chain correlates with its transport to the cell surface and its post-translational conversion to a relatively hydrophobic form. This post-translational modification is hydroxylamine resistant and may be responsible for the assembly and transport of membrane immunoglobulin to the cell surface in B cells.", "doi": "10.1073/pnas.84.21.7654", "pmcid": "PMC299358", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1987-11-01", "series_number": "21", "volume": "84", "issue": "21", "pages": "7654-7658" }, { "id": "authors:yat4q-x7225", "collection": "authors", "collection_id": "yat4q-x7225", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LANmcb87", "type": "article", "title": "Increased frequency of N-region insertion in a murine pre-B-cell line infected with a terminal deoxynucleotidyl transferase retroviral expression vector", "author": [ { "family_name": "Landau", "given_name": "Nathaniel R.", "clpid": "Landau-Nathaniel-R" }, { "family_name": "Schatz", "given_name": "David G.", "clpid": "Schatz-David-G" }, { "family_name": "Rosa", "given_name": "Margaret", "clpid": "Rosa-Margaret" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The role of terminal deoxynucleotidyl transferase (TdT) in the insertion of N regions into the junctional sites of immunoglobulin genes was investigated. Pre-B-cell lines capable of continuous rearrangement of immunoglobulin light-chain genes and differing only in the presence or apparent absence of TdT were derived by infecting cells with a TdT retroviral expression vector or a control vector. The cell lines were then superinfected with a retrovirus-based artificial immunoglobulin gene rearrangement substrate. The substrate was allowed to rearrange in the cell lines and the rearranged proviruses were rescued from the cell lines. Nucleotide sequence analysis of the V-J junctions of the proviral rearranged genes showed a fivefold greater frequency of N-region insertion in proviruses rescued from the TdT+ cell lines than in those rescued from the TdT- cell lines, so that at least 50% of the rearrangements that occurred in the presence of TdT had N regions. It is thus evident that TdT can stimulate N-region insertion, and the enzyme is presumably directly responsible for adding nucleotides at V-J and other immunoglobulin and T-cell receptor gene junctions.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1987-09", "series_number": "9", "volume": "7", "issue": "9", "pages": "3237-3243" }, { "id": "authors:51btb-vdz73", "collection": "authors", "collection_id": "51btb-vdz73", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BERmcb87", "type": "article", "title": "The first intron in the human c-abl gene is at least 200 kilobases long and is a target for translocations in chronic myelogenous leukemia", "author": [ { "family_name": "Bernards", "given_name": "Andre", "clpid": "Bernards-Andre" }, { "family_name": "Rubin", "given_name": "Charles M.", "clpid": "Rubin-Charles-M" }, { "family_name": "Westbrook", "given_name": "Carol A.", "clpid": "Westbrook-Carol-A" }, { "family_name": "Paskind", "given_name": "Michael", "clpid": "Paskind-Michael" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The c-abl protooncogene is unusual in two respects; it has multiple, widely space N-terminal coding exons transcribed by different promoters, and it is the target of the translocations that form the Philadelphia chromosome found in cells of chronic myelogenous leukemia patients. To understand the organization of the gene in normal and chronic myelogenous leukemia patient DNA we have mapped c-abl by pulsed field gradient gel electrophoresis. We find that one of the alternative 5' exons of the gene lies at least 200 kilobases upstream of the remaining c-abl exons, posing formidable transcription and splicing problems. The 5'-most c-abl exon includes an unusually long 1,276-base-pair segment that contains 15 ATG codons and multiple short open reading frames, upstream of the abl initiator codon. Its peculiar structure suggests that c-abl may be decapitated in most chronic myelogenous leukemia patients, and we demonstrate that this is the case in the chronic myelogenous leukemia cell line K562.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1987-09", "series_number": "9", "volume": "7", "issue": "9", "pages": "3231-3236" }, { "id": "authors:4qk9e-6fk72", "collection": "authors", "collection_id": "4qk9e-6fk72", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120626-093550673", "type": "article", "title": "In vitro transcription of immunoglobulin genes in a B-cell extract: effects of enhancer and promoter sequences", "author": [ { "family_name": "Sen", "given_name": "Ranjan", "clpid": "Sen-Ranjan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Transfection experiments have led to the identification of three DNA sequences that are responsible for the tissue-specific expression of immunoglobulin genes. As a first step toward characterizing these regulatory phenomena at the biochemical level, we report the development of an in vitro transcription system from cells of the B lymphoid lineage. In these extracts, transcription of the MOPC41 kappa promoter is correctly initiated and dependent on the presence of an upstream sequence element located between -44 and -79 base pairs from the cap site. Second, although standard in vitro transcriptions are not affected by the presence or absence of enhancer sequences, we observed that the addition of polyethylene glycol led to a B-cell extract-specific suppression of transcription from a template that carries an immunoglobulin enhancer.", "doi": "10.1128/MCB.7.5.1989", "pmcid": "PMC365307", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1987-05", "series_number": "5", "volume": "7", "issue": "5", "pages": "1989-1994" }, { "id": "authors:b937y-z7z48", "collection": "authors", "collection_id": "b937y-z7z48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PANjvir87", "type": "article", "title": "Characterization of endonuclease activities in Moloney murine leukemia virus and its replication-defective mutants", "author": [ { "family_name": "Panet", "given_name": "Amos", "clpid": "Panet-Amos" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To study Moloney murine leukemia virus (M-MulV) proteins associated with the integration of proviral DNA into the host chromosome, we isolated endonuclease activities from purified virion preparations of the wild type and two of its replication mutants. A major endonuclease activity was identified in virions of M-MuLV; the enzyme catalyzed nicks in double-stranded DNA in the presence of either Mn2+ or Mg2+ and was stimulated by ATP. The endonuclease nicked DNA adjacent to all four nucleotides with some preference for G and C. The same enzyme, and in comparable amounts, was isolated from two virus replication mutants: dl2905, deficient in the processing of Pr65gag and Pr200gag-pol, and dl50401, deficient for the virus integration function. In the process of these experiments, the residual reverse transcriptase in mutant dl2905 was shown to be the mature size, implying that the uncleaved precursor lacks enzymatic activity. It appears that the major endonuclease activity found in virions of M-MuLV is not encoded by either the gag or pol genes.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1987-05", "series_number": "5", "volume": "61", "issue": "5", "pages": "1756-1760" }, { "id": "authors:vhj77-x3n49", "collection": "authors", "collection_id": "vhj77-x3n49", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ALEpnas87", "type": "article", "title": "Continuing Rearrangement of Immunoglobulin and T-Cell Receptor Genes in a Ha-Ras-Transformed Lymphoid Progenitor Cell Line", "author": [ { "family_name": "Alessandrini", "given_name": "Alessandro", "clpid": "Alessandrini-Alessandro" }, { "family_name": "Pierce", "given_name": "Jacalyn H.", "clpid": "Pierce-Jacalyn-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Desiderio", "given_name": "Stephen V.", "clpid": "Desiderio-Stephen-V" } ], "abstract": "The arrangement of immunoglobulin genes has been examined in a series of lymphoid cell lines transformed with the Harvey murine sarcoma virus. One cell line, HAFTL-1, expresses antigenic markers characteristic of B-lymphoid cells and undergoes frequent rearrangement at the JH locus (where J = joining and H = heavy chain) during propagation in culture. By molecular cloning and nucleotide sequence determination, these rearrangements were found to represent the earliest postulated step in heavy chain gene assembly: the joining of a diversity (D) segment to a JH segment. The HAFTL-1 cell line also undergoes infrequent D\u03b2-to-J\u03b2 joining at the T-cell receptor \u03b2 locus in culture. The observations presented here suggest that the HAFTL-1 cell line represents the early stage of B-cell differentiation at which immunoglobulin gene rearrangement is initiated.", "doi": "10.1073/pnas.84.7.1799", "pmcid": "PMC304528", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1987-04-01", "series_number": "7", "volume": "84", "issue": "7", "pages": "1799-1803" }, { "id": "authors:fedxc-z8g72", "collection": "authors", "collection_id": "fedxc-z8g72", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CITjem87.832", "type": "article", "title": "Elevated myc expression and c-myc amplification in spontaneously occurring B lymphoid cell lines", "author": [ { "family_name": "Citri", "given_name": "Yoav", "clpid": "Citri-Yoav" }, { "family_name": "Braun", "given_name": "Jonathan", "clpid": "Braun-Jonathan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Recently, a minor subpopulation of murine B lymphocytes, Ly-1+ B cells, has been distinguished by its unique ontogeny, tissue distribution, and prominence in certain autoimmune and neoplastic B cell diseases. We have previously described a simple murine spleen culture system that results in the spontaneous and exclusive outgrowth of long-term Ly-1+ B cell lines (B Ly-1 cells). Here, we report that the immortal growth property of B Ly-1 cells correlates with a 10-45-fold elevation of steady-state myc RNA and 2-10-fold amplification of the c-myc locus. While c-myc amplification has been observed in malignant cell lines derived from several tissues of origin, its occurrence in lymphoid cells has not been previously reported. The consistent c-myc amplification in B Ly-1 cells may reflect a unique state of this locus in the Ly-1+ B lymphocyte lineage, and contribute to the spontaneous immortalization of this B cell population in vitro, and its apparent predilection for malignant transformation in vivo.", "doi": "10.1084/jem.165.4.1188", "pmcid": "PMC2188571", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1987-04", "series_number": "4", "volume": "165", "issue": "4", "pages": "1188-1194" }, { "id": "authors:x067r-vqk84", "collection": "authors", "collection_id": "x067r-vqk84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:WEApnas87", "type": "article", "title": "B lymphocyte-specific protein binding near an immunoglobulin kappa-chain gene J segment", "author": [ { "family_name": "Weaver", "given_name": "David", "clpid": "Weaver-David" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Nuclear extracts from pre-B and B cell lines contain a nuclear DNA binding protein (kappa locus protein, KLP) that specifically recognizes a DNA sequence in the immunoglobulin kappa light chain joining (J) segment gene region. KLP is not observed in mature B cells, T cells, or nonlymphoid cell types. Two tandem binding sites for KLP designated KI and KII have been identified by methylation interference analysis to be immediately proximal to the J-kappa-1 nonamer-heptamer recognition sequences and separated by 38 base pairs from each other. Fragments of DNA containing KI and KII sites compete for binding to KLP, and both protein-DNA complexes have the same electrophoretic mobility. Other flanking sequences of immunoglobulin gene fragments do not bind to KLP. The position of KLP-DNA binding and its tissue-specific expression suggest that it may be involved in the regulation of lymphoid gene DNA rearrangements by targeting recombinase to the kappa-chain gene region.", "doi": "10.1073/pnas.84.6.1516", "pmcid": "PMC304465", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1987-03-15", "series_number": "6", "volume": "84", "issue": "6", "pages": "1516-1520" }, { "id": "authors:thh8p-a7e25", "collection": "authors", "collection_id": "thh8p-a7e25", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SPEmcb87", "type": "article", "title": "Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer", "author": [ { "family_name": "Speck", "given_name": "Nancy A.", "clpid": "Speck-Nancy-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Binding sites for six distinct nuclear factors on the 75-base-pair repeat of the Moloney murine leukemia virus enhancer have been identified by an electrophoretic mobility shift assay combined with methylation interference. Three of these factors, found in WEHI 231 nuclear extracts, which we have named LVa, LVb, and LVc (for leukemia virus factors a, b, and c) have not been previously identified. Nuclear factors that bind to the conserved simian virus 40 corelike motif, the NF-1 motif, and the glucocorticoid response element were also detected. Testing of multiple cell lines showed that most factors appeared ubiquitous, except that the NF-1 binding factor was found neither in nuclear extracts from MEL cells nor in the embryonal carcinoma cell lines PCC4 and F9, and core-binding factor was relatively depleted from MEL and F9 nuclear extracts.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1987-03", "series_number": "3", "volume": "7", "issue": "3", "pages": "1101-1110" }, { "id": "authors:teeqf-dmv17", "collection": "authors", "collection_id": "teeqf-dmv17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BERjvir86", "type": "article", "title": "Genetic complementation among poliovirus mutants derived from an infectious cDNA clone", "author": [ { "family_name": "Bernstein", "given_name": "Harris D.", "clpid": "Bernstein-Harris-D" }, { "family_name": "Sarnow", "given_name": "Peter", "clpid": "Sarnow-Peter" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We constructed several well-defined mutations in the nonstructural portion of the poliovirus type I (Mahoney strain) genome by making small insertions in an infectious cDNA clone. The derived viral strains carrying the mutations exhibited a variety of distinct plaque phenotypes. Thus, we were able to examine genetic complementation between different pairs of mutants by comparing the yields of progeny virus in mixed and single infections. Two mutants bearing lesions in the 2A and 3A regions of the genome, which are defective in the inhibition of host cell translation and the synthesis of viral RNA, respectively, could be rescued efficiently by genetic complementation; three replication-deficient mutants containing insertions in the 2B, 3D (replicase), and 3'-untranslated regions could not. Both the 2A and 3A mutants could be rescued by each other and by all of the other mutants tested. Because yield enhancement was apparent well before the completion of a single infectious cycle, it is likely that complementation of both mutants involved early diffusion of functional products. These data provide the first unambiguous evidence that the nonstructural portion of the poliovirus genome contains multiple complementation groups. The data also suggest that certain nonstructural functions act only in cis.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1986-12", "series_number": "3", "volume": "60", "issue": "3", "pages": "1040-1049" }, { "id": "authors:6ex98-bj112", "collection": "authors", "collection_id": "6ex98-bj112", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120627-095332043", "type": "article", "title": "Abelson Virus Abrogation of Interleukin-3 Dependence in a\n Lymphoid Cell Line", "author": [ { "family_name": "Mathey-Prevot", "given_name": "Bernard", "clpid": "Mathey-Prevot-Bernard" }, { "family_name": "Nabel", "given_name": "Gary", "clpid": "Nabel-Gary-J" }, { "family_name": "Palacios", "given_name": "Ronald", "clpid": "Palacios-Ronald" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Among several tyrosine-protein kinases, only v-abl could abrogate interleukin 3 dependence of a lymphoblastoid cell line; v-src and v-fps proteins gave partial or no interleukin 3 independence, respectively. Lymphokine independence was achieved via a nonautocrine mechanism. Direct involvement of c-myc in this process was not evident.", "doi": "10.1128/MCB.6.11.4133", "pmcid": "PMC367185", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1986-11", "series_number": "11", "volume": "6", "issue": "11", "pages": "4133-4135" }, { "id": "authors:5v91m-t2g74", "collection": "authors", "collection_id": "5v91m-t2g74", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ANDjvir86", "type": "article", "title": "Lack of evidence for VPg priming of poliovirus RNA synthesis in the host factor-dependent in vitro replicase reaction", "author": [ { "family_name": "Andrews", "given_name": "Nancy C.", "clpid": "Andrews-Nancy-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Anti-VPg immunoprecipitable RNA labeled in vitro during a poliovirus RNA polymerase reaction was formed by the elongation of VPg-containing template fragments rather than by initiation with VPg. The reaction was dependent on a host factor (terminal uridylyl transferase). The incorporation of labeled UTP could be detected with only the host factor present.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1986-04", "series_number": "1", "volume": "58", "issue": "1", "pages": "212-215" }, { "id": "authors:t6bbx-hrp67", "collection": "authors", "collection_id": "t6bbx-hrp67", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SARpnas86", "type": "article", "title": "A Poliovirus Temperature-Sensitive RNA Synthesis Mutant Located in a Noncoding Region of the Genome", "author": [ { "family_name": "Sarnow", "given_name": "Peter", "clpid": "Sarnow-Peter" }, { "family_name": "Bernstein", "given_name": "Harris D.", "clpid": "Bernstein-Harris-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have constructed an 8-base-pair insertion mutation in the 3' noncoding region of an infectious poliovirus cDNA clone that gives rise to a temperature-sensitive RNA synthesis mutant upon transfection into mammalian cells. The mutated cDNA was used to establish a cell line that releases the mutant poliovirus in a temperature-dependent fashion, representing a unique persistent viral infection. A poliovirus mutant mapping in the noncapsid region of the viral genome can be complemented in this cell line, implying that the cell line expresses viral proteins at the nonpermissive temperature.", "doi": "10.1073/pnas.83.3.571", "pmcid": "PMC322905", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1986-02-01", "series_number": "3", "volume": "83", "issue": "3", "pages": "571-575" }, { "id": "authors:7k0ap-bf308", "collection": "authors", "collection_id": "7k0ap-bf308", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120626-124326427", "type": "article", "title": "Purification of a terminal uridylyltransferase that acts as host factor in the in vitro poliovirus replicase reaction", "author": [ { "family_name": "Andrews", "given_name": "Nancy C.", "clpid": "Andrews-Nancy-C" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Poliovirus RNA polymerase requires a host factor to initiate RNA synthesis in vitro. The host factor was previously purified to near homogeneity from HeLa cells but was not assigned an enzymatic activity. This report describes the purification of a terminal uridylyltransferase that can act as host factor. By all criteria examined it is identical to the factor purified previously. It has the same molecular weight (68,000), chromatographic properties, and cellular localization. We present evidence that terminal uridylyltransferase can add uridine residues to the 3' poly(A) end of virion RNA and that these anneal back to the poly(A) and form a hairpin primer for polymerase.", "doi": "10.1073/pnas.83.2.221", "pmcid": "PMC322829", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1986-01-01", "series_number": "2", "volume": "83", "issue": "2", "pages": "221-225" }, { "id": "authors:17vy8-2ee13", "collection": "authors", "collection_id": "17vy8-2ee13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120627-143833298", "type": "article", "title": "Poliovirus Mutant That Does Not Selectively Inhibit Host Cell\n Protein Synthesis", "author": [ { "family_name": "Bernstein", "given_name": "Harris D.", "clpid": "Bernstein-Harris-D" }, { "family_name": "Sonenberg", "given_name": "Nahum", "clpid": "Sonenberg-Nahum" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A poliovirus type I (Mahoney strain) mutant was obtained by inserting three base pairs into an infectious cDNA clone. The extra amino acid encoded by the insertion was in the amino-terminal (protein 8) portion of the P2 segment of the polyprotein. The mutant virus makes small plaques on HeLa and monkey kidney (CV-1) cells at all temperatures. It lost the ability to mediate the selective inhibition of host cell translation which ordinarily occurs in the first few hours after infection. As an apparent consequence, the mutant synthesizes far less protein than does wild-type virus. In mutant-infected CV-1 cells enough protein was produced to permit a normal course of RNA replication, but the yield of progeny virus was very low. In mutant-infected HeLa cells there was a premature cessation of both cellular and viral protein synthesis followed by a premature halt of viral RNA synthesis. This nonspecific translational inhibition was distinguishable from wild-type-mediated inhibition and did not appear to be part of an interferon or heat shock response. Because the mutant is recessive, our results imply that (at least in HeLa cells) wild-type poliovirus not only actively inhibits translation of cellular mRNAs, but also avoids early inhibition of its own protein synthesis. Cleavage of the cap-binding complex protein P220, which has been associated with the selective inhibition of capped mRNA translation, did not occur in mutant-infected cells. This result supports the hypothesis that cleavage of P220 plays an important role in normal poliovirus-mediated translational inhibition.", "doi": "10.1128/MCB.5.11.2913", "pmcid": "PMC369102", "issn": "0270-7306", "publisher": "American Society for Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1985-11", "series_number": "11", "volume": "5", "issue": "11", "pages": "2913-2923" }, { "id": "authors:yg5v1-j2068", "collection": "authors", "collection_id": "yg5v1-j2068", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FOUjbc85", "type": "article", "title": "Purification and characterization of a protein-tyrosine kinase encoded by the Abelson murine leukemia virus", "author": [ { "family_name": "Foulkes", "given_name": "J. Gordon", "clpid": "Foulkes-J-Gordon" }, { "family_name": "Chow", "given_name": "Marie", "clpid": "Chow-Marie" }, { "family_name": "Gorka", "given_name": "Carolyn", "clpid": "Gorka-Carolyn" }, { "family_name": "Frackelton", "given_name": "A. Raymond, Jr.", "clpid": "Frackelton-A-Raymond-Jr" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Sequences termed v-abl, which encode the protein-tyrosine kinase activity of Abelson murine leukemia virus, have been expressed in Escherichia coli as a fusion product (ptabl50 kinase). This fusion protein contains 80 amino acids of SV40 small t and the 403 amino acid protein kinase domain of v-abl. We report here the purification and characterization of this kinase. The purified material contains two proteins (Mr = 59,800 and 57,200), both of which possess sequences derived from v-abl. Overall purification was 3,750-fold, with a 31% yield, such that 117 micrograms of kinase could be obtained from 40 g of E. coli within 6-7 days. The specific kinase activity is over 170 mumol of phosphate min-1 mumol-1, comparable to the most active protein- serine kinases. Kinase activity is insensitive to K+, Na+, Ca2+, Ca2+- calmodulin, cAMP, or cAMP-dependent protein kinase inhibitor. The Km for ATP is dependent on the concentration of the second substrate. GTP can also be used as a phosphate donor. The enzyme can phosphorylate peptides consisting of as few as two amino acids and, at a very low rate, free tyrosine. Incubation of the kinase with [gamma-32P]ATP results in incorporation of 1.0 mol of phosphate/mol of protein. This reaction, however, cannot be blocked by prior incubation with unlabeled ATP. Incubation of 32P-labeled kinase with either ADP or ATP results in the synthesis of [32P]ATP. This suggests the phosphotyrosine residue on the Abelson kinase contains a high energy phosphate bond.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1985-07-05", "series_number": "13", "volume": "260", "issue": "13", "pages": "8070-8077" }, { "id": "authors:9h65r-ttj79", "collection": "authors", "collection_id": "9h65r-ttj79", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ANDjbc85", "type": "article", "title": "Poliovirus replicase stimulation by terminal uridylyl transferase", "author": [ { "family_name": "Andrews", "given_name": "Nancy C.", "clpid": "Andrews-Nancy-C" }, { "family_name": "Levin", "given_name": "Daniel", "clpid": "Levin-Daniel" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In an in vitro poliovirus replication system, purified viral polymerase, plus sense virion RNA, and a host factor have been previously shown to be necessary for the transcription of minus strands. We have found that a partially purified eukaryotic initiation factor-2 (eIF-2) fraction from rabbit reticulocytes can replace HeLa host factor in the replicase reaction. This enzyme preparation contains eIF-2 and two other major proteins. In addition to eIF-2 activity, which does not appear to play a role in the replicase reaction, we find that the fraction contains terminal uridylyl transferase activity. The enzyme adds UMP moieties to the 3' end of primer RNA molecules. The number of UMP residues added depends on the primer. Although long tails of heterogeneous lengths (50 to 100 nucleotides) can be polymerized on the 3' end of oligo(U), a poly(A) primer accepts only four U's. The terminal uridylyl transferase activity requires only UTP, Mg2+, a sulfhydryl reagent, and an RNA primer for activity. It is partially associated with ribosomes. We provide preliminary evidence that it may be responsible for host factor-like activity. We present a model for minus strand synthesis by poliovirus replicase, based on the hypothesis that a terminal uridylyl transferase can participate in initiation.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1985-06-25", "series_number": "12", "volume": "260", "issue": "12", "pages": "7628-7635" }, { "id": "authors:arhxz-w8307", "collection": "authors", "collection_id": "arhxz-w8307", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MANjvir85", "type": "article", "title": "Varying the position of a retrovirus packaging sequence results in the encapsidation of both unspliced and spliced RNAs", "author": [ { "family_name": "Mann", "given_name": "Richard", "clpid": "Mann-Richard" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "By using a retroviral construct derived from Moloney murine leukemia virus and capable of expressing the dominant selectable neo gene, we measured the effects of moving or deleting a sequence (psi) known to be required in cis for the packaging of genomic RNA into virus particles. When psi was at its wild-type position (in SVX virus) near the 5' end of the RNA, the titer of infectious virus production was 5 X 10(6) G-418-resistant CFU per ml. The titer was decreased approximately fivefold when psi was moved, in its proper orientation, to near the 3' end of the virus (SVX-psi C) and was decreased approximately 600-fold when psi was moved, in its proper orientation, into the U3 region of the long terminal repeat. When psi was deleted (SVX-psi-) or inserted in the opposite orientation at either of these two positions, the titer was decreased by 3000-fold relative to SVX. In SVX-psi C, psi was no longer in the intron (as it is in SVX and Moloney murine leukemia virus) but was moved to a region which is only exonic. This resulted in the encapsidation of both spliced and unspliced RNAs, their efficient reverse transcription, and their integration into the genome of an infected cell. A number of proviruses resulting from integration of either spliced or unspliced RNAs were cloned. Four of these clones were subjected to sequence analysis in the region of the splice sites, and it was determined which sites are used by these viruses and also which are used by Moloney murine leukemia virus.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1985-05", "series_number": "2", "volume": "54", "issue": "2", "pages": "401-407" }, { "id": "authors:kv5fk-23f24", "collection": "authors", "collection_id": "kv5fk-23f24", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PRYjvir85b", "type": "article", "title": "Protein stabilization explains the gag requirement for transformation of lymphoid cells by Abelson murine leukemia virus", "author": [ { "family_name": "Prywes", "given_name": "Ron", "clpid": "Prywes-Ron" }, { "family_name": "Hoag", "given_name": "Jennifer", "clpid": "Hoag-Jennifer" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The single protein encoded by Abelson murine leukemia virus is a fusion of sequence from the retroviral gag genes with the v-abl sequence. Deletion of most of the gag region from the transforming protein results in a virus capable of transforming fibroblasts but no longer capable of transforming lymphoid cells. Smaller deletions in gag reveal that p15 gag sequences are responsible for this effect, whereas deletion of p12 sequences had no effect on lymphoid transformation. In transformed fibroblasts, p15-deleted and normal proteins had similar activities and subcellular localization. When the p15-deleted genome was introduced into previously transformed lymphoid lines, its protein product exhibited a marked instability. The tyrosine-specific autophosphorylation activity per cell was less than 1/20th that of the nondeleted protein. Although pulse-Ia-beling showed that the p15-deleted protein was synthesized efficiently, immunoblotting demonstrated that its steady-state level was less than 1/10th that of the nondeleted Abelson protein. The specific instability of the p15-deleted protein in lymphoid cells explains the requirement of these sequences for lymphoid but not fibroblast transformation.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1985-04", "series_number": "1", "volume": "54", "issue": "1", "pages": "123-132" }, { "id": "authors:3ej1f-5t285", "collection": "authors", "collection_id": "3ej1f-5t285", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PRYjvir85a", "type": "article", "title": "The minimum transforming region of v-abl is the segment encoding protein-tyrosine kinase", "author": [ { "family_name": "Prywes", "given_name": "Ron", "clpid": "Prywes-Ron" }, { "family_name": "Foulkes", "given_name": "J. Gordon", "clpid": "Foulkes-J-Gordon" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Only 1.2 kilobases (kb) at the 5' end of the 3.9-kb v-abl sequence in Abelson murine leukemia virus is required for fibroblast transformation. A precise delineation of this minimum transforming region was made by using small 5' or 3' deletions. Insertions of four amino acids, generated by putting synthetic DNA linkers into various restriction enzyme cleavage sites, abolished transforming activity, indicating that much of the internal sequence of the minimum transforming region plays a critical role in the transformation process. This 5' 1.2 kb of v-abl encodes protein-tyrosine kinase activity when expressed in Escherichia coli. Each of the mutations which caused a loss of transformation activity also resulted in a loss of protein-tyrosine kinase activity when expressed in E. coli. The minimum transforming region of v-abl contains amino acid homology to other protein-tyrosine kinase oncogenes, and a comparison with these oncogenes is presented.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1985-04", "series_number": "1", "volume": "54", "issue": "1", "pages": "114-122" }, { "id": "authors:z154q-jnm43", "collection": "authors", "collection_id": "z154q-jnm43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHOpnas85", "type": "article", "title": "Synthetic Peptides from Four Separate Regions of the Poliovirus Type 1 Capsid Protein VP1 Induce Neutralizing Antibodies", "author": [ { "family_name": "Chow", "given_name": "M.", "clpid": "Chow-Marie" }, { "family_name": "Yabrov", "given_name": "R.", "clpid": "Yabrov-R" }, { "family_name": "Bittle", "given_name": "J.", "clpid": "Bittle-J" }, { "family_name": "Hogle", "given_name": "J.", "clpid": "Hogle-J" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Peptides from different regions of the poliovirus type 1 capsid protein VP1 were synthesized. Antibodies raised against these peptides in rabbits and rats recognized the cognate peptides and denatured VP1. Peptides from four regions of VP1 generated antisera with neutralizing titers specifically against poliovirus type 1. Antisera against all other regions of VP1 failed to neutralize virus infectivity, although some of the antisera clearly bound to native virions. Thus, the neutralizing determinants on VP1 reside in specific noncontiguous regions of the protein and can be defined by specific peptides from these regions.", "doi": "10.1073/pnas.82.3.910", "pmcid": "PMC397157", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1985-02-01", "series_number": "3", "volume": "82", "issue": "3", "pages": "910-914" }, { "id": "authors:46fwx-fnj71", "collection": "authors", "collection_id": "46fwx-fnj71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MALpnas85", "type": "article", "title": "Phosphorylation of Ribosomal Protein S6 on Serine after Microinjection of the Abelson Murine Leukemia Virus Tyrosine-Specific Protein Kinase into Xenopus oocytes", "author": [ { "family_name": "Maller", "given_name": "James L.", "clpid": "Maller-James-L" }, { "family_name": "Foulkes", "given_name": "J. Gordon", "clpid": "Foulkes-J-Gordon" }, { "family_name": "Erikson", "given_name": "Eleanor", "clpid": "Erikson-Eleanor" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Phosphorylation of ribosomal protein S6 in NIH 3T3 fibroblasts is dependent on the presence of serum, but after transformation of these cells by Abelson murine leukemia virus (Ab-MuLV), S6 remained highly phosphorylated on serine residues either in the absence or the presence of serum. To investigate whether S6 phosphorylation in this system was a consequence of the action of the Ab-MuLV tyrosine-specific protein kinase, purified Ab-MuLV kinase made in Escherichia coli was microinjected into Xenopus oocytes and was observed to cause a 7- to 15-fold increase in the phosphorylation of S6 on serine residues. Two-dimensional phosphopeptide maps of S6 phosphorylated in Ab-MuLV-transformed NIH cells in the absence of serum were identical to those of S6 isolated from normal cells grown in the presence of serum. In addition, S6 from oocytes injected with Ab-MuLV kinase yielded an S6 phosphopeptide map indistinguishable from that of serum-stimulated NIH 3T3 cells, whereas S6 from control oocytes lacked several phosphopeptides. Ab-MuLV kinase did not phosphorylate S6 directly in vitro, and microinjection of a mutant Ab-MuLV protein lacking kinase activity had no effect. These results indicate that the Ab-MuLV kinase interacts with a cellular pathway to enhance S6 phosphorylation by directly or indirectly activating an S6 protein kinase and/or inactivating an S6 protein phosphatase.", "doi": "10.1073/pnas.82.2.272", "pmcid": "PMC397019", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1985-01-15", "series_number": "2", "volume": "82", "issue": "2", "pages": "272-276" }, { "id": "authors:60wgw-cwa33", "collection": "authors", "collection_id": "60wgw-cwa33", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:WANjbc85", "type": "article", "title": "Localization of tyrosine kinase-coding region in v-abl oncogene by the expression of v-abl-encoded proteins in bacteria", "author": [ { "family_name": "Wang", "given_name": "Jean Y. J.", "clpid": "Wang-Jean-Yin-Jen" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A series of plasmids containing different segments of the v-abl oncogene have been constructed to express different portions of the v- abl protein in bacteria. The tyrosine kinase activity of these proteins was determined by an in vitro assay employing histones or angiotensin II as substrates for the v-abl-encoded tyrosine kinase. These experiments show that the 5'-1.2 kilobases of v-abl is necessary and sufficient to produce an active tyrosine kinase which is functional as a monomeric soluble protein. The kinase-coding region corresponds to the minimal region of v-abl required for the transformation of fibroblasts. The kinase-coding region also coincides with the conserved protein sequences which are found in other tyrosine kinases. A compact domain of the v-abl protein including this kinase-coding region can accumulate to high levels in bacteria. The C-terminal region of the v- abl protein is not needed for the kinase activity and is rapidly degraded in bacteria.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1985-01-10", "series_number": "1", "volume": "260", "issue": "1", "pages": "64-71" }, { "id": "authors:jqtzk-a5a13", "collection": "authors", "collection_id": "jqtzk-a5a13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DEPmcb84", "type": "article", "title": "Molecular basis of heavy-chain class switching and switch region deletion in an Abelson virus-transformed cell line", "author": [ { "family_name": "DePinho", "given_name": "Ronald", "clpid": "DePinho-Ronald-A" }, { "family_name": "Kruger", "given_name": "Kelly", "clpid": "Kruger-Kelly" }, { "family_name": "Andrews", "given_name": "Nancy", "clpid": "Andrews-Nancy-C" }, { "family_name": "Lutzker", "given_name": "Stuart", "clpid": "Lutzker-Stuart" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" } ], "abstract": "We demonstrated that a subclone of an Abelson murine leukemia virus-transformed B-lymphoid cell line switched from mu to gamma 2b expression in vitro, by the classical recombination-deletion mechanism. In this line, the expressed VHDJH region and the C gamma 2b constant region gene were juxtaposed by a recombination event which linked the highly repetitive portions of the S mu and S gama 2b regions and resulted in the loss of the C mu gene from the intervening region. An additional recombination event in this subclone involved an internal deletion in the S mu region of the expressed (switched) allele. One end of this deletion occurred very close to the switch recombination point. Despite the recombination-deletion mechanism of switching, the gamma 2b-producing line retained two copies of the C mu gene and two copies of the sequence just 5' to the S gamma 2b recombination point. The possible significance of the retention of these sequences to the mechanism of class switching is discussed.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1984-12", "series_number": "12", "volume": "4", "issue": "12", "pages": "2905-2910" }, { "id": "authors:97vg4-swc02", "collection": "authors", "collection_id": "97vg4-swc02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BERpnas84", "type": "article", "title": "Two Regulatory Elements for Immunoglobulin kappa Light Chain Gene Expression", "author": [ { "family_name": "Bergman", "given_name": "Yehudit", "clpid": "Bergman-Yehudit" }, { "family_name": "Rice", "given_name": "Douglas", "clpid": "Rice-Douglas" }, { "family_name": "Grosschedl", "given_name": "Rudolf", "clpid": "Grosschedl-Rudolf" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "By using internal deletions within a rearranged immunoglobulin kappa light chain gene, the presence of an intron regulatory sequence (enhancer) has been confirmed. Its presence is required for high-level transcription from a plasmid after transfection into myeloma cells. Transfection efficiency was monitored by the activity of a deleted H4 histone gene included in the plasmid. The intron element could be moved upstream of the gene in both orientations, fulfilling the definition of an enhancer. By using 5' deletions, a second regulatory element was located upstream of the \"TATA\" box, between positions -69 and -104. These two elements both are required for efficient kappa chain gene expression.", "doi": "10.1073/pnas.81.22.7041", "pmcid": "PMC392072", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1984-11-15", "series_number": "22", "volume": "81", "issue": "22", "pages": "7041-7045" }, { "id": "authors:628nf-4gs65", "collection": "authors", "collection_id": "628nf-4gs65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LANpnas84", "type": "article", "title": "Cloning of terminal transferase cDNA by antibody screening", "author": [ { "family_name": "Landau", "given_name": "Nathaniel R.", "clpid": "Landau-Nathaniel-R" }, { "family_name": "St. John", "given_name": "Thomas P.", "clpid": "St-John-Thomas-P" }, { "family_name": "Weissman", "given_name": "Irving L.", "clpid": "Weissman-Irving-L" }, { "family_name": "Wolf", "given_name": "Susan C.", "clpid": "Wolf-Susan-C" }, { "family_name": "Silverstone", "given_name": "Allen E.", "clpid": "Silverstone-Allen-E" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A cDNA library was prepared from a terminal deoxynucleotidyltransferase-containing thymoma in the phage vector \u03bbgt11. By screening plaques with anti-terminal transferase antibody, positive clones were identified of which some had \u03b2-galactosidase-cDNA fusion proteins identifiable after electrophoretic fractionation by immunoblotting with anti-terminal transferase antibody. The predominant class of cross-hybridizing clones was determined to represent cDNA for terminal transferase by showing that one representative clone hybridized to a 2200-nucleotide mRNA in close-matched enzyme-positive but not to enzyme-negative cells and that the cDNA selected a mRNA that translated to give a protein of the size and antigenic characteristics of terminal transferase. Only a small amount of genomic DNA hybridized to the longest available clone, indicating that the sequence is virtually unique in the mouse genome.", "doi": "10.1073/pnas.81.18.5836", "pmcid": "PMC391806", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1984-09-15", "series_number": "18", "volume": "81", "issue": "18", "pages": "5836-5840" }, { "id": "authors:2qra2-2tv05", "collection": "authors", "collection_id": "2qra2-2tv05", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHAjvir84", "type": "article", "title": "Mechanism of RNA primer removal by the RNase H activity of avian myeloblastosis virus reverse transcriptase", "author": [ { "family_name": "Champoux", "given_name": "James J.", "clpid": "Champoux-James-J" }, { "family_name": "Gilboa", "given_name": "Eli", "clpid": "Gilboa-Eli" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The single-stranded DNA containing the Moloney murine leukemia virus origin for plus-strand synthesis was cloned in M13mp2 and used as a template for avian myeloblastosis virus reverse transcriptase in the presence of Moloney RNA which had been treated with pancreatic RNase A. The RNA pieces containing the polypurine stretch near the plus-strand origin were processed, presumably by RNase H, to generate primers for DNA synthesis which initiated both at the correct origin site and at one nucleotide downstream from the correct site. Approximately 50% of the labeled DNA fragments synthesized under these conditions retained the priming RNA on their 5' ends. When the isolated fragments were hybridized back to the template DNA and again treated with the reverse transcriptase, all of the RNA was removed from the labeled DNA. By using 5'-end-labeled pancreatic RNase A-resistant fragments, it was possible to show that the RNA primers were removed intact. It appears from these results that the RNase H activity associated with the enzyme shows a preference for cutting at the junction between the RNA and DNA moieties of such complexes and therefore is ideally suited for removing RNA primers.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1984-03", "series_number": "3", "volume": "49", "issue": "3", "pages": "686-691" }, { "id": "authors:5se7m-30z90", "collection": "authors", "collection_id": "5se7m-30z90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FALjvir84", "type": "article", "title": "Liposome encapsulation of retrovirus allows efficient superinfection of resistant cell lines", "author": [ { "family_name": "Faller", "given_name": "Douglas V.", "clpid": "Faller-Douglas-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Cell lines which are infected with retrovirus are resistant to superinfection by a related retrovirus. Packaging of whole virions within synthetic lipid vesicles allows efficient infection of such resistant cell lines. This system is more efficient in introducing encapsulated virus into infected cells than into uninfected cells.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1984-01", "series_number": "1", "volume": "49", "issue": "1", "pages": "269-272" }, { "id": "authors:y4xf9-bj870", "collection": "authors", "collection_id": "y4xf9-bj870", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CRApnas83", "type": "article", "title": "Genome-linked protein VPg of poliovirus is present as free VPg and VPg-pUpU in poliovirus-infected cells", "author": [ { "family_name": "Crawford", "given_name": "Nigel M.", "clpid": "Crawford-Nigel-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "VPg is a virus-encoded protein covalently attached to the 5' end of poliovirus virion RNA. We have used antibody prepared against chemically synthesized VPg to detect two forms of VPg in infected cells. Both forms were specifically immunoprecipitated from lysates of infected cells labeled with [3H]leucine. One appears to be unmodified VPg because it had the same electrophoretic mobility as synthetic VPg. The other had a larger apparent molecular weight than VPg and could be labeled in vivo with 32Pi. Its structure is VPg-pUpU, the UMP dinucleotide being attached to VPg via a phosphodiester bond to tyrosine, the third amino acid from the NH2 terminus of VPg. This structure is identical to that found at the 5' end of virion and minus-strand RNA.", "doi": "10.1073/pnas.80.24.7452", "pmcid": "PMC389969", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1983-12-15", "series_number": "24", "volume": "80", "issue": "24", "pages": "7452-7455" }, { "id": "authors:12b8n-ese62", "collection": "authors", "collection_id": "12b8n-ese62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:TICpnas83", "type": "article", "title": "Molecular cloning and characterization of hepatitis A virus cDNA", "author": [ { "family_name": "Ticehurst", "given_name": "John R.", "clpid": "Ticehurst-John-R" }, { "family_name": "Racaniello", "given_name": "Vincent R.", "clpid": "Racaniello-Vincent-R" }, { "family_name": "Baroudy", "given_name": "Bahige M.", "clpid": "Baroudy-Bahige-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Purcell", "given_name": "Robert H.", "clpid": "Purcell-Robert-H" }, { "family_name": "Feinstone", "given_name": "Stephen M.", "clpid": "Feinstone-Stephen-M" } ], "abstract": "Double-stranded cDNA was synthesized from hepatitis A virus (HAV) RNA and inserted into the Pst I site of pBR322. Restriction endonuclease digestion and cross-hybridization of fragments yielded a map of overlapping cloned cDNAs that included at least 99% of the viral genome. Molecular clones containing HAV cDNA were identified by hybridizing cloned cDNA to electrophoretically resolved RNA from uninfected and HAV-infected tissue culture cells. Cloned cDNA probes specifically hybridized to RNA from infected cells, and the predominant species identified had the characteristic genomic length of picornaviral RNA (~7,500 nucleotides). A partial sequence from the 3' end of the genome revealed 414 bases in an open reading frame followed by two closely spaced stop codons, a 60-base noncoding region, and a tract of poly(A).", "doi": "10.1073/pnas.80.19.5885", "pmcid": "PMC390180", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1983-10-01", "series_number": "19", "volume": "80", "issue": "19", "pages": "5885-5889" }, { "id": "authors:3r24h-qgy20", "collection": "authors", "collection_id": "3r24h-qgy20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KANpnas83", "type": "article", "title": "Isolation of amplified DNA sequences from IMR-32 human neuroblastoma cells: Facilitation by fluorescence-activated flow sorting of metaphase chromosomes", "author": [ { "family_name": "Kanda", "given_name": "N.", "clpid": "Kanda-N" }, { "family_name": "Schreck", "given_name": "R.", "clpid": "Schreck-R" }, { "family_name": "Alt", "given_name": "F.", "clpid": "Alt-Frederick-W" }, { "family_name": "Bruns", "given_name": "G.", "clpid": "Bruns-G" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Latt", "given_name": "S.", "clpid": "Latt-Samuel-A" } ], "abstract": "Human neuroblastoma IMR-32 cells have large homogeneously staining regions (HSRs), primarily in the short arms of chromosome 1. We have constructed a recombinant phage library that is enriched for DNA present in the HSR of this chromosome by using fluorescence-activated flow sorting for initial chromosome purification. Eleven distinct cloned DNA segments were identified that showed significantly greater hybridization to IMR-32 genomic DNA, detected by Southern blotting, than to normal human genomic DNA. These sequences have also been localized to the HSR of chromosome 1 by in situ hybridization. Based on an approximate 50-fold sequence amplification for each cloned segment and a total HSR size of 150,000 kilobases, the amplified unit in the HSR is estimated to be 3,000 kilobases. Sequences homologous to all cloned HSR DNA segments were mapped to human chromosome 2 by using human-mouse hybrid cells. Further work using in situ hybridization demonstrated that cloned HSR segments were localized in the short arm of chromosome 2 in both normal and IMR-32 cells. Thus, the amplification of these sequences in IMR-32 cells may have involved transposition from chromosome 2 to chromosome 1.", "doi": "10.1073/pnas.80.13.4069", "pmcid": "PMC394202", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1983-07-01", "series_number": "13", "volume": "80", "issue": "13", "pages": "4069-4073" }, { "id": "authors:dw30h-x5b76", "collection": "authors", "collection_id": "dw30h-x5b76", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120712-124936634", "type": "article", "title": "Cellular RNA Homologous to the Abelson Murine Leukemia\n Virus Transforming Gene: Expression and Relationship to the\n Viral Sequence", "author": [ { "family_name": "Wang", "given_name": "Jean Yin Jen", "clpid": "Wang-Jean-Yin-Jen" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To examine the expression of the cellular homolog of the Abelson murine\nleukemia virus transforming gene (the v-abl sequence), a DNA probe representing\nthe v-abl sequence was prepared. The probe detected two cytoplasmic polyadenylic\nacid-containing c-abl RNAs of about 6.5 and 5.5 kilobases in a variety of\nrodent cells, and slightly larger RNAs were detected in human cells. These two\nRNA species were found in all normal tissues or cell lines examined, but at\ndiffering concentrations: liver cells had the least, fibroblastic cell lines had the\nmost. By using a probe able to detect the cellular but not the viral gene, the two\nRNAs were shown to be present in Abelson murine leukemia virus-transformed\ncells at levels found either in their untransformed counterparts or in similar cell\ntypes transformed by other means. The target cells of the virus have a somewhat\nelevated level of the two RNAs although expression of the c-abl gene is not\nrestricted to these cells. The v-abl sequence lacks 0.35 and 0.85 kilobases of the c-abl RNA on the 5' and 3' ends, respectively. Thus, the Abelson murine leukemia\nvirus transforming gene is an internal fragment of the transcript of a normal\ncellular gene.", "pmcid": "PMC368599", "issn": "0270-7306", "publisher": "American Society of Microbiology", "publication": "Molecular and Cellular Biology", "publication_date": "1983-05", "series_number": "5", "volume": "3", "issue": "5", "pages": "773-779" }, { "id": "authors:p7ppw-0b614", "collection": "authors", "collection_id": "p7ppw-0b614", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LATjvir83", "type": "article", "title": "Cloning and analysis of reverse transcript P160 genomes of Abelson murine leukemia virus", "author": [ { "family_name": "Latt", "given_name": "Samuel A.", "clpid": "Latt-Samuel-A" }, { "family_name": "Goff", "given_name": "Stephen P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Tabin", "given_name": "Clifford J.", "clpid": "Tabin-Clifford-J" }, { "family_name": "Paskind", "given_name": "Michael", "clpid": "Paskind-Michael" }, { "family_name": "Wang", "given_name": "Jean Y.-J.", "clpid": "Wang-Jean-Yin-Jen" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Circular duplex reverse transcripts of the genome of a strain of Abelson murine leukemia virus that encodes a 160,000-molecular-weight protein were isolated, cleaved with HindIII restriction endonuclease, and cloned into the unique HindIII site of lambda phage Charon 21A. Recombinant phage clones, some of which were infectious in transfection assays, were found to contain a 789-base-pair region specific for Abelson murine leukemia virus; this region is not found in other strains of this virus. The extra sequence was localized by restriction endonuclease and electron microscopic heteroduplex analysis. Sequence analysis showed no homology at the ends of the extra sequence, implying that it was deleted by an event that did not utilize sequence homology. The sequence of this unique region has an open reading frame through its entirety.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1983-03", "series_number": "3", "volume": "45", "issue": "3", "pages": "1195-1199" }, { "id": "authors:w1aaj-rw728", "collection": "authors", "collection_id": "w1aaj-rw728", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:RICpnas82", "type": "article", "title": "Regulated expression of an immunoglobulin kappa gene introduced into a mouse lymphoid cell line", "author": [ { "family_name": "Rice", "given_name": "Douglas", "clpid": "Rice-Douglas" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have introduced a functionally rearranged murine \u0138 light chain immunoglobulin (Ig) gene into an Abelson murine leukemia virus-transformed lymphoid cell line. Plasmid pSV2gpt-\u03ba41, containing the \u0138 light chain gene from the myeloma MOPC41 and the selectable marker gene gpt, was introduced into 81A-2 cells by the calcium phosphate coprecipitation technique. Cells expressing the gpt gene were selected by growth in medium containing mycophenolic acid. One transfected cell line, \u0138-2, was shown to make \u0138 mRNA and polypeptide chains and to assemble the \u0138 chain product with \u03b32b heavy chains to form an apparently complete IgG2b. When bacterial lipopolysaccharide was added to the growth medium, levels of mRNA and polypeptide increased, showing regulated expression of the introduced \u0138 gene.", "doi": "10.1073/pnas.79.24.7862", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1982-12-15", "series_number": "24", "volume": "79", "issue": "24", "pages": "7862-7865" }, { "id": "authors:d3fhj-qx975", "collection": "authors", "collection_id": "d3fhj-qx975", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CHOpnas82", "type": "article", "title": "Isolated poliovirus capsid protein VP1 induces a neutralizing response in rats", "author": [ { "family_name": "Chow", "given_name": "Marie", "clpid": "Chow-Marie" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Antibodies were raised in rats against the poliovirus type 1 capsid proteins, VP1, VP2, and VP3. Antibodies directed against VP1 from type 1 poliovirus (Mahoney) neutralized type 1 but not type 2 poliovirus. Antibodies raised against VP2 and VP3 failed to neutralize type 1 virus. Thus, VP1 appears to be a neutralizing antigen for poliovirus and in its denatured form presents to the immune system its neutralizing determinants.", "doi": "10.1073/pnas.79.23.7518", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1982-12-01", "series_number": "23", "volume": "79", "issue": "23", "pages": "7518-7521" }, { "id": "authors:a89nb-90s22", "collection": "authors", "collection_id": "a89nb-90s22", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:TRAjvir82", "type": "article", "title": "Protease bypass of temperature-sensitive murine leukemia virus maturation mutants", "author": [ { "family_name": "Traktman", "given_name": "Paula", "clpid": "Traktman-Paula" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Cells infected with certain temperature-sensitive mutants of Moloney murine leukemia virus synthesize the virion precursor proteins but neither bud virions nor cleave precursor proteins to their mature form. Addition of proteases to cells infected with these mutants caused cleavage of the precursor proteins Pr65gag and Pr180gag-pol to their mature forms at the nonpermissive temperature. Concomitantly there was release from the cells of morphologically normal virions. The enzymatically inactive Pr180gag-pol was cleaved to active reverse transcriptase (p85), which was found in the released particles. External protease treatment apparently bypassed the lesion in these viral mutants, suggesting that their defect may involve a virus-specific protease.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1982-12", "series_number": "3", "volume": "44", "issue": "3", "pages": "1039-1046" }, { "id": "authors:rvwbz-0ee27", "collection": "authors", "collection_id": "rvwbz-0ee27", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120717-092841129", "type": "article", "title": "Expression of an Abelson murine leukemia virus-encoded protein in Escherichia coli causes extensive phosphorylation of tyrosine residues", "author": [ { "family_name": "Wang", "given_name": "Jean Yin Jen", "clpid": "Wang-Jean-Yin-Jen" }, { "family_name": "Queen", "given_name": "Cary", "clpid": "Queen-Cary" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A segment of the Abelson murine leukemia virus (A-MuLV) genome was inserted into an Escherichia coli plasmid designed to allow the expression of the protein encoded by the viral gene. Bacteria expressing the A-MuLV-encoded protein were isolated; they had new phosphorylated proteins in which the phosphate was linked to tyrosine residues. These proteins included many that must be E. coli protein. One phosphotyrosine-containing protein of 62,000 molecular weight had reactivity with antiserum specific for authentic A-MuLV protein. The A-MuLV protein thus appears to be a tyrosine-specific protein kinase which is active in E. coli.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1982-11-25", "series_number": "22", "volume": "257", "issue": "22", "pages": "13181-13184" }, { "id": "authors:y1fdg-nqd37", "collection": "authors", "collection_id": "y1fdg-nqd37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120717-091213541", "type": "article", "title": "Purification and Properties of a Host Cell Protein Required for Poliovirus Replication in Vitro", "author": [ { "family_name": "Baron", "given_name": "Margaret H.", "clpid": "Baron-Margaret-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A host cell protein required for poliovirus RNA-dependent RNA replicase activity in vitro has been purified several thousand-fold from an uninfected HeLa cell postmitochondrial supernatant. A single protein of apparent Mr = approximately 67,000 daltons and pI 6.3 is associated with this \"host factor\" activity. Poly(U)-Sepharose chromatography of the template-dependent replicase isolated from poliovirus-infected cells results in the complete loss of replicase activity if a salt gradient is used to develop the column. Host factor elutes early in the salt gradient and restores replicase activity to protein fractions eluted later in the gradient. The host factor, estimated to be present at 50,000-100,000 copies/cell, interacts physically with replicase.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1982-10-25", "series_number": "20", "volume": "257", "issue": "20", "pages": "12351-12358" }, { "id": "authors:myx4y-qee24", "collection": "authors", "collection_id": "myx4y-qee24", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120717-091003406", "type": "article", "title": "In Vitro Copying of Viral Positive Strand RNA by Poliovirus Replicase. Characterization of the reaction and its products", "author": [ { "family_name": "Baron", "given_name": "Margaret H.", "clpid": "Baron-Margaret-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Poliovirus replicase can be isolated in a form which depends on either oligo(U) or on a host cell protein for the initiation of copying of poliovirion (plus strand) RNA. The product of replicase reactions--initiated either with host factor or with oligo(U)--includes full length (35 S) RNA molecules, largely in double-stranded form, which contain the ribonuclease T1-resistant oligonucleotides of the poliovirus minus strand. For the oligo(U)-stimulated reaction, it is shown that the oligo(U) primer is covalently associated with full length product at its 5'-end. For either the host factor- or oligo(U)-dependent reactions, full length molecules appear only after 15 min of synthesis. The fraction of 35 S product is increased by raising the concentration of the limiting nucleoside triphosphate. The reaction is inhibited by as little as 100 mM salt, although it is stimulated by low (20 mM) salt concentrations. Zinc stimulates overall synthesis, but not the rate of appearance of full length molecules; the reaction is inhibited by agents which chelate zinc. Although synthesis of full length products occurs much more slowly than in the infected cell, this soluble system appears to mimic quite faithfully the initial steps of poliovirus replication.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1982-10-25", "series_number": "20", "volume": "257", "issue": "20", "pages": "12359-12366" }, { "id": "authors:sf3tp-tqs83", "collection": "authors", "collection_id": "sf3tp-tqs83", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BARjvir82", "type": "article", "title": "Antibodies against a synthetic peptide of the poliovirus replicase protein: reaction with native, virus-encoded proteins and inhibition of virus-specific polymerase activities in vitro", "author": [ { "family_name": "Baron", "given_name": "Margaret H.", "clpid": "Baron-Margaret-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A carboxy-terminal peptide of the poliovirus replicase protein (p63) was chemically synthesized, coupled to bovine serum albumin carrier, and injected into rabbits. The resulting antisera reacted with six virus-specific proteins from HeLa cells infected with poliovirus: NCVP 0b, NCVP 1b, NCVP 2, a protein of about 60,000 daltons, p63, and NCVP 6b. The identity of the 60,000-dalton protein is not known, but the other results were consistent with previous experimental approaches which demonstrated that p63 and the other four polypeptides have common coding sequences. An amino-terminal peptide of p63 failed to elicit an immune response in rabbits. Antibodies raised against the p63 carboxy-terminal peptide inhibited poliovirus replicase and polyuridylic acid polymerase activities in vitro, providing strong support for earlier suggestions that these activities are a property of a single virus-specific polypeptide.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1982-09", "series_number": "3", "volume": "43", "issue": "3", "pages": "969-978" }, { "id": "authors:vz4aj-paf84", "collection": "authors", "collection_id": "vz4aj-paf84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ALTpnas82", "type": "article", "title": "Joining of Immunoglobulin Heavy Chain Gene Segments: Implications from a Chromosome with Evidence of Three D-JH Fusions", "author": [ { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A chromosomal segment with a unique structure around the immunoglobulin heavy chain joining region (JH) has been molecularly cloned from an Abelson murine leukemia virus-transformed cell line. Attached to JH3 in the cloned DNA, in inverted sequence, is the DNA from JH1 to the JH2 recognition sequence. The inverted segment is attached at its other end to the 5' recognition sequence of a diversity segment (D). To form this structure, three joining events must have occurred on the same chromosome. One of these events could have been a normal D-JH joining but the others must have been irregular events including ones that result in inversions. One of the joining events left fused recognition elements from JH2 and a D whose sequence shows that, during joining, reciprocal joinings of the recognition elements must occur to fuse the heptameric elements back to back. Because joined D and JH undergo deletion of terminal coding sequence during recombination but the joined heptameric recognition sequences do not contain the deleted sequence, joining must be a nonreciprocal event. Also, extra nucleotides are inserted between D and JH as part of the joining process; it is suggested that this added sequence is a product of the activity of terminal deoxynucleotidyltransferase at the D/JH (and probably the VH/D) joints and that it represents a new element of heavy chain gene structure, the N region.", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1982-07-01", "series_number": "13", "volume": "79", "issue": "13", "pages": "4118-4122" }, { "id": "authors:wjmn3-87571", "collection": "authors", "collection_id": "wjmn3-87571", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120717-133113420", "type": "article", "title": "Synthesis of Murine Leukemia Virus Plus Strong Stop DNA\n Initiates at a Unique Site", "author": [ { "family_name": "Mitra", "given_name": "Sudha W.", "clpid": "Mitra-Sudra-Warrier" }, { "family_name": "Chow", "given_name": "Marie", "clpid": "Chow-Marie" }, { "family_name": "Champoux", "given_name": "James", "clpid": "Champoux-James-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The 5'-terminal segment of plus strong stop DNA has been isolated from an endogenous virion reverse transcription reaction and characterized. The plus strong stop DNA is shown to initiate with the sequence 5'AATGAAAGA.... The 5'-terminal nucleotide is a deoxyribonucleotide. No residual protein or RNA moiety was found attached to the plus strong stop DNA. Thus, the mechanism which primes plus strand synthesis is still unclear. No evidence for multiple initiation sites or heterogeneous starts is observed. This data indicates that the initiation of plus strong stop DNA synthesis by the virion RNA-dependent DNA polymerase is a precise event which occurs at a unique site on the retrovirus genome.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1982-06-10", "series_number": "11", "volume": "257", "issue": "11", "pages": "5983-5986" }, { "id": "authors:bwkhg-yh017", "collection": "authors", "collection_id": "bwkhg-yh017", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:DASjvir82", "type": "article", "title": "Antibody to a host protein prevents initiation by the poliovirus replicase", "author": [ { "family_name": "Dasgupta", "given_name": "Asim", "clpid": "Dasgupta-Asim" }, { "family_name": "Hollingshead", "given_name": "Philip", "clpid": "Hollingshead-Philip" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "In vitro transcription of poliovirus RNA was catalyzed by the combination of a virus-coded polymerase and a host cell protein (host factor). Antibody to host factor inhibited template-dependent synthesis of complementary RNA where presumably RNA chain initiation occurred. On the contrary, elongation of already initiated RNA chains catalyzed by the replicase-template complex was not inhibited by anti-host factor antibody. These results strongly favored our previous notion that the host factor was needed for the initiation step of viral complementary RNA synthesis.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1982-06", "series_number": "3", "volume": "42", "issue": "3", "pages": "1114-1117" }, { "id": "authors:g9y11-zm963", "collection": "authors", "collection_id": "g9y11-zm963", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ALTmcb82", "type": "article", "title": "Multiple immunoglobulin heavy-chain gene transcripts in Abelson murine leukemia virus-transformed lymphoid cell lines", "author": [ { "family_name": "Alt", "given_name": "Frederick W.", "clpid": "Alt-Frederick-W" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Enea", "given_name": "Vincenzo", "clpid": "Enea-Vincenzo" }, { "family_name": "Siden", "given_name": "Edward", "clpid": "Siden-Edward" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Lymphoid cells transformed by Abelson murine leukemia virus (A-MuLV) contain three classes of RNA transcripts from immunoglobulin mu genes. P mu-mRNAs (productive) correspond to the normal 2.7-kilobase (kb) membrane (mu m) and 2.4-kb secreted (mu s) mu mRNA species both in size and coding capacity and occur at approximately equal abundance in most mu-positive (pre-B-like) A-MuLV transformants. A mu-mRNAs (aberrant) generally fall into one of two categories--aberrantly small 2.3-kb mu m and 2.0-kb mu s mRNAs which encode aberrantly small mu polypeptide chains, or normal-sized, V H-containing mu RNAs which do not encode immunologically identifiable mu polypeptide chains. In one case, the latter type of A mu-mRNA was demonstrated to result from an in-phase termination codon in the D segment of the mu mRNA. Also, most, if not all, A-MuLV transformants express members of a 3.0 to 1.9-kb set of C mu-containing, but V H-negative S mu-RNAs (for sterile), the expression of which may occur simultaneously with but independently of P mu-mRNAs or A mu-mRNAs. The S mu-RNA sequences do not encode immunologically identifiable mu chains and can be produced by cells with unrearranged heavy-chain alleles, such as T-lymphocytes, although the structure of the S mu-RNAs from T-lymphoid cells appears to be different from that of B-lymphoid cell S mu-RNAs. Certain A-MuLV transformants also express gamma-RNA sequences that are probably analogous to the three different forms of mu RNA. These data support the concept that heavy-chain allelic exclusion, like that of light chains, is not mediated by control at the DNA or RNA levels but is probably a consequence of feedback control from cytoplasmic mu chains.", "issn": "0270-7306", "publisher": "Molecular and Cellular Biology", "publication": "Molecular and Cellular Biology", "publication_date": "1982-04", "series_number": "4", "volume": "2", "issue": "4", "pages": "386-400" }, { "id": "authors:kctma-kzd85", "collection": "authors", "collection_id": "kctma-kzd85", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120717-091825058", "type": "article", "title": "Transfection of Fibroblasts by Cloned Abelson Murine Leukemia Virus DNA and Recovery of Transmissible Virus by Recombination with Helper Virus", "author": [ { "family_name": "Goff", "given_name": "Stephen P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Tabin", "given_name": "Clifford J.", "clpid": "Tabin-Clifford-J" }, { "family_name": "Wang", "given_name": "Jean Yin-Jen", "clpid": "Wang-Jean-Yin-Jen" }, { "family_name": "Weinberg", "given_name": "Robert", "clpid": "Weinberg-Robert-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A cloned, permuted DNA copy of the Abelson murine leukemia virus (A-MuLV) genome was capable of eliciting the morphological transformation of NIH/3T3 fibroblasts when applied to cells in a calcium phosphate precipitate. The efficiency of the process was extremely low, yielding approximately one transformant per microgram of DNA under conditions which give 104 transfectants per microgram of other DNAs (e.g., Moloney sarcoma virus proviral DNA). The DNA was able to induce foci, even though the 3\u2032 end of the genome was not present. The transforming gene was thus localized to the 5\u2032 portion of the genome. The transformed cells all produced viral RNA and the virus-specific P90 protein. Transmissible virus could be rescued from these cells at very low frequencies by superinfection with helper virus; the rescued A-MuLV virus had variable 3\u2032 ends apparently derived by recombination with the helper. Dimerization of the permuted A-MuLV cloned genome to reconstruct a complete provirus did not improve transformation efficiency. Virus could be rescued from these transformants, however, at a high efficiency. Cotransfection of the permuted A-MuLV DNA with proviral M-MuLV DNA yielded a significant increase in the efficiency of transformation and cotransfection of dimeric A-MuLV and proviral M-MuLV resulted in a high-efficiency transformation yielding several thousand more transformants per microgram than A-MuLV DNA alone. We propose that helper virus efficiently rescues A-MuLV from transiently transfected cells which would not otherwise have grown into foci. We hypothesize that multiple copies of A-MuLV DNA introduced into cells by transfection are toxic to cells. In support of this hypothesis, we have shown that A-MuLV DNA sequences can inhibit the stable transformation of cells by other selectable DNAs.", "pmcid": "PMC256749", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1982-01", "series_number": "1", "volume": "41", "issue": "1", "pages": "271-285" }, { "id": "authors:vmvgs-q3h48", "collection": "authors", "collection_id": "vmvgs-q3h48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BOSjvir81", "type": "article", "title": "Localization of the Abelson murine leukemia virus protein in a detergent-insoluble subcellular matrix: architecture of the protein", "author": [ { "family_name": "Boss", "given_name": "Michael A.", "clpid": "Boss-Michael-A" }, { "family_name": "Dreyfuss", "given_name": "Gideon", "clpid": "Dreyfuss-Gideon" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We examined the interaction of Abelson murine leukemia virus protein P120 with other cellular components after extraction with the nonionic detergent Triton X-100. Most of the Abelson murine leukemia virus P120-associated kinase activity was found in the detergent-insoluble matrix in both lymphoid and fibroblast cell lines. The P120 labeled during a short exposure of cells to [35S]-methionine was mainly in the detergent-insoluble matrix (lymphoid cells) or equally distributed in the detergent-insoluble matrix and the soluble fraction (fibroblasts). Steady-state-labeled P120 was distributed equally in the two fractions (lymphoid cells) or mostly in the soluble portion (fibroblasts). Thus, there was an apparent movement of P120 from the detergent-insoluble matrix to the detergent-soluble fraction and a concomitant loss of enzymatic activity. When the detergent-insoluble matrix was incubated with [32P]ATP in situ, phosphorylation of tyrosine residues of P120 was observed. We found an 80,000-molecular-weight fragment of P120 (designated F80) after extraction of fibroblast cells with detergent. F80 was not found in extracted lymphoid cells, but mixing labeled lymphoid cells and unlabeled fibroblasts before extraction produced the fragment. F80 contained the gag determinants of P120 but did not react with Abelson-specific serum. These data allowed us to assign various features of the protein to regions of the P120 molecule and to localize the Abelson-specific antigenic determinants to the C-terminal region of the molecule.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1981-11", "series_number": "2", "volume": "40", "issue": "2", "pages": "472-481" }, { "id": "authors:dfsqd-60p91", "collection": "authors", "collection_id": "dfsqd-60p91", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SHOjvir81", "type": "article", "title": "Intramolecular integration within Moloney murine leukemia virus DNA", "author": [ { "family_name": "Shoemaker", "given_name": "Charles", "clpid": "Shoemaker-Charles" }, { "family_name": "Hoffmann", "given_name": "Joseph", "clpid": "Hoffmann-Joseph" }, { "family_name": "Goff", "given_name": "Stephen P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "By screening a library of unintegrated, circular Moloney murine leukemia virus (M-MuLV) DNA cloned in lambda phage, we found that approximately 20% of the M-MuLV DNA inserts contained internal sequence deletions or inversions. Restriction enzyme mapping demonstrated tht the deleted segments frequently abutted a long terminal repeat (LTR) sequence, whereas the inverted segments were usually flanked by LTR sequences, suggesting that many of the variants arose as a consequence of M-MuLV DNA molecules integrating within their own DNA. Nucleotide sequencing also suggested that most of the variant inserts were generated by autointegration. One of the recombinant M-MuLV DNA inserts contained a large inverted repeat of a unique M-MuLV sequence abutting an LTR. This molecule was shown by nucleotide sequencing to have arisen by an M-MuLV DNA Molecule integrating within a second M-MuLV DNA molecule before cloning. The autointegrated M-MuLV DNA had generally lost two base pairs from the LTR sequence at each junction with target site DNA, whereas a four-base-pair direct repeat of target site DNA flanked the integrated viral DNA. Nucleotide sequencing of preintegration target site DNA showed that this four-base-pair direct repeat was present only once before integration and was thus reiterated by the integration event. The results obtained from the autointegrated clones were supported by nucleotide sequencing of the host-virus junction of two cloned M-MuLV integrated proviruses obtained from infected rat cells. Detailed analysis of the different unique target site sequences revealed no obvious common features.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1981-10", "series_number": "1", "volume": "40", "issue": "1", "pages": "164-172" }, { "id": "authors:bbsb4-mhv19", "collection": "authors", "collection_id": "bbsb4-mhv19", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120719-161708980", "type": "article", "title": "Phosphorylation of the Abelson Murine Leukemia Virus Transforming Protein", "author": [ { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Ponticelli", "given_name": "Alfred", "clpid": "Ponticelli-Alfred" }, { "family_name": "Gifford", "given_name": "Ann", "clpid": "Gifford-Ann" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Elder", "given_name": "John", "clpid": "Elder-John" } ], "abstract": "The Abelson murine leukemia virus transforming gene product is a phosphorylated protein encoded by both viral and cellular sequences. This gene product has an amino-terminal region derived from the gag gene of its parent virus and\na carboxyl-terminal region (abl) derived from a normal murine cellular gene.\nUsing a combination of partial proteolytic cleavage techniques and antisera specific for gag and abl sequences, we mapped in vivo phosphorylation sites to different regions of the protein. Phosphoproteins encoded by strain variants and transformation-defective mutants of Abelson murine leukemia virus with defined deletions in the primary sequence of the abl region were compared by two-dimensional\nlimit digest peptide mapping. Specific phosphorylation pattern differences for wild-type and mutant proteins probably represented deletions of specific phosphate acceptor sites in the abl region. An in vitro autophosphorylation activity copurified with the Abelson murine leukemia virus protein from transformation-competent strains. A peptide analysis of such in vitro reactions\ndemonstrated that these phosphorylation sites were restricted to the aminoterminal region, and the specific sites appeared to be unrelated to the sites found\non proteins phosphorylated in vivo. Thus, the autophosphorylation reaction probably correlates with an activity important in transformation, but the specific\nend product in vitro bears little resemblance to its function in vivo.", "pmcid": "PMC171320", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1981-09", "series_number": "3", "volume": "39", "issue": "3", "pages": "870-878" }, { "id": "authors:qxmjp-gv673", "collection": "authors", "collection_id": "qxmjp-gv673", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:RACpnas81", "type": "article", "title": "Molecular cloning of poliovirus cDNA and determination of the complete nucleotide sequence of the viral genome", "author": [ { "family_name": "Racaniello", "given_name": "Vincent R.", "clpid": "Racaniello-Vincent-R" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The complete 7410 nucleotide sequence of the poliovirus type I genome was obtained from cloned cDNA. Double-stranded poliovirus cDNA was synthesized and inserted into the Pst I site of plasmid pBR322, and three clones were derived that together provided DNA copies of the entire poliovirus genome. Two of the clones contained inserts of 2.5 and 6.5 kilobases and represented all but the 5' 115 bases of poliovirus RNA. A third clone was generated from primer-extended DNA and contained sequences from the 5' end of the viral RNA. An open reading frame that was identified in the nucleotide sequence starting 743 bases from the 5' end of the RNA and extending to a termination codon 71 bases from the 3' end contained known poliovirus polypeptide sequence.", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1981-08", "series_number": "8", "volume": "78", "issue": "8", "pages": "4887-4891" }, { "id": "authors:t97ae-qyt13", "collection": "authors", "collection_id": "t97ae-qyt13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120718-102107731", "type": "article", "title": "Multiple differences between the nucleic acid sequences of the IgG2a^a and IgG2a^b alleles of the mouse", "author": [ { "family_name": "Schreier", "given_name": "Peter H.", "clpid": "Schreier-Peter-H" }, { "family_name": "Bothwell", "given_name": "Alfred L. M.", "clpid": "Bothwell-Alfred-L-M" }, { "family_name": "Mueller-Hill", "given_name": "Benno", "clpid": "Mueller-Hill-Benno" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To compare the structure of IgG2a alleles we have determined the complete DNA sequence of the constant region, coding sequence, and 3' untranslated region of a cDNA clone, pAB gamma 2a-1, which was derived from the C57BL/6 mouse strain (b allotype). This sequence was compared with the corresponding IgG2a DNA sequence of BALB/c origin (a allotype). The DNA sequences showed 10% differences, and the deduced protein sequences differed by about 15%. These differences were not evenly distributed: most differences were in the hinge region, the CH3 domain and the 3' untranslated region. It is evident that many alterations in the IgG2a alleles have occurred since the a and b haplotypes were separated--some of these changes were point mutations but some appear to have resulted from gene conversion of the IgG2a^b allele by the IgG2b^b allele.", "doi": "10.1073/pnas.78.7.4495", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1981-07", "series_number": "7", "volume": "78", "issue": "7", "pages": "4495-4499" }, { "id": "authors:9chtk-4y316", "collection": "authors", "collection_id": "9chtk-4y316", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120718-102042825", "type": "article", "title": "Genome structure of Abelson murine leukemia virus variants: proviruses in fibroblasts and lymphoid cells", "author": [ { "family_name": "Goff", "given_name": "Stephen P.", "clpid": "Goff-Stephen-P" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Gilboa", "given_name": "Eli", "clpid": "Gilboa-Eli" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have prepared full-length DNA clones of the Abelson murine leukemia virus (A-MuLV) genome. A specific probe homologous to the central portion of the A-MuLV genome was prepared by nick translation of a subcloned restriction fraction from the cloned DNA. The probe was used to examine the genome structure of several A-MuLV variants. The conclusions are: (i) three viruses coding for Abelson-specific proteins of molecular weight 120,000, 100,000, and 90,000 had genomes indistinguishable in size, suggesting that the shorter proteins are the result of early translational termination; (ii) compared with the genome encoding the 120,000-dalton (120K) protein, a genome coding for a 160K protein was 0.8 kilobase larger in the A-MuLV-specific region; and (iii) a genome coding for a 92K protein had a 700-base pair deletion internal to the coding region. This mutant was transformation defective: its 92K protein lacked the protein kinase activity normally associated with the A-MuLV protein, and cells containing the virus were not morphologically transformed. In addition, we determined the number of A-MuLV proviruses in each of several transformed fibroblast and lymphoid cells prepared by infection in vitro. These experiments show that a single copy of the A-MuLV provirus is sufficient to transform both types of cells and that nonproducer cells generally have only one integrated provirus.", "pmcid": "PMC171177", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1981-05", "series_number": "2", "volume": "38", "issue": "2", "pages": "460-468" }, { "id": "authors:85r6n-4dj57", "collection": "authors", "collection_id": "85r6n-4dj57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120718-101950135", "type": "article", "title": "Chromosomal location of structural genes encoding murine immunoglobulin \u03bb light chains. Genetics of murine \u03bb light chains", "author": [ { "family_name": "D'Eustachio", "given_name": "Peter", "clpid": "D'Eustachio-Peter" }, { "family_name": "Bothwell", "given_name": "Alfred L. M.", "clpid": "Bothwell-Alfred-L-M" }, { "family_name": "Takaro", "given_name": "Timothy K.", "clpid": "Takaro-Timothy-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Ruddle", "given_name": "Frank H.", "clpid": "Ruddle-Frank-H" } ], "abstract": "To determine the chromosomal localization of murine lambda light (L) chain structural genes, DNA from a panel of 11 mouse x hamster somatic cell hybrids was scored for the presence of sequences homologous to cloned lambda DNA probe molecules. Six of the hybrids had detectable lambda I and lambda II gene sequences. In all six, the full complement of murine sequences was present, and in its germline configuration. The remaining hybrids lacked any detectable murine lambda L chain gene sequences. The only mouse chromosome present in all of the positive hybrids and absent from the negative ones was number 16, allowing the assignment of lambda L chain structural genes to this chromosome. Together with the previous assignments of the kappa L chain genes to chromosome 6 and heavy chain genes to chromosome 12, this finding completes the mapping of Ig structural genes in the mouse at the chromosomal level.", "doi": "10.1084/jem.153.4.793", "pmcid": "PMC2186131", "issn": "0022-1007", "publisher": "The Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1981-04", "series_number": "4", "volume": "153", "issue": "4", "pages": "793-800" }, { "id": "authors:0y7hf-p7325", "collection": "authors", "collection_id": "0y7hf-p7325", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROTjvir81", "type": "article", "title": "Increased concentration of an apparently identical cellular protein in cells transformed by either Abelson murine leukemia virus or other transforming agents", "author": [ { "family_name": "Rotter", "given_name": "Varda", "clpid": "Rotter-Varda" }, { "family_name": "Boss", "given_name": "Michael A.", "clpid": "Boss-Michael-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Abelson murine leukemia virus (A-MuLV)-transformed cells, simian virus 40 (SV40)-transformed cells, and chemically transformed cells all have increased levels of a 50,000-molecular-weight host cell protein. The protein was detected with sera raised to the A-MuLV-transformed and chemically transformed cells and was tightly bound to T-antigen in extracts of SV40-transformed cells. Partial protease digests showed that the proteins from all three sources were indistinguishable. The three proteins were phosphorylated in cells, and the linkage of phosphate to the A-MuLV-associated P50 was to a serine residue. By immunofluorescence methods, P50-related protein was found on the surface of both normal lymphoid cells and A-MuLV-transformed lymphoid cells, but cell fractionation showed that the majority of P50 was free in the cytoplasm of the transformed cells. Immunofluorescence also showed that P50 was found in granules in the cytoplasm of both untransformed and SV40-transformed fibroblasts. Other cells gave indistinct patterns. Cocapping experiments showed that the A-MuLV-specified P120 protein is weakly associated with the surface P50-related protein of lymphoid cells, but no association of P120 and P50 could be demonstrated by immunoprecipitation methods. Although a monoclonal antiserum to P50 was used in many of these studies, the identity of the bulk P50 protein with the molecules that are reactive at the cell surface requires further study.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1981-04", "series_number": "1", "volume": "38", "issue": "1", "pages": "336-346" }, { "id": "authors:6zbpv-n5390", "collection": "authors", "collection_id": "6zbpv-n5390", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GOFjvir81a", "type": "article", "title": "Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase", "author": [ { "family_name": "Goff", "given_name": "Stephen", "clpid": "Goff-Stephen-P" }, { "family_name": "Traktman", "given_name": "Paula", "clpid": "Traktman-Paula" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A rapid assay for retroviral reverse transcriptase activity released into the culture medium by infected cells was developed. With the assay, 4,000 clonally infected cell lines could be tested in a few hours. We have adapted the assay for use as a screen for the detection of spontaneous viral mutants. Mutants of Moloney murine leukemia virus have been isolated which (i) produce a thermolabile reverse transcriptase, (ii) are temperature sensitive for release of enzyme activity, or (iii) can only productively infect cells already producing gag-related polypeptides. The assay has also been useful for the isolation of nonproducer cells infected with various replication-defective transforming viruses.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1981-04", "series_number": "1", "volume": "38", "issue": "1", "pages": "239-248" }, { "id": "authors:zb2nx-ag889", "collection": "authors", "collection_id": "zb2nx-ag889", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SIDpnas81", "type": "article", "title": "Synthesis of immunoglobulin \u00b5 chain gene products precedes synthesis of light chains during B-lymphocyte development", "author": [ { "family_name": "Siden", "given_name": "E.", "clpid": "Siden-E" }, { "family_name": "Alt", "given_name": "F. W.", "clpid": "Alt-F-W" }, { "family_name": "Shinefeld", "given_name": "L.", "clpid": "Shinefeld-L" }, { "family_name": "Sato", "given_name": "V.", "clpid": "Sato-V" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Immunoglobulin (Ig) gene expression has been followed during the later stages of development of the murine fetal liver. Biosynthetic labeling and immunoprecipitation were used to isolate Ig-related polypeptides from fetal and neonatal livers. By examination of the specific immune precipitates, the earliest detectable Ig was shown to consist only of \u00b5 heavy chain. At about the time of birth, when light chain synthesis became evident, separation of surface Ig-positive cells from surface Ig-negative cells by using anti-Ig-coated dishes showed that cells lacking surface Ig (pre-B lymphocytes) synthesized only \u00b5 chains. Thus, commencement of light chain synthesis was closely coordinated with the appearance of surface Ig. Ig RNA species were examined by electrophoretic fractionation and hybridization with cloned Ig DNA sequences. The sizes and amounts of Ig mRNA were found to correlate with the pattern of \u00b5 and light chain protein biosynthesis. \u00b5 chain RNA species appeared earlier in gestation than light chain RNA did, and only after birth did light chain sequences reach levels equivalent to those of \u00b5 chain. Cell populations enriched in pre-B lymphocytes also contained an excess of \u00b5 over light chain mRNA.", "doi": "10.1073/pnas.78.3.1823", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1981-03", "series_number": "3", "volume": "78", "issue": "3", "pages": "1823-1827" }, { "id": "authors:qn0w3-nxr35", "collection": "authors", "collection_id": "qn0w3-nxr35", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROTjvir80", "type": "article", "title": "Abelson murine leukemia virus-induced tumors elicit antibodies against a host cell protein, P50", "author": [ { "family_name": "Rotter", "given_name": "Varda", "clpid": "Rotter-Varda" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Coffman", "given_name": "Robert", "clpid": "Coffman-Robert" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "When BALB/c mice were injected with a syngeneic cell line transformed by Abelson murine leukemia virus (A-MuLV), the tumor was usually lethal. In sera from tumor-bearing mice, and at highest levels in sera from mice that reject their tumors, was an antibody that immunoprecipitates a specific protein from [35S]-methionine-labeled A-MuLV-transformed BALB/c cells. This protein was not the previously characterized A-MuLV-specific protein (P120) but a 50,000-molecular-weight protein (P50). Such sera may also immunoprecipitate P120, but no other protein was reproducibly precipitated by them. A monoclonal antibody (RA3-2C2) that has been shown to stain normal B-lymphocytes also selectively immunoprecipitated P50. P50 was present in A-MuLV-transformed lymphoid and fibroblastic cells of a variety of mouse strains. One A-MuLV-transformed cell line had a very low P50 level, the L1-2 tumor of C57L origin. This tumor was previously shown to be rejected by C57L mice and is used to produce anti-P120 (anti-AbT) sera. P50 was not a Moloney MuLV protein and was found at low levels in normal cells of cells transformed by agents other than A-MuLV; thus, it was probably a host cell protein whose concentration was selectively accentuated by A-MuLV transformation. P50 was phosphorylated and, by using indirect immunofluorescence, anti-P50 serum stained live A-MuLV-transformed cells. The protein was not glycosylated and did not label by lactoperoxidase-catalyzed iodination. Thus, P50 was very like P120 in its cellular localization and properties, but it did not exhibit proptein kinase activity in vitro. The selective accentuation of this protein in A-MuLV transformants and its strong antigenicity in syngeneic animals suggest that it is a unique and functionally important protein.", "pmcid": "PMC353673", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1980-11", "series_number": "2", "volume": "36", "issue": "2", "pages": "547-555" }, { "id": "authors:1yg0k-6fv58", "collection": "authors", "collection_id": "1yg0k-6fv58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120719-094733119", "type": "article", "title": "A transformation-defective mutant of Abelson murine leukemia virus lacks protein kinase activity", "author": [ { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Goff", "given_name": "Stephen", "clpid": "Goff-Stephen-P" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A transformation-defective mutant of Abelson murine leukemia virus (A-MuLV), called A-MuLV-P92td, has been isolated. The mutant encodes a serologically identifiable A-MuLV protein of molecular weight 92,000 (P92) but it lacks the ability to transform either fibroblasts or bone marrow lymphoid cells. In contrast to the protein made by transforming strains of A-MuLV, the protein made by A-MuLV-P92td does not becme phosphorylated during in vitro incubation with [\u03b3-^(32)P]ATP. If the protein is mixed with proteins from cells transformed by a functional A-MuLV strain, phosphorylation of P92 occurs, showing that its ability to accept phosphate is not altered by the mutation. These parallel changes provide genetic evidence that the A-MuLV protein is a transforming protein and that its associated protein kinase activity (EC 2.7.1.37) is a crucial part of its transforming ability.", "doi": "10.1073/pnas.77.8.4993", "pmcid": "PMC349976", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1980-08", "series_number": "8", "volume": "77", "issue": "8", "pages": "4993-4997" }, { "id": "authors:cpzys-dbd88", "collection": "authors", "collection_id": "cpzys-dbd88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:AMBjbc80", "type": "article", "title": "Purification and properties of a HeLa cell enzyme able to remove the 5'- terminal protein from poliovirus RNA", "author": [ { "family_name": "Ambros", "given_name": "Victor", "clpid": "Ambros-Victor" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Using a rapid phenol extraction assay, an enzyme was purified from uninfected HeLa cells that can cleave the 5'-terminal protein (VPg) from poliovirus RNA. Both cytoplasmic and nuclear extracts had enzymes with similar behavior. A polypeptide of molecular weight 27,000 was the major one present in the purified preparation. Assuming that this protein is the enzyme, a very low turnover number was calculated for it. The purified enzyme would cleave the tyrosine-phosphate bond linking VPg to poliovirus RNA with minimal degradation of the RNA or of VPg. If the RNA was first treated with proteinase K to degrade VPg, leaving a small peptide on the RNA, this peptide could also be removed by the enzyme. If the RNA was degraded with T1 RNase, leaving VPg attached to a nonanucleotide, the enzyme still would cleave off VPg, although incompletely. If the RNA was degraded completely, leaving either pUp or pU attached to VPg, the enzyme would not remove the nucleotides from the protein. Thus, for the enzyme to be active requires some length of polynucleotide attached to the protein but only a short peptide need be present for the enzyme to act.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1980-07-25", "series_number": "14", "volume": "255", "issue": "14", "pages": "6739-6744" }, { "id": "authors:3dcfr-7vh14", "collection": "authors", "collection_id": "3dcfr-7vh14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120719-130834887", "type": "article", "title": "Structure of a cloned circular Moloney murine leukemia virus DNA molecule containing an inverted segment: implications for retrovirus integration", "author": [ { "family_name": "Shoemaker", "given_name": "Charles", "clpid": "Shoemaker-Charles" }, { "family_name": "Goff", "given_name": "Stephen", "clpid": "Goff-Stephen-P" }, { "family_name": "Gilboa", "given_name": "Eli", "clpid": "Gilboa-Eli" }, { "family_name": "Paskind", "given_name": "Michael", "clpid": "Paskind-Michael" }, { "family_name": "Mitra", "given_name": "Sudha W.", "clpid": "Mitra-Sudra-Warrier" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Closed circular Moloney murine leukemia virus (M-MuLV) DNA was prepared from recently infected cells and cloned in a lambda vector. Four classes of cloned M-MuLV inserts were found: Class I, full length 8.8-kilobase (kb) inserts with two tandem long terminal repeats (LTRs) of 600 base pairs; class 2, 8.2-kb inserts with a single copy of a LTR; class 3, M-MuLV DNA inserts with various portions deleted; and class 4, an 8.8-kb insert with an internal sequence inversion. Determination of nucleotide sequence at the junction between the two LTRs from a class 1 insert suggested that circularization occurred by blunt-end ligation of an 8.8-kb linear DNA. The class 4 molecule had an inversion that was flanked by inverted LTRs, each of which had lost two terminal base pairs at the inversion end points. Also, four base pairs that were present only once in standard M-MuLV DNA were duplicated at either end of the inversion. This molecule was interpreted as resulting from an integrative inversion in which M-MuLV DNA has integrated into itself. Its analysis thus provided explicit information concerning the mechanism by which retrovirus DNA integrates into host cell DNA. Models of retrovirus integration based on bacterial DNA transposition mechanisms are proposed.", "doi": "10.1073/pnas.77.7.3932", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1980-07", "series_number": "7", "volume": "77", "issue": "7", "pages": "3932-3936" }, { "id": "authors:32z4r-30050", "collection": "authors", "collection_id": "32z4r-30050", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:JOLjvir80", "type": "article", "title": "Distribution of endogenous murine leukemia virus DNA sequences among mouse chromosomes", "author": [ { "family_name": "Jolicoeur", "given_name": "Paul", "clpid": "Jolicoeur-Paul" }, { "family_name": "Rassart", "given_name": "Eric", "clpid": "Rassart-Eric" }, { "family_name": "Kozak", "given_name": "Christine", "clpid": "Kozak-Christine-A" }, { "family_name": "Ruddle", "given_name": "Frank", "clpid": "Ruddle-Frank-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We used mouse-Chinese hamster somatic cell hybrids which lose mouse chromosomes to examine the distribution of murine leukemia virus DNA sequences in the genome of A/HeJ mice. We analyzed total cellular DNA from various hybrid clones for the presence of viral sequences by molecular hybridization and used the Southern blot hybridization procedure to identify viral DNA in cellular restriction endonuclease fragments. Our results show that murine leukemia virus DNA sequences are distributed among many mouse chromosomes in this strain. Chromosome 4 was shown to contain murine leukemia virus DNA sequences.", "pmcid": "PMC288660", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1980-03", "series_number": "3", "volume": "33", "issue": "3", "pages": "1229-1235" }, { "id": "authors:vmy2b-c7a11", "collection": "authors", "collection_id": "vmy2b-c7a11", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120718-141059759", "type": "article", "title": "Purification of a factor that restores translation of vesicular stomatitis virus mRNA in extracts from poliovirus-infected HeLa cells", "author": [ { "family_name": "Trachsel", "given_name": "Hans", "clpid": "Trachsel-Hans" }, { "family_name": "Sonenberg", "given_name": "Nahum", "clpid": "Sonenberg-Nahum" }, { "family_name": "Shatkin", "given_name": "Aaron J.", "clpid": "Shatkin-AAaron-J" }, { "family_name": "Rose", "given_name": "John K.", "clpid": "Rose-John-K" }, { "family_name": "Leong", "given_name": "Kahan", "clpid": "Leong-Kahan" }, { "family_name": "Bergmann", "given_name": "John E.", "clpid": "Bergmann-John-E" }, { "family_name": "Gordon", "given_name": "Julian", "clpid": "Gordon-Julian" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "It was previously shown that the poliovirus-induced inhibition of translation of capped mRNAs can be reversed by a protein found in preparations of the eukaryotic initiation factor eIF-4B [Rose, J. K., Trachsel, H., Leong, K. & Baltimore, D. (1978) Proc. Natl. Acad. Sci. USA 75, 2732--2736]. This \"restoring factor\" has now been purified from a high-salt wash of rabbit reticulocyte ribosomes by taking advantage of its tight association with factor eIF-3 at low salt concentrations. It did not copurify with the major M_r 80,000 polypeptide of eIF-4B preparations but did copurify with a M_r 24,000 polypeptide previously shown to bind to the cap structures of mRNAs [Sonenberg, N., Rupprecht, K. M., Hecht, S. M. & Shatkin, A. J. (1979) Proc. Natl. Acad. Sci. USA 76, 4345--4349]. Both the electrophoretic mobility and the tryptic peptide pattern of the restoring factor were indistinguishable from those of the cap-binding protein, and the restoring factor could be crosslinked to the 5'-terminal cap on mRNA. Thus, is appears that poliovirus inhibits cellular protein synthesis by inactivation of some crucial property of the cap-binding protein.", "doi": "10.1073/pnas.77.2.770", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1980-02", "series_number": "2", "volume": "77", "issue": "2", "pages": "770-774" }, { "id": "authors:b98bj-fc884", "collection": "authors", "collection_id": "b98bj-fc884", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120724-142222116", "type": "article", "title": "Biosynthesis of Murine Terminal Deoxynucleotidyltransferase", "author": [ { "family_name": "Silverstone", "given_name": "Allen", "clpid": "Silverstone-Allen-E" }, { "family_name": "Sun", "given_name": "Leslie", "clpid": "Sun-Leslie" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "An immunoprecipitation assay for measuring synthesis of murine terminal deoxynucleotidyltransferase (EC 2.7.7.31) has been developed using rabbit antiserum to calf terminal transferase. The antiserum precipitates a single Mr = 60,000 polypeptide (TdT-60) from all cell lines and tissues that contain enzymologically demonstrable terminal transferase. This polypeptide is not precipitated from labeled extracts of cells that lack terminal transferase by enzymological criteria. TdT-60 fractionates with terminal transferase during phosphocellulose chromatography and sediments with it in a sucrose gradient. TdT-60 is not detectably processed to lower molecular weight polypeptides, and terminal transferase activity sediments as a Mr = 60,000 activity; thus, we believe it to be the active form of terminal transferase. Using this assay we have demonstrated that terminal transferase is synthesized in both the murine thymus and the bone marrow at a rate proportional to its biochemically measured steady state level. After cortisone treatment of mice, the Mr = 60,000 polypeptide disappears from the thymus and then reappears as the thymus begins to be repopulated.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1980-01-25", "series_number": "2", "volume": "255", "issue": "2", "pages": "791-796" }, { "id": "authors:awngd-83m44", "collection": "authors", "collection_id": "awngd-83m44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:LOHjem79", "type": "article", "title": "Synthetic phospholipid vesicles containing a purified viral antigen and cell membrane proteins stimulate the development of cytotoxic T lymphocytes", "author": [ { "family_name": "Loh", "given_name": "Dennis", "clpid": "Loh-Dennis" }, { "family_name": "Ross", "given_name": "Alonzo H.", "clpid": "Ross-Alonzo-H" }, { "family_name": "Hale", "given_name": "Arthur H.", "clpid": "Hale-Arthur-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Eisen", "given_name": "Herman N.", "clpid": "Eisen-Herman-N" } ], "abstract": "Synthetic phospholipid vesicles (liposomes) containing the purified glycoprotein (G) of vesicular stomatitis virus (VSV) and solubilized membrane proteins from cells of the appropriate H-2 haplotype elicited H-2-restricted cytotoxic T lymphocytes (CTL) that lysed VSV-infected target cells. The CTL were elicited by intact liposomes, not by released components. Thus, when spleen cells from VSV-primed H-2d X H- 2b hybrid mice were stimulated with liposomes having G protein + membrane proteins from cells with one of the parental H-2 haplotypes, the resulting CTL lysed only VSV-infected target cells with that parent's H-2 type. This result argues against the view that T cells in general recognize only processed antigenic fragments on macrophages. Moreover, liposomes were only effective when G protein and cell membrane proteins were included in the same vesicles. This result suggests that for effective interaction with CTL precursors the antigen (G protein) and products of the H-2 complex must be closer to each other than 600-1,000 angstrom, the diameter of the lipid vesicles used in this study.", "doi": "10.1084/jem.150.5.1067", "pmcid": "PMC2185710", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1979-11", "series_number": "5", "volume": "150", "issue": "5", "pages": "1067-1074" }, { "id": "authors:drd3c-42408", "collection": "authors", "collection_id": "drd3c-42408", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120727-131617278", "type": "article", "title": "Preparation of Syngeneic Tumor Regressor Serum Reactive\n with the Unique Determinants of the Abelson Murine\n Leukemia Virus-Encoded P120 Protein at the Cell Surface", "author": [ { "family_name": "Witte", "given_name": "O. N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Rosenberg", "given_name": "N.", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Antisera reactive with the Abelson murine leukemia virus (A-MuLV)-specified P120 (anti-AbT sera) were produced in C57L/J mice. Of many strains tested, only C57L/J reproducibly rejected syngenic A-MuLV-induced tumor cells; after multiple immunizations their sera would immunoprecipitate both P120 and Moloney-MuLV (M-MuLV) proteins. Using labeled A-MuLV-induced nonproducer cells, only P120 could be detected by anti-AbT sera, suggesting that it may be the only A-MuLV-specified protein. Reactivity of anti-AbT sera with P120 was not blocked by M-MuLV virion proteins, implying that the sera recognize a portion of P120 that is not homologous to any M-MuLV product. Anti-AbT sera stained the surface of live, A-MuLV-transformed nonproducer cells in a two-stage immunofluorescence assay, and such staining was not blocked by M-MuLV protein. Also, intact A-MuLV-transformed cells absorbed much of the reactivity of certain anti-AbT sera for P120. Thus a portion of P120 appears to be exposed on the surface of transformed cells. P120 lacks detectable carbohydrate, is not affected by endoglycosidase H, and cannot be labeled by lactoperoxidase-catalyzed iodination. Thus P120 is an unusual surface protein.", "pmcid": "PMC353505", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1979-09", "series_number": "3", "volume": "31", "issue": "3", "pages": "776-784" }, { "id": "authors:k5ce1-n4d62", "collection": "authors", "collection_id": "k5ce1-n4d62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MITpnas79", "type": "article", "title": "Synthesis of a 600-nucleotide-long plus-strand DNA by virions of Moloney murine leukemia virus", "author": [ { "family_name": "Mitra", "given_name": "Sudha Warrier", "clpid": "Mitra-Sudha-Warrier" }, { "family_name": "Goff", "given_name": "Stephen", "clpid": "Goff-Stephen-P" }, { "family_name": "Gilboa", "given_name": "Eli", "clpid": "Gilboa-Eli" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A discrete, 600-nucleotide-long plus-strand DNA has been identified among the products of reverse transcription by virions of Moloney murine leukemia virus. Its polarity was shown by hybridization to minus-strand DNA. It appears to be copied from the right end of minus-strand DNA because (i) its restriction endonuclease cleavage pattern corresponds to the redundant 600-base segment found at either end of the ultimate double-stranded reverse transcription product, (ii) its synthesis is actinomycin D sensitive, and (iii) its synthesis begins during the first hour of a reverse transcription reaction when only the right-hand end of minus-strand DNA is available as template. We therefore call this DNA plus-strong-stop DNA by analogy with the minus-strong-stop DNA copied from the left end of the viral RNA. Both strong-stop DNAs are made early during in vitro reactions and decline in concentration later, consistent with postulated roles as initiators of long minus- and plus-strand DNA. Unlike minus-strong-stop DNA, plus-strong-stop DNA remains as a double-stranded nucleic acid after its synthesis, as shown by S1 nuclease resistance. A primer to initiate plus-strong-stop DNA synthesis has not been identified; the product found thus far has no detectable RNA attached to it.", "doi": "10.1073/pnas.76.9.4355", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1979-09", "series_number": "9", "volume": "76", "issue": "9", "pages": "4355-4359" }, { "id": "authors:fksbh-cf466", "collection": "authors", "collection_id": "fksbh-cf466", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SHIjvir79", "type": "article", "title": "Virus production by Abelson murine leukemia virus-transformed lymphoid cells", "author": [ { "family_name": "Shields", "given_name": "Anthony", "clpid": "Shields-Anthony" }, { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Cell lines obtained by in vitro transformation of bone marrow with Abelson murine leukemia virus (A-MuLV) can be divided into three classes: producers, releasing reverse transcriptase-containing particles and infectious virus; nonproducers, releasing no viral particles; and defective producers, the most common phenotype, releasing particulate reverse transcriptase in the absence of infectious virus. When such cell lines were analyzed 1 to 2 weeks after their isolation, however, all produced infectious virus. Because these cell lines were carried in culture, many ceased to release infectious virus but produced defective virions. One defective producer, SWR4, has been extensively studied. The particles it produces have the same density as that of virions of Moloney murine leukemia virus (M-MuLV). The particles contain no 35 to 70S RNA, as determined by analysis of [3H]uridine-labeled particles, and exhibit no endogenous reverse transcriptase activity. Although the reverse transcriptase enzyme is of normal size, the major structural protein of the defective virions has a molecular weight of 28,000 (p28), in contrast to the p30 of M-MuLV, and no viral glycoprotein was evident. The defective particles do not appear to arise either from the helper virus or from Abelson virus. An alteration of the protein of the helper virus is an unlikely source of p28 because particles produced by lymphoid cells transformed with another strain of M-MuLV as helper (M-MuLV-TB) contained p28 with an unaltered cleavage pattern, although M-MuLV-TB p30 differs from M-MuLV p30. The A-MuLV genome lacks the capacity to code for the reverse transcriptase virions. Clones of fibroblasts infected with A-MuLV only occasionally produce defective particles. The defective particles therefore probably arose from an endogenous virus that is preferentially expressed in the class of lymphoid cells transformed by A-MuLV. This interpretation implies that the majority of A-MuLV-transformed lymphoid cells completely lose expression of the helper virus genome.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1979-08", "series_number": "2", "volume": "31", "issue": "2", "pages": "557-567" }, { "id": "authors:06j8s-x9106", "collection": "authors", "collection_id": "06j8s-x9106", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BESjvir79b", "type": "article", "title": "Virus-Like 30S RNA in Mouse Cells", "author": [ { "family_name": "Besmer", "given_name": "Peter", "clpid": "Besmer-Peter" }, { "family_name": "Olshevsky", "given_name": "Udy", "clpid": "Olshevsky-Udy" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Dolberg", "given_name": "David", "clpid": "Dolberg-David" }, { "family_name": "Fan", "given_name": "Hung", "clpid": "Fan-Hung" } ], "abstract": "Uninfected JLS-V9 mouse cells are known to express high levels of viral sequences that hybridize to complementary DNA made by the BrdU-induced virus of JLS-V9 cells. The genome in the BrdU-induced virus has been found to consist mainly of an RNA species that migrates as 30S RNA material during electrophoresis through agarose gels. This virus-like 30S RNA, designated VL30 RNA, apparently represents a new class of endogenous defective retroviruses that are not generally evident because of their defectiveness and lack of biological function. Fingerprint analysis and hybridization studies show that VL30 RNA does not have homology with the standard nondefective murine leukemia viruses. Upon superinfection with a nondefective murine leukemia virus, or upon induction of endogenous virus with BrdU, VL30 RNA is rescued into virions by phenotypic mixing. When VL30 RNA is rescued by BrdU induction, the VL30 RNA is mainly organized as a 50S complex, but when VL30 is rescued by superinfection, VL30 is also found in 70S RNA. Rescued VL30 RNA sequences can be reverse transcribed by the virion-associated DNA polymerase in an endogenous reaction. Many mouse cells express the sequences, whereas heterologous cells such as rat or rabbit cells do not contain them. By using hybridization of a complementary DNA probe to cellular RNA immobilized on paper, no subgenomic RNA related to the VL30 RNA could be found in cells expressing the VL30 sequences. From 20 to 50 copies of these sequences were found to be contained in the mouse genome. VL30 RNA is probably present in most stocks of leukemia and sarcoma viruses made in mouse cells.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1979-03", "series_number": "3", "volume": "29", "issue": "3", "pages": "1168-1176" }, { "id": "authors:vrwkw-an486", "collection": "authors", "collection_id": "vrwkw-an486", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BESjvir79a", "type": "article", "title": "Isolation and characterization of a mouse cell line containing a defective Moloney murine leukemia virus genome", "author": [ { "family_name": "Besmer", "given_name": "Peter", "clpid": "Besmer-Peter" }, { "family_name": "Fan", "given_name": "Hung", "clpid": "Fan-Hung" }, { "family_name": "Paskind", "given_name": "Michael", "clpid": "Paskind-Michael" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A culture of mouse cells containing a 1,000-nucleotide deletion mutant of Moloney murine leukemia virus has been isolated. The deletion did not affect the size or function of the 21S mRNA that encodes the env gene products. Both the deleted RNA and the 21S mRNA were recovered in polyribosomes. Cells containing the deleted virus made no detectable Pr180gag-pol. Pr65gag synthesis with also absent, but a 45,000-molecular-weight gag gene product was found that might be encoded by the deleted genome. Biosynthesis of Pr80env proceeded normally in these cells; the intracellular precursor was cleaved and migrated to the cell surface as gp70. The cells could not be superinfected by homologous Moloney murine leukemia virus presumably because of surface restriction due to the gp70. Although the cells express the Moloney murine leukemia virus gp70 on their surface, they will not make pseudotypes after infection with vesicular stomatitis virus implying that Pr65gag may play a critical role in pseudotype formation. Induction of endogenous virus expression in the cells carrying the deletion mutant generated an N-tropic murine leukemia virus that can fuse XC cells. This may represent a recombinant between the deletion mutant and an endogenous virus.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1979-03", "series_number": "3", "volume": "29", "issue": "3", "pages": "1023-1034" }, { "id": "authors:ejn3b-2de61", "collection": "authors", "collection_id": "ejn3b-2de61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120725-134020118", "type": "article", "title": "Poliovirus Polyuridylic Acid Polymerase and RNA Replicase Have the Same Viral Polypeptide", "author": [ { "family_name": "Flanegan", "given_name": "James B.", "clpid": "Flanegan-James-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A poliovirus-specific polyuridylic acid [poly(U)] polymerase that copies a polyadenylic acid template complexed to an oligouridylic acid primer was isolated from the membrane fraction of infected HeLa cells and was found to sediment at 4 to 5S on a linear 5 to 20% glycerol gradient. When the poly(U) polymerase was isolated from cells labeled with [^(35)S]methionine and was analyzed by glycerol gradient centrifugation and polyacrylamide gel electrophoresis, the position of only one viral protein was found to correlate with the location of enzyme activity. This protein had an apparent molecular weight of 62,500 based on its electrophoretic mobility relative to that of several molecular weight standards and was designated p63. When the poly(U) polymerase was isolated from the soluble fraction of a cytoplasmic extract, the activity was found to sediment at about 7S. In this case, however, both p63 and NCVP2 (77,000-dalton precursor of p63) cosedimented with the 7S activity peak. When the 7S polymerase activity was purified by phosphocellulose chromatography, both p63 and NCVP2 were found to co-chromatograph with poly(U) polymerase activity. The poliovirus replicase complexed with its endogenous RNA template was isolated from infected cells labeled with [^(35)S]methionine and was centrifuged through a linear 15 to 30% glycerol gradient. The major viral polypeptide component in a 26S peak of replicase activity was p63, but small amounts of other poliovirus proteins were also present. When the replicase-template complex was treated with RNase T1 before centrifugation, a single peak of activity was found that sedimented at 20S and contained only labeled p63. Thus, p63 was found to be the only viral polypeptide in the replicase bound to its endogenous RNA template, and appears to be active as a poly(U) polymerase either as a monomer protein or as a 7S complex.", "pmcid": "PMC353130", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1979-01", "series_number": "1", "volume": "29", "issue": "1", "pages": "352-360" }, { "id": "authors:k830a-kng05", "collection": "authors", "collection_id": "k830a-kng05", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170213-071350586", "type": "article", "title": "Production of a Discrete, Infectious, Double-stranded DNA by Reverse Transcription in Virions of Moloney Murine Leukemia Virus", "author": [ { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Gilboa", "given_name": "E.", "clpid": "Gilboa-Eli" }, { "family_name": "Rothenberg", "given_name": "E.", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Yoshimura", "given_name": "F.", "clpid": "Yoshimura-F" } ], "abstract": "One of the most unique viral replication schemes is that of the retroviruses (a class that includes the RNA tumor viruses). These viruses synthesize a double-stranded (DS) DNA copy of their single-stranded (SS) RNA genome as the initial event following infection of susceptible cells (see Weinberg 1977). The details of this process\u2014called reverse transcription\u2014are still obscure, but the general outlines have become clear during the last few years.", "doi": "10.1101/SQB.1979.043.01.093", "issn": "0091-7451", "publisher": "Cold Spring Harbor Laboratory", "publication": "Cold Spring Harbor Symposia on Quantitative Biology", "publication_date": "1979", "series_number": "0", "volume": "43", "issue": "0", "pages": "869-874" }, { "id": "authors:vgfqn-h9e47", "collection": "authors", "collection_id": "vgfqn-h9e47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:AMBjbc78", "type": "article", "title": "Protein is linked to the 5' end of poliovirus RNA by a phosphodiester linkage to tyrosine", "author": [ { "family_name": "Ambros", "given_name": "Victor", "clpid": "Ambros-Victor" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Purification and partial characterization of the poliovirus RNA-linked protein (VPg) are described. VPg has been freed from the RNA by ribonuclease digestion and phenol extraction. Gel filtration chromatography of VPg-pUp (labeled with 32P) in 0.5% sodium dodecyl sulfate or 6 M guanidine HCl indicates that it has a molecular weight of about 12,000. VPg is bound to the 5' end of poliovirion RNA by a phosphodiester bond between a tyrosine residue in the VPg molecule and the 5'-terminal uridine. After acid hydrolysis of [3H]tyrosine-labeled VPg-pU, free tyrosine can be released by venom phosphodiesterase. Acid hydrolysis of VPg-p labeled with either 32P or [3H] tyrosine yields tyrosine-phosphate. There appears to be only 1 tyrosine residue per VPg molecule.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1978-08-10", "series_number": "15", "volume": "253", "issue": "15", "pages": "5263-5266" }, { "id": "authors:jcjtr-sn388", "collection": "authors", "collection_id": "jcjtr-sn388", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120802-101224844", "type": "article", "title": "Identification of a Protein Linked to Nascent Poliovirus RNA and to the Polyuridylic Acid of Negative-Strand RNA", "author": [ { "family_name": "Pettersson", "given_name": "Ralf F.", "clpid": "Pettersson-Ralf-F" }, { "family_name": "Ambros", "given_name": "Victor", "clpid": "Ambros-Victor" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A protein similar to that previously demonstrated on poliovirus RNA and replicative intermediate RNA (VPg) was found on all sizes of nascent viral RNA molecules and on the polyuridylic acid isolated from negative-strand RNA. ^(32)P-labeled nascent chains were released from their template RNA and fractionated by exclusion chromatography on agarose. Fingerprint analysis using two-dimensional polyacrylamide gels of RNase T1 oligonucleotides derived from nascent chains of different lengths showed that a size fractionation of nascent chains was achieved. VPg was recovered from nascent chains varying in length from 7,500 nucleotides (full-sized RNA) to about 500 nucleotides. No other type of 5' terminus could be demonstrated on nascent RNA, and the yield of VPg was consistent with one molecule of the protein on each nascent chain. These results are consistent with the concept that the protein is added to the 5' end of the growing RNA chains at a very early stage, possibly as a primer of RNA synthesis. Analysis of the polyuridylic acid tract isolated from the replicative intermediate and double-stranded RNAs indicated that a protein of the same size as that found on the nascent chains and virion RNA is also linked to the negative-strand RNAs. It is likely that a similar mechanism is responsible for initiation of synthesis of both plus- and minus-strand RNAs.", "pmcid": "PMC354174", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1978-08", "series_number": "2", "volume": "27", "issue": "2", "pages": "357-365" }, { "id": "authors:qztw0-v2n86", "collection": "authors", "collection_id": "qztw0-v2n86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:RUDjem78", "type": "article", "title": "Assignment of the receptor for ecotropic murine leukemia virus to mouse chromosome 5", "author": [ { "family_name": "Ruddle", "given_name": "Nancy H.", "clpid": "Ruddle-Nancy-H" }, { "family_name": "Conta", "given_name": "Barbara S.", "clpid": "Conta-Barbara-S" }, { "family_name": "Leinwand", "given_name": "Leslie", "clpid": "Leinwand-Leslie" }, { "family_name": "Kozak", "given_name": "Christine", "clpid": "Kozak-Christine-A" }, { "family_name": "Ruddle", "given_name": "Frank", "clpid": "Ruddle-Frank-H" }, { "family_name": "Besmer", "given_name": "Peter", "clpid": "Besmer-Peter" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The gene for the receptor for ecotropic murine leukemia virus (Rev) has been assigned to mouse chromosome 5. This determination was made possible by an analysis of somatic cell hybrids between mouse and Chinese hamster cells. The parents of these hybrids were A/HeJ or Mus poschiavinus peritoneal exudate cells or BALB/c primary embryo fibroblasts and E36, a Chinese hamster lung fibroblast deficient in hypoxanthine guanine phosphoribosyltransferase. Segregation of mouse chromosomes in these hybrids was analyzed by chromosome banding and isozyme expression. Cells were tested for their ability to absorb and replicate vesicular stomatitis virus (murine leukemia virus [MuLV]) pseudotype particles and ecotropic MuLV as measured by the XC test. The presence of chromosome 5 was essential for receptor expression as determined by three statistical procedures. Segregation of the receptor for ecotropic murine leukemia virus was also followed in two series of subclones. In both, receptor expression was syntenic with phosphoglucomutase-1, an isozyme which has been mapped to mouse chromosome 5.", "doi": "10.1084/jem.148.2.451", "pmcid": "PMC2184946", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1978-08", "series_number": "2", "volume": "148", "issue": "2", "pages": "451-465" }, { "id": "authors:2w2ht-1s596", "collection": "authors", "collection_id": "2w2ht-1s596", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170209-082835063", "type": "article", "title": "Heteroduplex Analysis of the Nonhomology Region between Moloney MuLV and the Dual Host Range Derivative HIX Virus", "author": [ { "family_name": "Donoghue", "given_name": "Daniel J.", "clpid": "Donoghue-Daniel-J" }, { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Hopkins", "given_name": "Nancy", "clpid": "Hopkins-Nancy" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Sharp", "given_name": "Phillip A.", "clpid": "Sharp-Philip-A" } ], "abstract": "The dual host range virus HIX has been previously characterized as an envelope gene recombinant between Moloney murine leukemia virus (Mo-MuLV) and an unidentified xenotropic murine leukemia virus. Using long reverse transcripts of Mo-MuLV, a region of nonhomology has been mapped by electron microscopic analysis of heteroduplexes formed with HIX 35S virion RNA. In this nonhomology region, the Mo-MuLV cDNA strand measured approximately 900 nucleotides, mapping between 1.6 and 2.5 kilobases from the 3\u2032 end.\n\nIn a previous study, hybridization of Mo-MuLV 21S RNA with Mo-MuLV cDNA resulted in the formation of different heteroduplex structures diagnostic of a noncontiguously coded leader sequence at the 5\u2032 end of the 21S RNA. Following hybridization of poly(A)+ HIX 21S RNA with 8.2 kb Mo-MuLV cDNA, analogous heteroduplex structures were observed exhibiting the Mo-MuLV:HIX substitution loop in the DNA:RNA segment of the molecules. This analysis permitted more precise mapping of the nonhomology region with respect to the splice point in the 21S presumptive glycoprotein mRNA. The mapping of this nonhomology region in HIX virus provides an internal visual marker for the 3\u2032 end of the genome which may prove useful in future analyses of other deletion or substitution derivatives of Mo-MuLV.", "doi": "10.1016/0092-8674(78)90350-1", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1978-08", "series_number": "4", "volume": "14", "issue": "4", "pages": "959-970" }, { "id": "authors:17653-88m41", "collection": "authors", "collection_id": "17653-88m41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-152106075", "type": "article", "title": "High frequency of aberrant expression of moloney murine leukemia virus in clonal infections", "author": [ { "family_name": "Shields", "given_name": "Anthony", "clpid": "Shields-Anthony" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Clones of cells were isolated from single virus-single cell infections of NIH/3T3 cells with Moloney murine leukemia virus. Approximately one third of such clones aberrantly expressed viral gene functions. One clone produced virus with altered plaque morphology, while others failed to produce particles able to make plaques on XC cells. In addition, clones that made particles lacking reverse transcriptase were found, and these did not synthesize the reverse transcriptase precursor Pr180^(gag-pol). One clone (M23) lacked any detectable glycoprotein or reverse transcriptase. Despite these defects, each clone released particles of type C morphology, suggesting that gag gene function alone may be sufficient for particle production. All the particles contained viral RNA of 60\u201370S that was composed of the normal 35S size subunits except for M23, which had a deletion in the viral genome of approximately 1000\u20131500 nucleotides. A variety of defective clones were also isolated following infection of rat cells with Moloney virus. It is apparent that the murine leukemia virus genome is often mutated by spontaneous processes generating a wide range of phenotypes.", "doi": "10.1016/0092-8674(78)90245-3", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1978-07", "series_number": "3", "volume": "14", "issue": "3", "pages": "601-609" }, { "id": "authors:dhe4y-wkc94", "collection": "authors", "collection_id": "dhe4y-wkc94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROSpnas78", "type": "article", "title": "Inhibition of translation by poliovirus: Inactivation of a specific initiation factor", "author": [ { "family_name": "Rose", "given_name": "John K.", "clpid": "Rose-John-K" }, { "family_name": "Trachsel", "given_name": "Hans", "clpid": "Trachsel-Hans" }, { "family_name": "Leong", "given_name": "Kahan", "clpid": "Leong-Kahan" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Translation of vesicular stomatitis virus (VSV) mRNA, like host mRNA translation, is inhibited in cells infected with poliovirus. To study the mechanism of poliovirus-induced inhibition of protein synthesis, we prepared extracts from poliovirus-infected and uninfected HeLa cells. Poliovirus mRNA was translated in lysates from both infected and uninfected cells, while VSV mRNA was translated only in the lysate from uninfected cells. Addition of purified translation initiation factors to the extract from infected cells showed that one factor, eIF-4B, could restore VSV mRNA translation in the infected lysate, but did not increase poliovirus mRNA translation. Further experiments involving translation of VSV mRNA in mixed extracts from poliovirus-infected and uninfected cells showed (i) that there was not an excess of an inhibitor of VSV mRNA translation in the infected lysate, but (ii) that an activity that caused a slow inactivation of eIF-4B was present in the infected lysate. Inactivation of eIF-4B appears to be the mechanism by which poliovirus infection causes a selective inhibition of translation.", "doi": "10.1073/pnas.75.6.2732", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1978-06", "series_number": "6", "volume": "75", "issue": "6", "pages": "2732-2736" }, { "id": "authors:jy16d-zbc65", "collection": "authors", "collection_id": "jy16d-zbc65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120726-131556638", "type": "article", "title": "Relationship of retrovirus polyprotein cleavages to virion maturation studied with temperature-sensitive murine leukemia virus mutants", "author": [ { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Murine leukemia virus mutants ts3 (Moloney) and ts24 (Rauscher) both formed late-budding structures on the cell membrane at restrictive temperature. They both accumulated core polyproteins Pr65gag and Pr180gag-pol in cell membranes, but the envelope precursor was rapidly turned over. After shift to permissive temperature in the presence of cycloheximide, the accumulated precursors were sequentially cleaved via discrete intermediates both during the final stages of the budding process and in newly released virions to yield the finished virion core proteins and reverse transcriptase. The precursor form of reverse transcriptase was not enzymatically active and became activated partially or entirely inside released virions.", "pmcid": "PMC525900", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1978-06", "series_number": "3", "volume": "26", "issue": "3", "pages": "750-761" }, { "id": "authors:2qz3t-4y066", "collection": "authors", "collection_id": "2qz3t-4y066", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120726-131518549", "type": "article", "title": "Identification of an Abelson murine leukemia virus-encoded protein present in transformed fibroblast and lymphoid cells", "author": [ { "family_name": "Witte", "given_name": "O. N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Rosenberg", "given_name": "N.", "clpid": "Rosenberg-Naomi" }, { "family_name": "Paskind", "given_name": "M.", "clpid": "Paskind-Michael" }, { "family_name": "Shields", "given_name": "A.", "clpid": "Shields-Anthony" }, { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Extracts from lymphoid and fibroblast cell lines transformed by Abelson murine leukemia virus (A-MuLV) contain a protein of molecular weight 120,000 (P120). Immunoprecipitation with specific sera shows that P120 contains regions homologous to the 5'-terminal segment of the MULV gag gene complex--p15, p12, and at least part of p30--but lacks detectable determinants of p10, reverse transcriptase, and the envelope glycoprotein. P120 is phosphorylated and has an intracellular half-life of 3--6 hr. In vitro translation of virion RNA from A-MuLV, with Moloney MuLV as helper, yields a product of molecular weight 120,000 with serological reactivity similar to that of the cellular P120. Translation of the RNA from the helper gave no P120. P120 is expressed in all lymphoid and fibroblastic cell lines we have tested that were transformed by A-MuLV but is not detectable in a lymphoid line in which the A-MuLV genome was established by infection but was not responsible for the transformation. Expression of P120 is selectively retained in clones of A-MuLV-transformed lymphocytes that convert to a nonproducer state after loss of expression of helper MuLV intracellular precursors. These results suggest that the P120 product of the A-MuLV genome may be responsible for maintenance of the transformed phenotype of lymphoid and fibroblast cells transformed by the virus.", "doi": "10.1073/pnas.75.5.2488", "pmcid": "PMC392579", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1978-05", "series_number": "5", "volume": "75", "issue": "5", "pages": "2488-2492" }, { "id": "authors:sshd5-7nm32", "collection": "authors", "collection_id": "sshd5-7nm32", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROSjem78", "type": "article", "title": "The effect of helper virus on Abelson virus-induced transformation of lymphoid cells", "author": [ { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Abelson murine leukemia virus (A-MuLV)-transformed fibroblast nonproducer cells were used to prepare A-MuLV stocks containing a number of different helper viruses. The oncogenicity of the A-MuLV stocks was tested by animal inoculation and their ability to transform normal mouse bone marrow cells was measured in vitro. All of the A-MuLV stocks transformed fibroblast cells efficiently. However, only A-MuLV stocks prepared with helper viruses that are highly oncogenic were efficient in vivo and in vitro in hematopoietic cell transformation. In addition, inefficient helpers did not establish a stable infection in lymphoid nonproducer cells. Thus, helper virus has a more central role in lymphoid cell transformation than in fibroblast cell transformation.", "doi": "10.1084/jem.147.4.1126", "pmcid": "PMC2184241", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1978-04", "series_number": "4", "volume": "147", "issue": "4", "pages": "1126-1141" }, { "id": "authors:8ckqh-k1a80", "collection": "authors", "collection_id": "8ckqh-k1a80", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170207-111017078", "type": "article", "title": "Analysis of a 5' Leader Sequence on Murine Leukemia Virus 21S RNA: Heteroduplex Mapping with Long Reverse Transcriptase Products", "author": [ { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Donoghue", "given_name": "Daniel J.", "clpid": "Donoghue-Daniel-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The majority of the mRNA that specifies retrovirus glycoproteins is known to be derived from the 3\u2032 half of the genome. To examine whether the glycoprotein mRNA of murine leukemia viruses (MuLVs) might consist of portions derived from both the 5\u2032 and 3\u2032 ends of the viral genome, we performed hybridization with a 5\u2032-specific probe and heteroduplex analysis with long reverse transcribed DNA. A 5\u2032 probe was made by purifying a discrete 50 nucleotide-long reverse transcript attached to its tRNA primer. This probe was found to hybridize to RNA of the size of glycoprotein mRNA\u201421S, poly(A)-containing RNA\u2014indicating that the mRNA could have a 5\u2032 leader sequence.\n\nThe 5\u2032-specific sequences were studied by electron microscopic examination of hybrids between 21S RNA and the two longest discrete cDNA species synthesized in the endogenous reverse transcriptase reaction. One of these species, 8.8 kb long, is only made in the absence of actinomycin D, but it does not contain any self-complementary sequences, and therefore appears to be a complete transcript of the viral genome. The shorter of the two species, 8.2 kb long, is synthesized whether or not actinomycin D is present; it must terminate 500\u2013600 nucleotides internal to the 5\u2032 end of the template RNA. The structures observed in heteroduplexes of 21S RNA and these DNAs indicated the presence of a leader sequence approximately 500 nucleotides long at the 5\u2032 end of the 21S RNA. Sequences comprising this leader segment in the 21S RNA mapped at the 5\u2032 end of the genome RNA; the rest of the 21S RNA consisted of sequences from the 3\u2032 portion of the genome. Analysis of heteroduplexes with 8.2 kb DNA suggested that actinomycin D could block the reverse transcription of most of the sequence in the genome RNA that appears as a leader in the 21S RNA.", "doi": "10.1016/0092-8674(78)90318-5", "issn": "0092-8674", "publisher": "Elsevier", "publication": "Cell", "publication_date": "1978-03", "series_number": "3", "volume": "13", "issue": "3", "pages": "435-451" }, { "id": "authors:403xt-54d91", "collection": "authors", "collection_id": "403xt-54d91", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HALpnas78", "type": "article", "title": "Vesicular stomatitis virus glycoprotein is necessary for H-2-restricted lysis of infected cells by cytotoxic T lymphocytes", "author": [ { "family_name": "Hale", "given_name": "Arthur H.", "clpid": "Hale-Arthur-H" }, { "family_name": "Witte", "given_name": "Owen N.", "orcid": "0000-0003-4461-4533", "clpid": "Witte-O-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Eisen", "given_name": "Herman N.", "clpid": "Eisen-Herman-N" } ], "abstract": "Vesicular stomatitis virus (VSV) elicited cytotoxic thymus-derived lymphocytes (CTLs) in mice of the BALB/c and three congenic strains (BALB.b, BALB.k, BALB.HTG). CTL lysis of VSV-infected fibroblasts from the four strains was restricted by the target cells' major histocompatibility complex (H-2). Target cells were also infected with two temperature-sensitive mutants of VSV, tsM and tsG in which, respectively, the viral matrix protein and glycoprotein are not expressed at 39 degrees (restrictive temperature) on the infected cell's surface membrane. At the restrictive temperature, cells infected with wild-type VSV or tsM were lysed by CTLs, but cells infected with tsG were not. The requirement for the glycoprotein on the target cell was also evident from the ability of antisera to the glycoprotein to block completely CTL lysis of VSV-infected cells.", "doi": "10.1073/pnas.75.2.970", "pmcid": "PMC411381", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1978-02", "series_number": "2", "volume": "75", "issue": "2", "pages": "970-974" }, { "id": "authors:g29ys-szk29", "collection": "authors", "collection_id": "g29ys-szk29", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170207-083820520", "type": "article", "title": "In vitro synthesis of infectious DNA of murine leukaemia virus", "author": [ { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Smotkin", "given_name": "David", "clpid": "Smotkin-David" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Weinberg", "given_name": "Robert A.", "clpid": "Weinberg-Robert-A" } ], "abstract": "DNA synthesised in vitro by purified virions of murine leukaemia virus is infectious. Neither RNA nor protein is required for infectivity. Transfection with reverse transcriptase product shows a single-hit dose response and results in the production of complete, infectious virus.", "doi": "10.1038/269122a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1977-09-08", "series_number": "5624", "volume": "269", "issue": "5624", "pages": "122-126" }, { "id": "authors:x0rsh-emh47", "collection": "authors", "collection_id": "x0rsh-emh47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FLApnas77b", "type": "article", "title": "Poliovirus-specific primer-dependent RNA polymerase able to copy poly(A)", "author": [ { "family_name": "Flanegan", "given_name": "James B.", "clpid": "Flanegan-James-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A template-dependent RNA polymerase has been isolated from poliovirus-infected cells by assaying for the ability of the enzyme to copy poly(A) complexed to an oligo(U) primer. The polymerase was solubilized with detergent, and RNA was removed by precipitation with 2 M LiCl. The solubilized polymerase required both poly(A) and oligo(U) for activity and was stimulated by Mg2+ but was inhibited by Mn2+. Poly(A)\u00b7 oligo(U)-dependent poly(U) polymerase was not found in extracts of HeLa cells until about 2 hr after poliovirus infection, and then there was a linear increase in activity until about 5 hr. Analysis of the polymerase by glycerol gradient centrifugation showed that the majority of the activity sedimented at about 4 S, indicating that it was no longer complexed with high-molecular-weight RNA or cellular membranes. This poly(A)\u00b7 oligo(U)-dependent polymerase activity could represent an important component of the poliovirus RNA-dependent RNA polymerase.", "doi": "10.1073/pnas.74.9.3677", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1977-09", "series_number": "9", "volume": "74", "issue": "9", "pages": "3677-3680" }, { "id": "authors:mm4c1-91c57", "collection": "authors", "collection_id": "mm4c1-91c57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GUTjvir77", "type": "article", "title": "Morphogenesis of poliovirus. IV. existence of particles sedimenting at 150S and having the properties of provirion", "author": [ { "family_name": "Guttman", "given_name": "Naomi", "clpid": "Guttman-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "An apparent precursor to the poliovirion that cosediments with the virion at 150S was identified by its content of VP-0. It has properties previously associated with the provirion, a structure that sedimented at 125S, and it may be an alternate form of provirion. Like virions, the 150S precursor binds to and elutes from cells, after which it sediments at about 125S.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1977-08", "series_number": "2", "volume": "23", "issue": "2", "pages": "363-367" }, { "id": "authors:xqq94-87d67", "collection": "authors", "collection_id": "xqq94-87d67", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BESjvir77", "type": "article", "title": "Mechanism of restriction of ecotropic and xenotropic murine leukemia viruses and formation of pseudotypes between the two viruses", "author": [ { "family_name": "Besmer", "given_name": "Peter", "clpid": "Besmer-Peter" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Ecotropic and xenotropic murine leukemia viruses (MuLV's) constitute separate interference groups; within each group there is cross-interference, but between the groups there is no detectable interference. Interference is manifest against pseudotypes in which the vesicular stomatitis virus genome is contained within the coat of one of the murine leukemia viruses. The pseudotypes display the cell specificity of the leukemia viruses: pseudotypes with an ecotropic MuLV coat infect mouse cells but not rabbit or mink cells; pseudotypes with a xenotropic MuLV coat infect rabbit or mink cells well but mouse cells very poorly. Efficient pseudotype formation also occurs between the two MuLV classes, and both the interference patterns and the cell specificity of these pseudotypes are entirely determined by their envelope. Using these pseudotypes, ecotropic MuLV infection could be established in xenogeneic cells, and the resulting progeny could be scored by using a conventional XC cell assay. Also, xenotropic MuLV infection could be established in a mouse cell, showing that no absolute intracellular barrier against xenotropic virus growth exists in murine cells. The major barriers against both xenotropic and ecotropic MuLV therefore are cell surface barriers. Xenogeneic cells probably lack receptors for ecotropic MuLV, but murine cells may either lack receptors for xenotropic MuLV or have receptors that are blocked by endogenous expression of the glycoprotein of endogenous xenotropic MuLV.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "965-973" }, { "id": "authors:83sjc-4yt37", "collection": "authors", "collection_id": "83sjc-4yt37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HEWjvir77", "type": "article", "title": "Circular forms of Uukuniemi virion RNA: an electron microscopic study", "author": [ { "family_name": "Hewlett", "given_name": "Martinez J.", "clpid": "Hewlett-Martinez-J" }, { "family_name": "Pettersson", "given_name": "Ralf F.", "clpid": "Pettersson-Ralf-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Because the ribonucleoprotein forms of the segments of the Uukuniemi virus genome have previously been characterized as circular, we examined the isolated RNAs by electron microscopy under conditions of increasing denaturation. After spreading under moderately denaturing conditions (50 or 60% formamide), 50 to 70% of the molecules were circular. Increasing the formamide concentration to 70 and 85% decreased the number of circular forms, and only linear forms were observed after incubation of the RNA at 60 degrees C for 15 min in 99% formamide. When spread from 4 M urea-80% formamide--another condition known to denature RNA--only 5 to 30% circular molecules were observed. Pretreatment of the RNA with 0.5 M glyoxal at 37 degrees C for 15 min prior to spreading from 50% formamide gave less than 5% cirucular forms. Length measurement of the molecules showed that they were not significantly degraded by any of the methods employed. The circular molecules were destroyed by treatment with pancreatic RNase, but were unaffected by DNase or proteinase K treatment. After complete denaturation of the RNA, the circles could be reformed under reannealing conditions. We conclude that the three size classes of RNA that comprise the Uukuniemi virus genome are circular molecules probably maintained in that form by base pairing between inverted complementary sequences at the 3' and 5' ends of linear molecules.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "1085-1093" }, { "id": "authors:1sjas-xp078", "collection": "authors", "collection_id": "1sjas-xp078", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120801-114336136", "type": "article", "title": "Low-molecular-weight RNAs of Moloney murine leukemia virus: identification of the primer for RNA-directed DNA synthesis", "author": [ { "family_name": "Peters", "given_name": "Gordon", "clpid": "Peters-Gordon" }, { "family_name": "Harada", "given_name": "Fumio", "clpid": "Harada-Fumio" }, { "family_name": "Dahlberg", "given_name": "James E.", "clpid": "Dahlberg-James-E" }, { "family_name": "Panet", "given_name": "Amos", "clpid": "Panet-Amos" }, { "family_name": "Haseltine", "given_name": "William A.", "clpid": "Haseltine-William-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The small RNAs of Moloney murine leukemia virus (M-MuLV) were fractionated into at least 15 species by two-dimensional polyacrylamide gel electrophoresis. The pattern of small RNAs is significantly different from that of Rous sarcoma virus. A subset of the virion small RNAs is associated with the genome RNA in the 70S complex. One of the associated molecules, a cellular tRNA, is tightly bound to the genome RNA and serves as the major primer for M-MuLV RNA-directed DNA synthesis in vitro.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "1031-1041" }, { "id": "authors:scd9q-8bm33", "collection": "authors", "collection_id": "scd9q-8bm33", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120727-110028203", "type": "article", "title": "Analysis of the defects of temperature-sensitive mutants of vesicular stomatitis virus: intracellular degradation of specific viral proteins", "author": [ { "family_name": "Knipe", "given_name": "David", "orcid": "0000-0003-1554-6236", "clpid": "Knipe-David-M" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The metabolism of viral RNA and proteins has been studied in cells infected with temperature-sensitive mutant strains of vesicular stomatitis virus. Certain viral proteins encoded by the mutant strains, usually the putative mutant protein for the assigned complementation group, were shown to be degraded more rapidly at the nonpermissive temperature than were the wild-type proteins. Group III mutants (tsG33, tsM301) encode M proteins which are degraded three- to fourfold faster than the wild-type protein. This defect cannot be fully rescued by coinfection with wild-type virus, and thus the defect appears to be in the M protein itself. Mutants tsM601 (VI) and tsG41(IV) encode N proteins which are degraded much faster than the wild-type protein and also share the property of being defective in replication of viral RNA, suggesting a correlation between these phenotypic properties. Furthermore, the L proteins of tsG11(I) and tsG13(I) are more labile than the wild-type protein at the nonpermissive temperature. The G protein of tsM501(V) did not undergo the change in electrophoretic mobility previously shown to be the result of sialylation, suggesting that it is defective in maturation or glycosylation at the nonpermissive temperature. Three of the mutants previously isolated in this laboratory, tsM502(V), tsM601(VI), and tsM602(VI), were shown to be defective in viral RNA synthesis at the nonpermissive temperature. Mutant tsM601(VI) was defective mainly in viral RNA replication, whereas tsM502(V) appeared to be totally defective for viral RNA transcription and replication at the nonpermissive temperature.", "pmcid": "PMC515655", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "1140-1148" }, { "id": "authors:5r1yw-0f141", "collection": "authors", "collection_id": "5r1yw-0f141", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FLApnas77a", "type": "article", "title": "Covalent linkage of a protein to a defined nucleotide sequence at the 5'-terminus of virion and replicative intermediate RNAs of poliovirus", "author": [ { "family_name": "Flanegan", "given_name": "James B.", "clpid": "Flanegan-James-B" }, { "family_name": "Pettersson", "given_name": "Ralf F.", "clpid": "Pettersson-Ralf-F" }, { "family_name": "Ambros", "given_name": "Victor", "clpid": "Ambros-Victor" }, { "family_name": "Hewlett", "given_name": "Martinez J.", "clpid": "Hewlett-Martinez-J" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The 5'-terminus of poliovirus polyribosomal RNA is pUp. A candidate for the 5'-terminus of poliovirion RNA was recovered as a compound migrating toward the cathode when 32P-labeled virion RNA was completely digested with ribonucleases T1, T2, and A and analyzed by paper ionophoresis at pH 3.5. Treatment with proteinase K reversed its direction of migration, indicating the presence of protein. Treatment with venom phosphodiesterase liberated all of the radioactivity as pUp, suggesting that poliovirion RNA has a protein-pUp 5'-terminus. Treatment of virion RNA with T1 ribonuclease alone generated a proteinase K-sensitive oligoribonucleotide. Analysis of the oligoribonucleotide using ribonucleases A and U2 showed its structure to be protein-pU-U-A-A-A-A-C-A-G. Digests of replicative intermediate RNA contained sufficient protein-pUp to suggest that this structure is at the 5'-end of most nascent poliovirus RNA molecules. We suggest that a protein-nucleotide structure acts as a primer for initiating synthesis of poliovirus RNA.", "doi": "10.1073/pnas.74.3.961", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1977-03", "series_number": "3", "volume": "74", "issue": "3", "pages": "961-965" }, { "id": "authors:ctcc0-yeh57", "collection": "authors", "collection_id": "ctcc0-yeh57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120727-110057001", "type": "article", "title": "Maturation of viral proteins in cells infected with temperature-sensitive mutants of vesicular stomatitis virus", "author": [ { "family_name": "Knipe", "given_name": "David M.", "orcid": "0000-0003-1554-6236", "clpid": "Knipe-David-M" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" } ], "abstract": "Maturation of viral proteins in cells infected with mutants of vesicular stomatitis virus was studied by surface iodination and cell fractionation. The movement of G, M, and N proteins to the virion bud appeared to be interdependent. Mutations thought to be in G protein prevented its migration to the cell surface, allowed neither M nor N protein to become membrane bound, and blocked formation of viral particles. Mutant G protein appeared not to leave the endoplasmic reticulum at the nonpermissive temperature, but this defect was partially reversible. In cells infected with mutants that caused N protein to be degraded rapidly or prevented its assembly into nucleocapsids, M protein did not bind to membranes and G protein matured to the cell surface, but never entered structures with the density of virions. Mutations causing M protein to be degraded prevented virion formation, and G protein behaved as in cells infected by mutants in N protein. These results are consistent with a model of virion formation involving coalescence of soluble nucleocapsid and soluble M protein with G protein already in the plasma membrane.", "pmcid": "PMC515656", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "1149-1158" }, { "id": "authors:j7xcx-vff29", "collection": "authors", "collection_id": "j7xcx-vff29", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120802-083032069", "type": "article", "title": "Localization of two cellular forms of the vesicular stomatitis viral glycoprotein", "author": [ { "family_name": "Knipe", "given_name": "David M.", "orcid": "0000-0003-1554-6236", "clpid": "Knipe-David-M" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Two cell-associated forms of the glycoprotein (G) of vesicular stomatitis virus, termed G_1 and G_2, have been resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. G_1 has the higher electrophoretic mobility, but both forms migrate more slowly than G protein synthesized in a wheat germ cell-free system (G_0), which presumably is the unglycosylated form. G_1 is a kinetic precursor of the G_2 form, and the apparent cause of the electrophoretic difference between the two species is the presence of N-acetylneuraminic acid on the G_2 form. Conversion of G_1 to G_2 occurs 10 to 20 min prior to the appearance of the G_2 form of the protein on the cell surface. This suggests that the G protein may be completely glycosylated several minutes prior to its migration to the cell surface and that glycosylation is not the limiting step in its maturation. No glycoprotein comigrating with G_0 can be detected in the infected cells, even after 5-min labeling periods; this suggests that partial clycosylation of G occurs concomitantly with or immediately after its synthesis.", "doi": "10.1128/jvi.21.3.1121-1127.1977", "pmcid": "PMC515653", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1977-03", "series_number": "3", "volume": "21", "issue": "3", "pages": "1121-1127" }, { "id": "authors:6krr9-gyv44", "collection": "authors", "collection_id": "6krr9-gyv44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROTjvir77", "type": "article", "title": "Increased Length of DNA Made by Virions of Murine Leukemia Virus at Limiting Magnesium Ion Concentration", "author": [ { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Conditions have been developed for reverse transcription by detergent-disrupted virions of Moloney murine leukemia virus which permit synthesis of molecules that appear to be complete transcripts of the 35S RNA subunits. At limiting Mg2+ concentration, DNA is synthesized in good yield, up to a maximum size of about 2.4 x 10^6 daltons. DNA larger than 2 x 10^6 daltons, taken from alkaline sucrose gradients, has no detectable self-complementarity and was protected from digestion by S1 nuclease to an extent of 90% by annealing to 70S RNA. All size classes ofDNA made in these reactions are primed with RNA, because all are initiated with a pApdA junction. To produce such long molecules, it is necessary to keep the concentration of Mg2+ in the reaction mixture below the total concentration of deoxyribonucleoside triphosphates. Under these conditions, degradation of the RNA template is minimized. The rate of DNA synthesis is also slowed by 30 to 50%, but products longer than 5,000 nucleotides, which are not found otherwise, are completed between 3 and 6 h of reaction.", "pmcid": "PMC353803", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1977-01", "series_number": "1", "volume": "21", "issue": "1", "pages": "168-178" }, { "id": "authors:acp0x-77n39", "collection": "authors", "collection_id": "acp0x-77n39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROSjvir76", "type": "article", "title": "5'-Terminus of Moloney Murine Leukemia Virus 35S RNA Is m7G5' ppp5' GmpCp", "author": [ { "family_name": "Rose", "given_name": "John K.", "clpid": "Rose-John-K" }, { "family_name": "Haseltine", "given_name": "William A.", "clpid": "Haseltine-William-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The 5'-terminal sequence m7G5' ppp5' GmpCp was isolated from Moloney murine leukemia virus 35S RNA after digestion of 32P-labeled RNA with RNases T1, T2, and A followed by pH 3.5 ionophoresis on DEAE paper.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1976-10", "series_number": "1", "volume": "20", "issue": "1", "pages": "324-329" }, { "id": "authors:jvsk9-h0f73", "collection": "authors", "collection_id": "jvsk9-h0f73", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-144004711", "type": "article", "title": "Ordered transcription of RNA tumor virus genomes", "author": [ { "family_name": "Haseltine", "given_name": "William A.", "clpid": "Haseltine-William-A" }, { "family_name": "Kleid", "given_name": "Dennis G.", "clpid": "Kleid-Dennis-G" }, { "family_name": "Panet", "given_name": "Amos", "clpid": "Panet-Amos" }, { "family_name": "Rothenberg", "given_name": "Ellen V.", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Recent improvements in the reaction conditions have allowed a detailed characterization of the DNA products synthesized in vitro by the reverse transcriptase of RNA tumor viruses from the 70 S genome. We have investigated the size distribution of DNA products synthesized in vitro under different reaction conditions using both Rous sarcoma virus (RSV) and Moloney murine leukemia virus (M-MuLV). Analysis of the reaction products on polyacrylamide gels shows that the majority of DNA synthesized, especially at high concentrations of dNTPs, comprised a set of DNA chains of discrete length the longest of which cover a major fraction of the genome. The effect of varying the time of incubation was to increase the fraction of the total DNA in longer chains. However, small DNA chains less than 200 nucleotides long were still abundant after 500 minutes. By varying which of the four dNTPs was at low concentration we revealed two classes of DNA fragments of discrete length, those present regardless of which dNTP was at low concentration (structural stops) and those which were made only when a specific dNTP was at a low concentration (sequence stops). A strong structural stop which gave a fragment 135 nucleotides long (M-MuLV) or 100 nucleotides long (RSV) comprised more than half of the population of DNA molecules even at the highest dNTP concentrations. The DNA products of the endogenous and exogenous (reconstructed) reactions were identical.\nThe DNA chains of discrete length were initiated with a tRNA (tRNA^(Trp) RSV, tRNA^(Pro) M-MuLV). The DNA fragments of both RSV and M-MuLV have a common initiation sequence. We have sequenced the first 18 nucleotides of M-MuLV. The initial sequences of RSV (AATGAAGC) and M-MuLV (AATGAAAGA) are remarkably similar suggesting a common evolutionary ancestry. We analyzed the pyrimidine tracts of DNA chains of increasing length by electrophoresis followed by homochromatography. The pyrimidine tracts of the shorter pieces form a subset of the pyrimidine tracts of the longer pieces. These data demonstrate that the in vitro products of discrete length were initiated with a tRNA primer at a unique site along the 35 S genome and grew by linear extension.", "doi": "10.1016/0022-2836(76)90303-X", "issn": "0022-2836", "publisher": "Elsevier", "publication": "Journal of Molecular Biology", "publication_date": "1976-09-05", "series_number": "1", "volume": "106", "issue": "1", "pages": "109-131" }, { "id": "authors:ymbkt-7ba53", "collection": "authors", "collection_id": "ymbkt-7ba53", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120813-163013262", "type": "article", "title": "Terminal deoxynucleotidyl transferase is found in prothymocytes", "author": [ { "family_name": "Silverstone", "given_name": "Allen E.", "clpid": "Silverstone-Allen-E" }, { "family_name": "Cantor", "given_name": "Harvey", "clpid": "Cantor-Harvey" }, { "family_name": "Goldstein", "given_name": "Gideon", "clpid": "Goldstein-Gideon" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Terminal deoxynucleotidyl transferase is an enzyme which has the unique property of polymerizing polydeoxynucleotides onto a primer in the absence of a template (1,2). This enzyme is found both in the thymus and the bone marrow of birds, rodents, and humans (3-7). Whether the marrow cells that contain terminal transferase are related to thymocytes, or are on a separate pathway of differentiation, is not yet known (7,8).\n\nTo determine the lineage of the murine bone marrow cells that have terminal transferase, we have investigated whether these cells have the antigen Thy-1 induced on the cells by treatment with thymopoietin (9). Thymopoietin is known to induce a set of characteristic T-cell markers including the Thy-1 alloantigen on the surface of a subpopulation of bone marrow cells committed to T-cell differentiation (prothymocytes) (10). Destruction of Thy- 1-positive cells after exposure to thymopoietin allows elimination of a substantial fraction of those bone marrow cells that can repopulate an irradiated thymus (11). We find that such an elimination after induction with the thymic polypeptide removes a substantial amount of terminal transferase from the bone marrow cell population, suggesting that at least one-half of the marrow cells bearing this enzyme are related to those found in the thymus.", "doi": "10.1084/jem.144.2.543", "pmcid": "PMC2190385", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1976-08-01", "series_number": "2", "volume": "144", "issue": "2", "pages": "543-548" }, { "id": "authors:6792b-x1m17", "collection": "authors", "collection_id": "6792b-x1m17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HASjvir76", "type": "article", "title": "Size of murine RNA tumor virus-specific nuclear RNA molecules", "author": [ { "family_name": "Haseltine", "given_name": "William A.", "clpid": "Haseltine-William-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "About 1% of the total RNA of cell lines producing murine leukemia virus is virus-specific RNA. About one-third of the virus-specific RNA is located within the nucleus. The size distribution of virus-specific RNA was determined before and after denaturation. Before denaturation, virus-specific RNA sequences sedimented as a heterogeneous population of RNA molecules, some of which sedimented very rapidly. After denaturation, most of the virus-specific RNA had a sedimentation coefficient of 35S or lower, but a small fraction of the nuclear virus-specific RNA sedimented more rapidly than 35S RNA even after denaturation.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1976-08", "series_number": "2", "volume": "19", "issue": "2", "pages": "331-337" }, { "id": "authors:7tfdx-3a932", "collection": "authors", "collection_id": "7tfdx-3a932", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:JOLpnas76", "type": "article", "title": "Effect of Fv-1 gene product on proviral DNA formation and integration in cells infected with murine leukemia viruses", "author": [ { "family_name": "Jolicoeur", "given_name": "Paul", "clpid": "Jolicoeur-Paul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The amounts of unintegrated murine leukemia virus-specific DNA detected by molecular hybridization in extracts of Fv-1n/n (strains NIH/3T3, SIM) or Fv-1b/b (strains JLS-V9, SIM.R) mouse cells after infection with N- or B-tropic viruses were found to be the same in both permissive and resistant cells. Therefore, formation of DNA products from the viral RNA template does not appear to be grossly affected by the Fv-1 gene product. Integration of virus-specific DNA into chromosomal cellular DNA was assayed by hybridization of radioactive complementary DNA to DNA from infected cells. With either NIH/3T3 or SIM.R cells infected with N- or B-tropic viruses, integration of proviral DNA could be detected in permissive cells but not in nonpermissive cells. The Fv-1 gene product therefore appears to prevent integration of proviral DNA.", "doi": "10.1073/pnas.73.7.2236", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1976-07", "series_number": "7", "volume": "73", "issue": "7", "pages": "2236-2240" }, { "id": "authors:pdrzw-87r50", "collection": "authors", "collection_id": "pdrzw-87r50", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROSjem76", "type": "article", "title": "A quantitative assay for transformation of bone marrow cells by Abelson murine leukemia virus", "author": [ { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A quantitative Abelson murine leukemia virus (A-MuLV) lymphoid cell transformation assay has been developed using a semisolid agarose culture system. Under these conditions lymphoid cell transformation was shown to vary linearly with the dose of A-MuLV used. The susceptibility of bone marrow cells from different strains of mice to A-MuLV-induced transformation can be estimated using the agarose assay. Strains with bone marrow cells of high, medium, and low susceptibility to A-MuLV can be identified. The assay has been used to study the susceptibility of cells from lymphoid organs of fetal and adult mice to A-MuLV. Cell suspensions from fetal liver, adult bone marrow, and adult spleen are susceptible to A-MuLV, while thymocytes are resistant to A-MuLV-induced transformation. Bovine serum albumin gradient fractionation of bone marrow cells before infection with A-MuLV demonstrates that the majority of A-MuLV-sensitive cells are recovered in a broad band partially overlapping the majority of the nucleated cells. The agarose assay system allows study of A-MuLV-lymphoid cell interaction at the level of single cell-single virus particle interaction.", "doi": "10.1084/jem.143.6.1453", "pmcid": "PMC2190217", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1976-06", "series_number": "6", "volume": "143", "issue": "6", "pages": "1453-1463" }, { "id": "authors:y7xmx-2sm58", "collection": "authors", "collection_id": "y7xmx-2sm58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KERjvir76", "type": "article", "title": "Translation of murine leukemia virus RNA in cell-free systems from animal cells", "author": [ { "family_name": "Kerr", "given_name": "Ian M.", "clpid": "Kerr-Ian-M" }, { "family_name": "Olshevsky", "given_name": "Udy", "clpid": "Olshevsky-Udy" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The virion RNA of Moloney murine leukemia virus (MuLV) has been translated in eukaryotic cell-free systems derived from mouse L- and human HeLa cells. In both systems at least three polypeptides, approximately 60,000, 70,000, and 180,000 in apparent molecular weight, were formed in response to the added 35S MuLV RNA. All three polypeptides were precipitable with antiserum to detergent-disrupted MuLV. Fingerprint analysis of tryptic digests indicated that all three contain anino acid sequences in common with each other and with the major methionine-containing structural proteins of the virion.", "doi": "10.1128/jvi.18.2.627-635.1976", "pmcid": "PMC515589", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1976-05", "series_number": "2", "volume": "18", "issue": "2", "pages": "627-635" }, { "id": "authors:h8xvn-mw193", "collection": "authors", "collection_id": "h8xvn-mw193", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KUNjbc76", "type": "article", "title": "Terminal deoxynucleotidyltransferase. Serological studies and radioimmunoassay", "author": [ { "family_name": "Kung", "given_name": "Patrick C.", "clpid": "Kung-Patrick-C" }, { "family_name": "Gottlieb", "given_name": "Paul D.", "clpid": "Gottleib-Paul-D" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Mouse antisera against calf terminal deoxynucleotidyltransferase (terminal transferase) have been prepared. The sera have been used to characterize terminal transferase both by studying inhibition of enzyme activity and by developing a competition radioimmunoassay using highly purified 125I-labeled terminal transferase. By either assay, anti-terminal transferase serum did not cross-react significantly with calf DNA polymerases alpha and beta, Escherichia coli DNA polymerase I, or the reverse transcriptase of Moloney mouse leukemia virus. The calf terminal transferase did, however, share cross-reactive but not identical determinants with human and murine terminal transferase. The radioimmunoassay could detect as little as 2 ng of terminal transferase/mg of soluble protein in a tissue extract. Thymocytes were found to contain 280 ng of terminal transferase/mg of cell protein or about 1 X 10^(5) molecules/cell; bone marrow had about 1% of the level of enzyme found in thymus. Extracts of spleen, peripheral white blood cells, lymph nodes, liver, muscle, and kidney all lacked detectable antigenicity of terminal transferase. These data indicate that terminal transferase is a tissue-specific enzyme and is not related to other DNA polymerases.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1976-04-25", "series_number": "8", "volume": "251", "issue": "8", "pages": "2399-2404" }, { "id": "authors:5d6kd-p8m24", "collection": "authors", "collection_id": "5d6kd-p8m24", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HEWpnas76", "type": "article", "title": "5'-terminal structure of poliovirus polyribosomal RNA is pUp", "author": [ { "family_name": "Hewlett", "given_name": "Martinez J.", "clpid": "Hewlett-Martinez-J" }, { "family_name": "Rose", "given_name": "John K.", "clpid": "Rose-John-K" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Poliovirus RNA purified from virus-specific polyribosomes does not contain m7G in a 5'-5'-pyrophosphate linkage at its 5'-end. The only potential 5'-end found in ribonuclease digests of this RNA is pUp, which is present in a yield of 1 mole/mole of poliovirus RNA. We conclude that a 5'-terminal m7G is not required for translation of at least one RNA species in animal cells.", "doi": "10.1073/pnas.73.2.327", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1976-02", "series_number": "2", "volume": "73", "issue": "2", "pages": "327-330" }, { "id": "authors:6y35a-qne61", "collection": "authors", "collection_id": "6y35a-qne61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROTjvir76", "type": "article", "title": "Synthesis of Long, Representative DNA Copies of the Murine RNA Tumor Virus Genome", "author": [ { "family_name": "Rothenberg", "given_name": "Ellen", "orcid": "0000-0002-3901-347X", "clpid": "Rothenberg-E-V" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Virions of Moloney murine leukemia virus can synthesize two classes of DNA molecules complementary to their 70S RNA. One class consists of molecules about 200 nucleotides long, which are of limited sequence complexity; these molecules are formed preferentially if the dNTP concentration during the reaction is low. The second class consists of very heterogeneous DNA molecules with weight-average size of about 1,000 nucleotides containing at least 70% of the viral RNA sequences in approximately equal concentration. The longest of these molecules can be 5,000 nucleotides long. This second class of DNA is formed in large amounts only in reactions containing dNTP concentrations of 0.2 mM or higher. In such reactions after 24 h of incubation, at least 35% of the input RNA is represented in DNA copies. The ability to make long, representative DNA transcripts of tumor virus RNA provides a source of excellent probes for molecular hybridization.", "pmcid": "PMC515400", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1976-01", "series_number": "1", "volume": "17", "issue": "1", "pages": "168-174" }, { "id": "authors:4qey2-y4x34", "collection": "authors", "collection_id": "4qey2-y4x34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:JOLjvir75", "type": "article", "title": "Effect of the Fv-1 locus on the titration of murine leukemia viruses", "author": [ { "family_name": "Jolicoeur", "given_name": "Paul", "clpid": "Jolicoeur-Paul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Titration of N- and B-tropic murine leukemia viruses on sensitive and resistant cell lines has been studied by direct XC plaque assay and infective center assay. The titration of cloned B-tropic virus by infective center assay on BALB/3T3 (Fv-1b/b) and NIH/3T3 (Fv-1n/n) cells gave one-hit patterns, with 100-fold less infected NIH/3T3 cells than BALB/3T3 cells. The titration of B-tropic virus on DBA/2 cells (Fv-1n/n) was also a one-hit. The titration of a one-hit curve, and there were about 100-fold less infected BALB/3T3 cells than NIH/3T3 cells. Comparable results were obtained by titrating the cloned N-tropic virus on congenic SIM (Fv-1n/n) and SIM.R (Fv-1b/b) cells or the Gross N-tropic virus on BALB/3T3 cells. Therefore, our data indicate that the multiple-hit phenomenon described previously may not be an essential part of the Fv-1 gene restriction.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1975-12", "series_number": "6", "volume": "16", "issue": "6", "pages": "1593-1598" }, { "id": "authors:nqq29-y9y78", "collection": "authors", "collection_id": "nqq29-y9y78", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SPEjvir75c", "type": "article", "title": "Poly(A) on mengovirus RNA", "author": [ { "family_name": "Spector", "given_name": "Deborah H.", "clpid": "Spector-Deborah-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The content and size of the poly(A) on Mengovirus RNA grown in both mouse L cells and HeLa cells have been examined. Virion RNA from either cell line could bind to poly(U) filters and contained RNase-resistant stretches of poly(A) which could be analyzed by electrophoresis in polyacrylamide gels. The size of the poly(A) on the Mengovirus RNA was independent of the host cell and averaged from 50 to 70 nucleotides.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1975-10", "series_number": "4", "volume": "16", "issue": "4", "pages": "1081-1084" }, { "id": "authors:7knxv-t3054", "collection": "authors", "collection_id": "7knxv-t3054", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:VILpnas75", "type": "article", "title": "Complete translation of poliovirus RNA in a eukaryotic cell-free system", "author": [ { "family_name": "Villa-Komaroff", "given_name": "Lydia", "clpid": "Villa-Komaroff-Lydia" }, { "family_name": "Guttman", "given_name": "Naomi", "clpid": "Guttman-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" } ], "abstract": "Poliovirus RNA stimulates incorporation of 35S from both [35S]methionine and formyl-[35S]methionyl-tRNAf{}Met in cell-free systems derived from HeLa cells or from poliovirus-infected HeLa cells. The largest product formed under the direction of the viral RNA is the same size as the polyprotein thought to represent translation of the entire RNA. Synthesis of this polyprotein and other large products was stimulated greatly by increasing the salt concentration during the reaction from the optimum for initiation (90 mM) to the optimum for elongation (155 mM). Only one initiation peptide could be identified, and a tryptic digest of the product contained mainly peptides that cochromatographed with peptides from authentic viral proteins. The RNA from a deletion mutant of poliovirus initiated protein synthesis at the same site used by standard RNA and programmed synthesis of an appropriately deleted set of polypeptides. The results strongly support the model of translation of poliovirus RNA from a single initiation site into a continuous polyprotein that is cleaved to form the functional proteins. It is suggested that uninfected HeLa cell extracts can carry out the cleavages of nascent polyprotein.", "doi": "10.1073/pnas.72.10.4157", "pmcid": "PMC433159", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1975-10", "series_number": "10", "volume": "72", "issue": "10", "pages": "4157-4161" }, { "id": "authors:t1cd3-qbx62", "collection": "authors", "collection_id": "t1cd3-qbx62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120801-131306461", "type": "article", "title": "Quantitation of avian RNA tumor virus reverse transcriptase by radioimmunoassay", "author": [ { "family_name": "Panet", "given_name": "Amos", "clpid": "Panet-Amos" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Hanafusa", "given_name": "Teruko", "clpid": "Hanafusa-Teruko" } ], "abstract": "A radioimmunoassay was developed that can detect and quantitate 3 ng or more of the avian RNA tumor virus reverse transcriptase. The assay detected no antigenic sites in Rous sarcoma virus alpha virions or in virions of a murine RNA tumor virus. About 70 molecules of reverse transcriptase were found per virion of avian myleloblastosis virus with this assay or with an assay based on antibody inhibition of enzymatic activity. The assay detected about 270 ng of enzyme per mg of cell protein in virus-producing cells; uninfected cells had much less antigenic material but contained some determinants able to displace radioactive antigen. No additional antigenic determinants on reverse transcriptase could be detected that were not found on the separated alpha subunit of the enzyme. Although sevenfold less sensitive than enzymatic activity as a measure of reverse transcriptase, the radioimmunoassay can detect antigen using small amounts of protein and in the presence of inhibtors.", "pmcid": "PMC354643", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1975-07", "series_number": "1", "volume": "16", "issue": "1", "pages": "146-152" }, { "id": "authors:7zb1q-epb54", "collection": "authors", "collection_id": "7zb1q-epb54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:PANpnas75", "type": "article", "title": "Specific binding of tryptophan transfer RNA to avian myeloblastosis virus RNA-dependent DNA polymerase (reverse transcriptase)", "author": [ { "family_name": "Panet", "given_name": "Amos", "clpid": "Panet-Amos" }, { "family_name": "Haseltine", "given_name": "William A.", "clpid": "Haseltine-William-A" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Peters", "given_name": "Gordon", "clpid": "Peters-Gordon" }, { "family_name": "Harada", "given_name": "Fumio", "clpid": "Harada-Fumio" }, { "family_name": "Dahlberg", "given_name": "James E.", "clpid": "Dahlberg-James-E" } ], "abstract": "The ability of tryptophan tRNA (tRNATrp) to initiate reverse transcription of the 70S RNA of avian RNA tumor viruses suggested that the reverse transcriptase (RNA-dependent DNA polymerase; deoxynucleosidetriphosphate: DNA deoxynucleotidyltransferase; EC 2.7.7.7) might have a specific binding site for the tRNA. A complex of tRNATrp and the avian myeloblastosis virus reverse transcriptase has been demonstrated using chromatography on Sephadex G-100 columns. Of all the chicken tRNA's, only tRNATrp and a tRNA4{}Met bind to the enzyme with high enough affinity to be selected from a mixture of the chicken cell tRNAs. The ability of tRNATrp to change the sedimentation rate of the enzyme indicates that tRNATrp is not binding to a contaminant in the enzyme preparation. Treatment of the enzyme with monospecific antibody to reverse transcriptase prevented binding of tRNA as well as inhibited the DNA polymerase activity of the enzyme. The ability of reverse transcriptase to utilize tRNATrp as a primer for DNA synthesis, therefore, appears to involve a highly specific site on the enzyme.", "doi": "10.1073/pnas.72.7.2535", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1975-07", "series_number": "7", "volume": "72", "issue": "7", "pages": "2535-2539" }, { "id": "authors:e9xh4-nds72", "collection": "authors", "collection_id": "e9xh4-nds72", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SPEjvir75a", "type": "article", "title": "Polyadenylic acid on poliovirus RNA. II. poly(A) on intracellular RNAs", "author": [ { "family_name": "Spector", "given_name": "Deborah H.", "clpid": "Spector-Deborah-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The content, size, and mechanism of synthesis of 3'-terminal poly(A) on the various intracellular species of poliovirus RNA have been examined. All viral RNA species bound to poly(U) filters and contained RNase-resistant stretches of poly(A) which could be analyzed by electrophoresis in polyacrylamide gels. At 3 h after infection, the poly(A) on virion RNA, relicative intermediate RNA, polyribosomal RNA, and total cytoplasmic 35S RNA was heterogeneous in size with an average length of 75 nucleotides. By 6 h after infection many of the intracellular RNA's had poly(A) of over 150 nucleotides in length, but the poly(A) in virion RNA did not increase in size suggesting that the amount of poly(A) which can be encapsidated is limited. At all times, the double-stranded poliovirus RNA molecules had poly(A) of 150 to 200 nucleotides. Investigation of the kinetics of poly(A) appearance in the replicative intermediate and in finished 35S molecules indicated that poly(A) is the last portion of the 35S RNA to be synthesized; no nascent poly(A) could be detected in the replicative intermediate. Although this result indicates that poliovirus RNA is synthesized 5' leads to 3' like other RNA's, it also suggests that much of the poly(A) found in the replicative intermediate is an artifact possibly arising from the binding of finished 35S RNA molecules to the replicative intermediate during extraction. The addition of poly(A) to 35S RNA molecules was not sensitive to guanidene.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1975-06", "series_number": "6", "volume": "15", "issue": "6", "pages": "1418-1431" }, { "id": "authors:nfk36-vn187", "collection": "authors", "collection_id": "nfk36-vn187", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SPEjvir75b", "type": "article", "title": "Polyadenylic acid on poliovirus RNA. III. In vitro addition of polyadenylic acid to poliovirus RNAs", "author": [ { "family_name": "Spector", "given_name": "Deborah H.", "clpid": "Spector-Deborah-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A crude RNA polymerase preparation was made from HeLa cells infected for 3 h with poliovirus. All virus-specific RNA species labeled in vitro (35S RNA, replicative intermediate RNA [RI], and double-stranded RNA [dsRNA]) would bind to poly(U) filters and contained RNase-resistant stretches of poly(A) which could be analyzed by electrophoresis in polyacrylamide gels. After incubation for 45 min with [3-H]ATP in the presence of the other three nucleoside triphosphates, the labeled poly(A) on the RI and dsRNA migrated on gels as relatively homogenous peaks approximately 200 nucleotides in length. In contrast, the poly(A) from the 35S RNA had a heterogeneous size distribution ranging from 50 to 250 nucleotides. In the absence of UTP, CTP, and GTP, the size of the newly labeled poly(A) on the dsRNA and RI RNA was the same as it was in the presence of all four nucleoside triphosphates. However the poly(A) on the 35S RNA lacked the larger sequences seen when the other three nucleoside triphosphates were present. When [3-H]ATP was used as the label in infected and uninfected extracts, heterogeneous single-stranded RNA sedimenting at less than 28S was also labeled. This heterogeneous RNA probably represents HeLa cytoplasmic RNA to which small lengths of poly(A) (approximately 15 nucleotides) had been added. These results indicate that in the in vitro system poly(A) can be added to both newly synthesized and preexisting RNA molecules. Furthermore, an enzyme capable of terminal addition of poly(A) exists in both infected and uninfected extracts.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1975-06", "series_number": "6", "volume": "15", "issue": "6", "pages": "1432-1439" }, { "id": "authors:4kvhd-75q37", "collection": "authors", "collection_id": "4kvhd-75q37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:BERpnas75", "type": "article", "title": "Summary statement of the Asilomar conference on recombinant DNA molecules", "author": [ { "family_name": "Berg", "given_name": "Paul", "clpid": "Berg-Paul" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Brenner", "given_name": "Sydney", "clpid": "Brenner-Sydney" }, { "family_name": "Roblin", "given_name": "Richard O., III", "clpid": "Roblin-Richard-O-III" }, { "family_name": "Singer", "given_name": "Maxine F.", "clpid": "Singer-Maxine-F" } ], "abstract": "This meeting was organized to review scientific progress in research on recombinant DNA molecules and to discuss appropriate ways to deal with the potential biohazards of this work. Impressive scientific achievements have already been made in this field and these techniques have a remarkable potential for furthering our understanding of fundamental biochemical processes in pro- and eukaryotic cells. The use of recombinant DNA methodology promises to revolutionize the practice of molecular biology. Although there has as yet been no practical application of the new techniques, there is every reason to believe that they will have significant practical utility in the future.", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1975-06", "series_number": "6", "volume": "72", "issue": "6", "pages": "1981-1984" }, { "id": "authors:yhqeb-dhw40", "collection": "authors", "collection_id": "yhqeb-dhw40", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:ROSpnas75", "type": "article", "title": "In vitro transformation of lymphoid cells by Abelson murine leukemia virus", "author": [ { "family_name": "Rosenberg", "given_name": "Naomi", "clpid": "Rosenberg-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Scher", "given_name": "Charles D.", "clpid": "Scher-Charles-D" } ], "abstract": "Cell cultures prepared from fetal murine liver were infected by Abelson murine leukemia virus. After about 2 weeks, proliferating cells of lymphoid morphology appeared in some of the cultures. Addition of 2-mercaptoethanol to the initial culture medium greatly enhanced the appearance of the lymphoid cells. Immunoglobulin determinants were evident on the cells in some cultures. Continuous passage of the cells in certain cultures was possible and the passaged cells could form tumors after animal inoculation. Because Abelson murine leukemia virus is able to induce in vitro malignant transformation of lymphoid cells, it probably causes leukemia by directly affecting cellular growth control.", "doi": "10.1073/pnas.72.5.1932", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1975-05", "series_number": "5", "volume": "72", "issue": "5", "pages": "1932-1936" }, { "id": "authors:z9y7g-y4m15", "collection": "authors", "collection_id": "z9y7g-y4m15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:KUNjem75", "type": "article", "title": "Murine terminal deoxynucleotidyl transferase: cellular distribution and response to cortisone", "author": [ { "family_name": "Kung", "given_name": "Patrick C.", "clpid": "Kung-Patrick-C" }, { "family_name": "Silverstone", "given_name": "Allen E.", "clpid": "Silverstone-Allen-E" }, { "family_name": "McCaffrey", "given_name": "Ronald P.", "clpid": "McCaffrey-Ronald-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The mouse thymus contains two forms of terminal deoxynucleotidyl transferase (TdT) which are distinguishable by the salt concentration necessary to elute them from a phosphocellulose column, by their distrubtion among the thymocyte subpopulations, and by their sensitivity to cortisone treatment. In the whole thymus the later eluting peak (peak II) is the predominant one with about 3-10% of the total activity appearing in peak I. Both peak I and peak II activities are most sensitively assayed by the polymerization of dGMP onto an oligo(dA) primer. The minor population of thymocytes which is less dense and cortisone-resistant contains a higher specific activity of peak I TdT. The majority of TdT activity is, however, found in the major population of thymocytes which occurs in the center region of a bovine serum albumin gradient and is cortisone-sensitive. A very low level of an activity indistinguishable from peak II TdT activity is also detected in the mouse bone marrow. Other tissues, such as spleen, liver, heart, and brain lack detectable amounts of TdT activity.", "doi": "10.1084/jem.141.4.855", "pmcid": "PMC2189756", "issn": "0022-1007", "publisher": "Rockefeller University Press", "publication": "Journal of Experimental Medicine", "publication_date": "1975-04", "series_number": "4", "volume": "141", "issue": "4", "pages": "855-865" }, { "id": "authors:cvgeq-dmw35", "collection": "authors", "collection_id": "cvgeq-dmw35", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:RETjvir75", "type": "article", "title": "Screening procedure for complementation-dependent mutants of vesicular stomatitis virus", "author": [ { "family_name": "Rettenmier", "given_name": "Carl W.", "clpid": "Rettenmier-Carl-W" }, { "family_name": "Dumont", "given_name": "Raymonde", "clpid": "Dumont-Raymonde" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "To isolate new types of vesicular stomatitis virus (VSV) mutants, a four-stage screen was developed which identifies and characterizes mutants capable of complementing the defect in the VSV temperature-sensitive mutant tsG11. Two types of mutants of VSV, Indiana serotype, have been found by using the screen; they are new temperature-sensitive mutants which are, of necessity, not in complementation group I and mutants which do not produce plaques under conditions of single infection at 31 C (the normal permissive temperature) and are, therefore, called complementation-dependent mutants. The newly isolated, temperature-sensitive mutants fall into three complementation groups, two of which are congruent with known complementation groups; the newly identified group extends to six the number of complementation groups of VSV Indiana. The nature of the complementation-dependent mutants has not been established, but one was shown to not contain a significant deletion in its nucleic acid.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1975-01", "series_number": "1", "volume": "15", "issue": "1", "pages": "41-49" }, { "id": "authors:ewbd6-yjy93", "collection": "authors", "collection_id": "ewbd6-yjy93", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:SPEpnas74", "type": "article", "title": "Requirement of 3'-terminal poly(adenylic acid) for the infectivity of poliovirus RNA", "author": [ { "family_name": "Spector", "given_name": "Deborah H.", "clpid": "Spector-Deborah-H" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Ribonuclease H (EC 3.1.4.34) has been used to remove selectively much of the 3'-terminal poly(adenylic acid) [poly(A)] from poliovirus RNA by treating the RNA with the enzyme in the presence of poly(dT). Over 80% of the poly(A) could be removed and the residuum was found as oligo(A) stretches attached to many or all of the viral RNA molecules. Reduction of the size of the poly(A) markedly decreased the specific infectivity of poliovirus RNA, indicating that poly(A) is necessary to the infectivity of the RNA. The virions in plaques deriving from infection with treated RNA have a normal amount and size of poly(A), indicating that mechanisms exist in infected cells to regenerate normal length poly(A) from truncated poly(A).", "doi": "10.1073/pnas.71.8.2983", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1974-08", "series_number": "8", "volume": "71", "issue": "8", "pages": "2983-2987" }, { "id": "authors:kjzry-1dx81", "collection": "authors", "collection_id": "kjzry-1dx81", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MARpnas74", "type": "article", "title": "Nucleotide sequences of human globin messenger RNA", "author": [ { "family_name": "Marotta", "given_name": "Charles A.", "clpid": "Marotta-Charles-A" }, { "family_name": "Forget", "given_name": "Bernard G.", "clpid": "Forget-Bernard-G" }, { "family_name": "Weissman", "given_name": "Sherman M.", "clpid": "Weissman-Sherman-M" }, { "family_name": "Verma", "given_name": "Inder M.", "clpid": "Verma-Inder-M" }, { "family_name": "McCaffrey", "given_name": "Ronald P.", "clpid": "McCaffrey-Ronald-P" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Globin messenger RNA, isolated from human peripheral blood reticulocytes, was transcribed into complementary DNA by use of the RNA-dependent DNA polymerase of avian myeloblastosis virus. The complementary DNA was then transcribed into 32P-labeled complementary RNA by E. coli RNA polymerase in the presence of \u03b1-32P-labeled ribonucleoside triphosphates. The fingerprint pattern obtained from ribonuclease T1 digests of human globin complementary RNA was specific and reproducible. Different patterns were obtained from digests of duck, mouse, and rabbit globin complementary RNA. The fingerprint patterns obtained from digests of purified natural human 10S globin messenger RNA, labeled in vitro with 125I or with [\u03b3-32P]ATP and polynucleotide kinase, were similar to that of the complementary RNA but contained some additional oligonucleotides. Sufficient nucleotide sequence information has been obtained from about 50% of the intermediate sized oligonucleotides (8-14 base residues long), to make possible examination of correspondence between these nucleotide sequences and globin amino-acid sequences. Approximately 70% of these oligonucleotide sequences can be matched to unique amino-acid sequences in the \u03b1- or \u00df -globin chains. The other 30% do not match known amino-acid sequences and presumably correspond to untranslated portions of the mRNA; some of these sequences, however, can be matched to amino-acid sequences in the abnormally long segment of the chain of hemoglobin Constant Spring, which is thought to result from a chain-termination mutation.", "doi": "10.1073/pnas.71.6.2300", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1974-06", "series_number": "6", "volume": "71", "issue": "6", "pages": "2300-2304" }, { "id": "authors:dshgb-bqe54", "collection": "authors", "collection_id": "dshgb-bqe54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:VERjvir74", "type": "article", "title": "Hamster leukemia virus: lack of endogenous DNA synthesis and unique structure of its DNA polymerase", "author": [ { "family_name": "Verma", "given_name": "Inder M.", "clpid": "Verma-Inder-M" }, { "family_name": "Meuth", "given_name": "Nora L.", "clpid": "Meuth-Nora-L" }, { "family_name": "Fan", "given_name": "Hung", "clpid": "Fan-Hung" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Infectious hamster leukemia virus (HaLV) contains a DNA polymerase different from those of murine and avian viruses. No endogenous reaction directed by the 60 to 70S RNA of HaLV could be demonstrated in detergenttreated HaLV virions, nor could the purified DNA polymerase copy added viral RNA. The virion RNA could, however, act as template for added avian myeloblastosis virus DNA polymerase and the HaLV DNA polymerase could efficiently utilize homopolymers as templates. The HaLV enzyme was like other reverse transcriptases in that certain ribohomopolymers were much better templates than the homologous deoxyribohomopolymers. No ribonuclease H activity could be shown in the HaLV enzyme, but neither could activity be found in the murine leukemia virus DNA polymerase. The hamster enzyme was unique in that poly(A) \u00b7oligo(dT) was a poor template, and globin mRNA primed with oligo(dT) was totally inactive as a template. Its uniqueness was also indicated by its subunit composition; electrophoresis of the HaLV DNA polymerase in sodium dodecyl sulfate-containing polyacrylamide gels revealed equimolar amounts of two polypeptides of molecular weight 68,000 and 53,000. The sedimentation rate of the enzyme in glycerol gradients was consistent with a structure containing one each of the two polypeptides. The enzyme thus appears to be structurally distinct from other known virion DNA polymerases. Its inability to carry out an endogenous reaction in vitro might result from an inability to utilize certain primers.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1974-05", "series_number": "5", "volume": "13", "issue": "5", "pages": "1075-1082" }, { "id": "authors:6c2ct-fy333", "collection": "authors", "collection_id": "6c2ct-fy333", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MORjvir74", "type": "article", "title": "Translation of vesicular stomatitis messenger RNA by extracts from mammalian and plant cells", "author": [ { "family_name": "Morrison", "given_name": "Trudy", "clpid": "Morrison-Trudy" }, { "family_name": "Stampfer", "given_name": "Martha", "clpid": "Stampfer-Martha" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Lodish", "given_name": "Harvey F.", "clpid": "Lodish-Harvey-F" } ], "abstract": "RNA was isolated from polyribosomes of vesicular stomatitis virus (VSV)-infected cells and tested for its ability to direct protein synthesis in extracts of animal and plant cells. In cell-free, non-preincubated extracts of rabbit reticulocytes, the 28S VSV RNA stimulated synthesis of a protein the size of the vesicular stomatitis virus L protein whereas the 13 to 15S RNA directed synthesis of the VSV M, N, NS, and possibly G proteins. In wheat germ extracts, 13 to 15S RNA also directed synthesis of the N, NS, M, and possibly G proteins. Analysis of extracts labeled with formyl [35S]methionine showed that the 28S RNA directed the initiation of synthesis of one protein, whereas the 13 to 15S RNA directed initiation of at least four proteins. It is concluded that the 28S RNA encodes only the L protein, whereas the 13 to 15S RNA is a mixture of species, presumably monocistronic, which code for the four other known vesicular stomatitis virus proteins.", "doi": "10.1128/jvi.13.1.62-72.1974", "pmcid": "PMC355259", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1974-01", "series_number": "1", "volume": "13", "issue": "1", "pages": "62-72" }, { "id": "authors:vk0t4-d7f10", "collection": "authors", "collection_id": "vk0t4-d7f10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120725-095758840", "type": "article", "title": "Defective Interfering Particles of Poliovirus. IV. Mechanisms of Enrichment", "author": [ { "family_name": "Cole", "given_name": "Charles N.", "clpid": "Cole-Charles-N" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Infection of HeLa cells by mixtures of standard poliovirus and defective, interfering (DI) poliovirus particles leads to a higher ratio of DI particles in the progeny than in the inoculum. The extent of this enrichment could be varied by various manipulations of the co-infected cells. At any time during the infection cycle, virions made within short times after addition of radioactive uridine were hyperenriched in DI particles; this transient hyperenrichment fell to the equilibrium enrichment level within 45 min after uridine addition. A shift of the temperature of infection from 37 to 31 C also led to a hyperenrichment of DI particles and pulse-labeling revealed a superimposed transient hyperenrichment. By contrast, cells continuously infected at 31 C showed a severe decrement in DI particles apparently because poliovirus DI particles behave as cold-sensitive mutants for RNA synthesis. Cycloheximide treatment early in the infection cycle also led to hyperenrichment. Study of the cycloheximide effect showed that the drug acted as if to change the input ratio of standard to DI particles. These effects on enrichment can be explained as aspects of two different phenomena: enrichment due to preferential DI RNA synthesis and enrichment due to preferential encapsidation of DI RNA. Both mechanisms probably play a role in the normal level of enrichment.", "pmcid": "PMC356783", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1973-12", "series_number": "6", "volume": "12", "issue": "6", "pages": "1414-1426" }, { "id": "authors:139t2-d5143", "collection": "authors", "collection_id": "139t2-d5143", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120726-100027537", "type": "article", "title": "Morphogenesis of Poliovirus II. Demonstration of a New Intermediate, the Proviron", "author": [ { "family_name": "Fernandez-Tomas", "given_name": "Carlos B.", "clpid": "Fernandez-Tomas-C-B" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Poliovirus-infected cells contain a previously unrecognized particle which appears to be an intermediate in virion synthesis and therefore has been named proviron. It sediments at about 125S, contains the three procapsid proteins, VP-0, VP-1, and VP-3, and has 35S viral RNA. It is disrupted both by sodium dodecyl sulfate and EDTA but the RNA resists digestion by ribonuclease. Pulsechase experiments and studies employing the virus-specific inhibitor, guanidine, all indicate that the proviron is formed by combination of newly made RNA with the procapsid. Cleavage of VP-0 to form VP-2 and VP-4 follows formation of the provirion and would be the final step in poliovirus morphogenesis.", "pmcid": "PMC356744", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1973-11", "series_number": "5", "volume": "12", "issue": "5", "pages": "1122-1130" }, { "id": "authors:rkdzq-qte06", "collection": "authors", "collection_id": "rkdzq-qte06", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:FERjvir73a", "type": "article", "title": "Morphogenesis of poliovirus III. Formation of provirion in cell-free extracts", "author": [ { "family_name": "Fernandez-Tomas", "given_name": "Carlos B.", "clpid": "Fernandez-Tomas-C-B" }, { "family_name": "Guttman", "given_name": "Naomi", "clpid": "Guttman-Naomi" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Formation of an apparent virion precursor, the provirion, can be demonstrated in cytoplasmic extracts of poliovirus-infected HeLa cells.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1973-11", "series_number": "5", "volume": "12", "issue": "5", "pages": "1181-1183" }, { "id": "authors:abazd-fha10", "collection": "authors", "collection_id": "abazd-fha10", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HUAjvir73", "type": "article", "title": "Growth of Pseudotypes of Vesicular Stomatitis Virus with N-Tropic Murine Leukemia Virus Coats in Cells Resistant to N-Tropic Viruses", "author": [ { "family_name": "Huang", "given_name": "Alice S.", "clpid": "Huang-Alice-S" }, { "family_name": "Besmer", "given_name": "Peter", "clpid": "Besmer-Peter" }, { "family_name": "Chu", "given_name": "Louise", "clpid": "Chu-Louise" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Formation of pseudotypes between murine RNA tumor viruses and vesicular stomatitis virus (VSV) has been confirmed. Pseudotypes of VSV genomes coated by the surface envelope from an N-tropic tumor virus grew equally well in cells homozygous for either the Fv-1n or Fv-1b alleles. Therefore, the product of the Fv-1 locus, which restricts growth of murine RNA tumor viruses, must act on an intracellular aspect of tumor virus replication, a step after attachment and penetration.", "doi": "10.1128/jvi.12.3.659-662.1973", "pmcid": "PMC356675", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1973-09", "series_number": "3", "volume": "12", "issue": "3", "pages": "659-662" }, { "id": "authors:xd2ww-g5c08", "collection": "authors", "collection_id": "xd2ww-g5c08", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120807-161758173", "type": "article", "title": "Identification of the Vesicular Stomatitis Virus Large Protein as a Unique Viral Protein", "author": [ { "family_name": "Stampfer", "given_name": "Martha", "clpid": "Stampfer-Martha" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Previous studies have noted the existence of a 190,000-daltoin vesicular stomatitis virus (VSV) protein called the large (L) protein. To determine whether this protein is a nonspecific aggregate, a precursor to the other VSV proteins, or a unique viral protein, its synthesis relative to the other VSV proteins was studied under conditions of inhibition of initiation of protein synthesis. Also, its tryptic peptides were compared to those of the other VSV proteins. In both cases the results were consistent with the identification of the large protein as a unique viral protein.", "pmcid": "PMC355133", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1973-04", "series_number": "4", "volume": "11", "issue": "4", "pages": "520-526" }, { "id": "authors:9j7eh-mbc33", "collection": "authors", "collection_id": "9j7eh-mbc33", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MCCpnas73", "type": "article", "title": "Terminal Deoxynucleotidyl Transferase in a Case of Childhood Acute Lymphoblastic Leukemia", "author": [ { "family_name": "McCaffrey", "given_name": "Ronald", "clpid": "McCaffrey-Ronald-P" }, { "family_name": "Smoler", "given_name": "Donna F.", "clpid": "Smoler-Donna-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Cells from a patient with childhood acute lymphoblastic leukemia contain an apparent DNA polymerase activity that was not found in any other cells except thymus cells. The enzyme has the properties of terminal transferase, an enzyme known to be found in thymocytes. The cells also contain the three major DNA polymerases found in growing cells. The results suggest that these tumor cells arose from a block in the differentiation of thymocytes. Terminal transferase may be a marker for the origin of leukemic cells.", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1973-02", "series_number": "2", "volume": "70", "issue": "2", "pages": "521-525" }, { "id": "authors:h32mk-w5q29", "collection": "authors", "collection_id": "h32mk-w5q29", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120724-145350321", "type": "article", "title": "Association of an Endorihonuclease with the Avian Myelohlastosis Virus Deoxyribonucleic Acid Polymerase", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Smoler", "given_name": "Donna F.", "clpid": "Smoler-Donna-F" } ], "abstract": "A ribonuclease degrading only RNA complexed to DNA is found associated with the avian myeloblastosis virus DNA polymerase. A convenient and sensitive assay for the enzyme is degradation of [^3H]poly(A) complexed to poly(dT). Using this assay, nuclease and DNA polymerase activities are inseparable by DEAE-Sephadex or phosphocellulose ion exchange chromatography or by glycerol gradient centrifugation. Poly(A) labeled selectively at each end can be used to demonstrate that the nuclease is an endonuclease, and chromatography of the digestion products of poly(A) confirms this result. The oligonucleotide digestion products can be further digested to 5'-AMP by venom phosphodiesterase, indicating that they are terminated by 3'-OH groups", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1972-11-25", "series_number": "22", "volume": "247", "issue": "22", "pages": "7282-7287" }, { "id": "authors:9ryzy-09p77", "collection": "authors", "collection_id": "9ryzy-09p77", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:VERjvir72", "type": "article", "title": "Covalent Linkage Between Ribonucleic Acid Primer and Deoxyribonucleic Acid Product of the Avian Myeloblastosis Virus Deoxyribonucleic Acid Polymerase", "author": [ { "family_name": "Verma", "given_name": "Inder M.", "clpid": "Verma-Inder-M" }, { "family_name": "Meuth", "given_name": "Nora L.", "clpid": "Meuth-Nora-L" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Initiation of deoxyribonucleic acid (DNA) synthesis by the avian myeloblastosis virus DNA polymerase was previously suggested to involve a ribonucleic acid (RNA) primer, the initial product being a DNA molecule joined by a phosphodiester bond to the RNA primer. The existence and nature of such an RNA-DNA joint was investigated by assaying for transfer of a 32P atom from an {alpha}-32P-deoxyribonucleotide to a 2'(3')-ribonucleotide after alkaline hydrolysis of the polymerase product. Such a transfer was observed, but only from {alpha}-32P-deoxyadenosine triphosphate and only to 2'(3')-adenosine monophosphate. This same transfer was observed in both the endogenous DNA polymerase reaction of purified virions and the reconstructed reaction of purified DNA polymerase plus purified 60 to 70S viral RNA. These results indicate a high level of specificity for the initiation process and support the idea of a low-molecular-weight initiator RNA as part of the 60 to 70S RNA complex.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1972-10", "series_number": "4", "volume": "10", "issue": "4", "pages": "622-627" }, { "id": "authors:1nytr-ars08", "collection": "authors", "collection_id": "1nytr-ars08", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120814-122451361", "type": "article", "title": "Direction of Polymerization by the Avian Myeloblastosis Virus Deoxyribonucleic Acid Polymerase", "author": [ { "family_name": "Smoler", "given_name": "Donna", "clpid": "Smoler-Donna-F" }, { "family_name": "Molineux", "given_name": "Ian", "clpid": "Molineux-Ian" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "An oligonucleotide primer is necessary to initiate polymerization of nucleotides by the DNA polymerase of avian myeloblastosis virus. The role of the primer was investigated by synthesizing the acid-soluble oligonucleotide [5'-^(32)P](dT)_(10). Conversion of this primer to an acid-insoluble form by the DNA polymerase in the presence of poly(A) indicated that the primer was physically incorporated into the product. The phosphate residue at the 5'-terminus of the primer remained sensitive to alkaline phosphatase, and synthesis therefore appeared to proceed by addition of mononucleotides at the 3'-OH of the primer.\n\nInhibition of DNA polymerase activity by dideoxythymidine triphosphate was observed using templates containing AMP or when the enzyme was copying the viral RNA found in the virion. Copying of poly(C) by the DNA polymerase was not sensitive to the analogue. These results corroborate the conclusion that the polymerase adds nucleotides to the 3'-OH of a primer and further indicate that copying of the endogenous viral RNA involves only polymerization on 3'-OH groups.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1971-12-25", "series_number": "24", "volume": "246", "issue": "24", "pages": "7697-7700" }, { "id": "authors:yx6tw-gb984", "collection": "authors", "collection_id": "yx6tw-gb984", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:TABjvir71", "type": "article", "title": "Effect of Pactamycin on Synthesis of Poliovirus Proteins: a Method for Genetic Mapping", "author": [ { "family_name": "Taber", "given_name": "Robert", "clpid": "Taber-Robert" }, { "family_name": "Rekosh", "given_name": "David", "clpid": "Rekosh-David" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "We have studied the effect of the drug pactamycin on protein synthesis in poliovirus-infected HeLa cells. At a concentration which primarily inhibits initiation of protein synthesis, the spectrum of poliovirus proteins synthesized is markedly changed. The amount of NCVP 1, the capsid precursor, is greatly reduced relative to NCVP 2 and the amount of NCVP X is slightly reduced. Since it is believed that there is only one major site for the initiation of protein synthesis on the poliovirus genome, we interpret this differential effect on the poliovirus proteins to be an indication of their relative distance from the initiation site. On this basis, we propose a gene order for the poliovirus genome (5' -> 3') of NCVP 1, NCVP X, NCVP 2.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1971-10", "series_number": "4", "volume": "8", "issue": "4", "pages": "395-401" }, { "id": "authors:cc0m2-8bn34", "collection": "authors", "collection_id": "cc0m2-8bn34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120725-094436127", "type": "article", "title": "Expression of Animal Virus Genomes", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The world of animal viruses appears to offer\nan unfathomable diversity of specimens but, as\nthe molecular biology of the replication of many\nviruses has been studied, a pattern of behavior\nhas emerged. The viruses can be divided into\nclasses, each of which has its own method of\ntransmitting its genetic information from one\ngeneration to the next and its own style of expressing\nits genetic information. Although in\nsome cases the data are still fragmentary it is\npossible to outline the behavior of these systems\nand to place them in a formal scheme. In this\npaper I will present such a scheme and I will\ndiscuss in some detail the behavior of three viral\nsystems which have been investigated in my\nlaboratory. Furthermore, I will discuss some of\nthe implications of the existence of these viral\nsystems in the context of the behavior of normal\ncells.", "pmcid": "PMC378387", "issn": "0005-3678", "publisher": "American Society for Microbiology", "publication": "Bacteriological Reviews", "publication_date": "1971-09", "series_number": "3", "volume": "35", "issue": "3", "pages": "235-241" }, { "id": "authors:8zr10-dkd46", "collection": "authors", "collection_id": "8zr10-dkd46", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120724-132033639", "type": "article", "title": "Primer Requirement and Template Specificity of the DNA Polymerase of RNA Tumor Viruses", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Smoler", "given_name": "Donna", "clpid": "Smoler-Donna-F" } ], "abstract": "Polyribonucleotides will act as efficient templates for the DNA polymerases found in the virions of avian myeloblastosis virus and mouse leukemia virus if a short complementary oligodeoxyribonucleotide primer is added. Synthesis of the complementary polydeoxyribonucleotide continues until an amount of polymer equal to the amount of initial template has been produced. The two viruses show slightly different specificities toward the four homoribopolymers. Polydeoxyribonucleotides are generally much poorer templates than the homologous polyribonucleotides, in most cases yielding no detectable synthesis. The DNA polymerase of RNA tumor viruses, therefore, have the same requirements for activity as do other DNA polymerases, except that they prefer polyribonucleotides over polydeoxyribonucleotides as templates.", "doi": "10.1073/pnas.68.7.1507", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1971-07", "series_number": "7", "volume": "68", "issue": "7", "pages": "1507-1511" }, { "id": "authors:vtg3n-h2428", "collection": "authors", "collection_id": "vtg3n-h2428", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120726-114113130", "type": "article", "title": "Defective Interfering Particles of Poliovirus I. Isolation and Physical Properties", "author": [ { "family_name": "Cole", "given_name": "Charles N.", "clpid": "Cole-Charles-N" }, { "family_name": "Smoler", "given_name": "Donna", "clpid": "Smoler-Donna-F" }, { "family_name": "Wimmer", "given_name": "Eckard", "clpid": "Wimmer-Eckard" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "A class of defective interfering (DI) poliovirus particles has been identified. The first was found as a contaminant of a viral stock; others have been isolated by serial passage at a high multiplicity of infection. The DI particles are less dense than standard virus and sediment more slowly. Their ribonucleic acid (RNA) sediments more slowly than standard RNA and has a higher electrophoretic mobility. Competition hybridization experiments with double-stranded viral RNA indicate that DI RNA is 80 to 90% of the length of standard RNA. The proteins of DI particles are indistinguishable from those of standard poliovirus.", "pmcid": "PMC356147", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1971-04", "series_number": "4", "volume": "7", "issue": "4", "pages": "478-485" }, { "id": "authors:ht6a9-twn97", "collection": "authors", "collection_id": "ht6a9-twn97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120801-153855963", "type": "article", "title": "Absence of Interference During High-Multiplicity Infection by Clonally Purified Vesicular Stomatitis Virus", "author": [ { "family_name": "Stampfer", "given_name": "Martha", "clpid": "Stampfer-Martha" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Huang", "given_name": "Alice S.", "clpid": "Huang-Alice-S" } ], "abstract": "Stocks of vesicular stomatitis virus free of defective interfering particles were produced by serial clonal isolation. High-multiplicity infections with these stocks led to no interference or formation of defective interfering particles. Defective interfering particles were generated by three successive passages at high multiplicity.", "pmcid": "PMC356132", "issn": "0022-538X", "publisher": "American Society for Microbiology", "publication": "Journal of Virology", "publication_date": "1971-03", "series_number": "3", "volume": "7", "issue": "3", "pages": "409-411" }, { "id": "authors:x61cq-kha51", "collection": "authors", "collection_id": "x61cq-kha51", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:HUAjvir71", "type": "article", "title": "Ribonucleic Acud Polymerase in Virions of Newcastle Disease Virus: Comparison with the Vesicular Stomatitis Virus Polymerase", "author": [ { "family_name": "Huang", "given_name": "Alice S.", "clpid": "Huang-Alice-S" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Bratt", "given_name": "Michael A.", "clpid": "Bratt-Michael-A" } ], "abstract": "The virions of Newcastle disease virus (NDV) contained an enzyme that catalyzed the incorporation of ribonucleotides into ribonucleic acid (RNA). Optimal conditions for this polymerase activity were identical to the conditions for the vesicular stomatitis virus (VSV) polymerase, and both enzymes were active for longer times at 32 C than at 37 C. However, the specific activity of the NDV polymerase was less than 3% that of the VSV polymerase. Product RNA species from the NDV and VSV polymerase reactions annealed specifically to the homologous virion RNA species. Transcriptive intermediates containing product RNA attached to the respective virion RNA could be identified in both systems.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1971-03", "series_number": "3", "volume": "7", "issue": "3", "pages": "389-394" }, { "id": "authors:2e472-nm737", "collection": "authors", "collection_id": "2e472-nm737", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:MANjvir71", "type": "article", "title": "Forms of Deoxyribonucleic Acid Produced by Virions of the Ribonucleic Acid Tumor Viruses", "author": [ { "family_name": "Manly", "given_name": "Kenneth F.", "clpid": "Manly-Kenneth-F" }, { "family_name": "Smoler", "given_name": "Donna F.", "clpid": "Smoler-Donna-F" }, { "family_name": "Bromfeld", "given_name": "Esther", "clpid": "Bromfeld-Esther" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The in vitro product of mouse leukemia virus deoxyribonucleic acid (DNA) polymerase can be separated into two fractions by sedimentation in sucrose gradients. These two fractions were analyzed for their content of single-stranded DNA, double-stranded DNA, and DNA-ribonucleic acid (RNA) hybrid by (i) digestion with enzymes of known specificity and (ii) equilibrium centrifugation in Cs2SO4 gradients. The major fraction early in the reaction contained equal amounts of single-stranded DNA and DNA-RNA hybrid and little double-stranded DNA. The major fraction after extensive synthesis contained equal amounts of single-and double-stranded DNA and little hybrid. In the presence of actinomycin D, the predominant product was single-stranded DNA. To account for these various forms of DNA, we postulate the following model: the first DNA synthesis occurs in a replicative complex containing growing DNA molecules attached to an RNA molecule. Each DNA molecule is displaced as single-stranded DNA by the synthesis of the following DNA strand, and the single-stranded DNA is copied to form double-stranded DNA either before or after release of the single strand from the RNA. Actinomycin blocks this conversion of single-to double-stranded DNA.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1971-01", "series_number": "1", "volume": "7", "issue": "1", "pages": "106-111" }, { "id": "authors:rtn2w-wnk02", "collection": "authors", "collection_id": "rtn2w-wnk02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200514-160705278", "type": "article", "title": "Viral RNA-dependent DNA Polymerase: RNA-dependent DNA Polymerase in Virions of RNA Tumour Viruses", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Two independent groups of investigators have found evidence of an enzyme in virions of RNA tumour viruses which synthesizes DNA from an RNA template. This discovery, if upheld, will have important implications not only for carcinogenesis by RNA viruses but also for the general understanding of genetic transcription: apparently the classical process of information transfer from DNA to RNA can be inverted.", "doi": "10.1038/2261209a0", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "1970-06-27", "series_number": "5252", "volume": "226", "issue": "5252", "pages": "1209-1211" }, { "id": "authors:2401n-26v97", "collection": "authors", "collection_id": "2401n-26v97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120725-095630032", "type": "article", "title": "Ribonucleic Acid Synthesis of Vesicular Stomatitis Virus,\n II. An RNA Polymerase in the Virion", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Huang", "given_name": "Alice S.", "clpid": "Huang-Alice-S" }, { "family_name": "Stampfer", "given_name": "Martha", "clpid": "Stampfer-Martha" } ], "abstract": "The virions of vesicular stomatitis virus contain an enzyme that catalyzes the incorporation of ribonucleotides into RNA. The product of the reaction is mainly RNA complementary in base sequence to that of vesicular stomatitis virus RNA.", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1970-06", "series_number": "2", "volume": "66", "issue": "2", "pages": "572-576" }, { "id": "authors:1tmvj-szq89", "collection": "authors", "collection_id": "1tmvj-szq89", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:STAjvir69", "type": "article", "title": "Ribonucleic acid synthesis of vesicular stomatitis virus. I. Species of Ribonucleic Acid Found in Chinese Hamster Ovary Cells Infected with Plaque-forming and Defective Particles", "author": [ { "family_name": "Stampfer", "given_name": "Martha", "clpid": "Stampfer-Martha" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Huang", "given_name": "Alice S.", "clpid": "Huang-Alice-S" } ], "abstract": "Plaque-forming B particles of vesicular stomatitis virus (VSV) induce the synthesis of virus-specific ribonucleic acid (RNA) in Chinese hamster ovary cells, whereas defective T particles do not. Infection with low input multiplicities of B results in the formation of four species of RNA. During infection with high multiplicities, RNA synthesis begins with mainly these four species of RNA but gradually shifts to a new pattern of RNA synthesis involving five other species of RNA. The change can also be induced by superinfection with T at 2.5 hr after infection with a low multiplicity of B. T added at the same time as B prevents virtually all RNA synthesis. Synthesis of the first group of RNA species correlates with the formation of B particles, whereas synthesis of the second group correlates with the formation of T particles. The various species of RNA formed after infection with VSV particles include single-stranded RNA, a completely double-stranded RNA, and RNA with partially double-stranded regions. These observations begin to establish a molecular basis for understanding the ability of T particles to interfere with the growth of B particles.", "issn": "0022-538X", "publisher": "Journal of Virology", "publication": "Journal of Virology", "publication_date": "1969-08", "series_number": "2", "volume": "4", "issue": "2", "pages": "154-161" }, { "id": "authors:8jsa2-hnx09", "collection": "authors", "collection_id": "8jsa2-hnx09", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:JACpnas68", "type": "article", "title": "Polypeptide cleavages in the formation of poliovirus proteins", "author": [ { "family_name": "Jacobson", "given_name": "Michael F.", "clpid": "Jacobson-Michael-F" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "The final step in poliovirus morphogenesis appears to be the combination of viral RNA with a protein shell called the procapsid.(1) Concomitant with the union of the RNA and the procapsid there is a cleavage of one of the procapsid proteins, producing two of the four proteins of the virion. We have now found that cleavages play an important role in the formation of most if not all poliovirus-specific proteins. Although most mammalian messenger RNA's appear to be monocistronic, it seems possible that a cleavage mechanism may function in the synthesis of some mammalian cell proteins.", "doi": "10.1073/pnas.61.1.77", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1968-09", "series_number": "1", "volume": "61", "issue": "1", "pages": "77-84" }, { "id": "authors:j39kc-01t96", "collection": "authors", "collection_id": "j39kc-01t96", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GIRpnas66", "type": "article", "title": "The effect of HeLa cell cytoplasm on the rate of sedimentation of RNA", "author": [ { "family_name": "Girard", "given_name": "Marc", "clpid": "Girard-Marc" }, { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Ordinarily, sedimentation analysis of RNA preparations is carried out in simple aqueous solutions. Recently, numerous investigators have carried out experiments where RNA's in cytoplasmic extracts from various types of cells have been analyzed by sedimentation through gradients of sucrose. The implicit assumption has been made that the presence of the cytoplasmic extract does not in itself affect the rate of sedimentation of the RNA. However, we have recently found that some component of HeLa cell cytoplasmic extracts causes a 1.5-2-fold increase in the sedimentation rate of a number of species of RNA. Since this result bears on the interpretation of many types of experiments, we will report the phenomenon at this time, even though we know little about its mechanism.", "doi": "10.1073/pnas.56.3.999", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1966-09", "series_number": "3", "volume": "56", "issue": "3", "pages": "999-1002" }, { "id": "authors:nfkdw-swf26", "collection": "authors", "collection_id": "nfkdw-swf26", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120815-100133967", "type": "article", "title": "An Intermediate in the Synthesis of Poliovirus RNA", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Girard", "given_name": "Marc", "clpid": "Girard-Marc" } ], "abstract": "The pairwise complementarity of the nucleotide residues in nucleic acids provides a simple mechanism for the specification of the sequence of residues in a nucleic acid. A molecule with a given sequence will specify a molecule with a complementary sequence and, in turn, the complementary molecule can specify the sequence of the original one. In the case of single-stranded RNA viruses, it is thus likely that a strand of complementary RNA will be the intracellular template for the synthesis of viral RNA (the molecule which exists in mature particles). This argument is strengthened by the finding of double-stranded RNA in cells infected with single-stranded RNA viruses. The hypothesis that the complementary molecule of RNA, in a double-stranded RNA, is the template for viral RNA synthesis requires that there be a region of hydrogen bonding between the growing molecule of viral RNA and the complementary RNA. As the new chain of viral RNA elongates, either it displaces the viral strand of the double-stranded RNA or it is not hydrogen-bonded except in proximity to the growing point. In either case, the growing strand of viral RNA plus its template will form a complex which will be partially single- and partially double-stranded. Since more than one molecule of nascent viral RNA could be attached to one double-stranded molecule, such complexes might be fairly large and easily distinguishable from true double-stranded RNA by their content of single-stranded RNA.\nWe shall present evidence in this paper for the existence of such a complex of single- and double-stranded RNA in cells infected with poliovirus. It is similar to a structure first identified in bacteria infected with an RNA bacteriophage which was named the replicative intermediate (RI). We shall retain this nomenclature.", "doi": "10.1073/pnas.56.2.741", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1966-08-01", "series_number": "2", "volume": "56", "issue": "2", "pages": "741-748" }, { "id": "authors:6hap1-t3427", "collection": "authors", "collection_id": "6hap1-t3427", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120815-100006123", "type": "article", "title": "In vitro Synthesis of Viral RNA by the Poliovirus RNA Polymerase", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" } ], "abstract": "Infection of cultured mammalian cells by either Mengovirus or poliovirus causes the appearance of a new cytoplasmic RNA polymerase. The enzymes induced by the two viruses are quite similar. Both show a requirement for magnesium ions,\nare inhibited by manganese ions, require all four nucleoside triphosphates for maximal activity, and catalyze the incorporation of each of the nucleoside monophosphates\ninto RNA. The two polymerases are found in particulate cytoplasmic structures and neither is sensitive to actinomycin, a compound which inhibits all normal RNA synthesis. A new cytoplasmic, virus-specific polymerase activity was originally sought because autoradiographic experiments had shown viral RNA synthesis to be an actinomycin-insensitive, cytoplasmic process. Since the polymerase activity which was found appeared in the cytoplasm of infected cells with approximately the kinetics of viral RNA synthesis and was insensitive to actinomycin, it was presumed to mediate viral RNA synthesis in the cytoplasm without the involvement of DNA. The present communication describes experiments which demonstrate that the bulk of the product of the in vitro reaction is poliovirus RNA and that a small proportion is double-stranded RNA. Experiments on the structural localization\nof the polymerase within the cytoplasm are also presented, and the mechanism of the reaction is discussed.", "doi": "10.1073/pnas.51.3.450", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1964-03-01", "series_number": "3", "volume": "51", "issue": "3", "pages": "450-456" }, { "id": "authors:2srfa-e3009", "collection": "authors", "collection_id": "2srfa-e3009", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120815-094910937", "type": "article", "title": "A New Ribonucleic Acid Polymerase Appearing after\n Mengovirus Infection of L-Cells", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Franklin", "given_name": "Richard M.", "clpid": "Franklin-Richard-M" } ], "abstract": "The ribonucleic acid viruses represent an anomaly in the biological world, being its only known entities which lack deoxyri-bonucleic acid. Nevertheless, these viruses readily transmit genetic characters, they can be mutated by agents which affect DNA (1) , and their RNA is sufficient to determine their heritable characteristics (2). In the light of present knowledge of genetic mechanisms, especially as elucidated by the work of Jacob and Monod (3), it is generally believed that viral RNA can function as a type of messenger RNA and experimental support for this notion exists (4). This leaves open the question of how RNA can duplicate, since cellular messenger RNA does not appear to be directly replicated, but is a complementary copy of DNA. The work described here was undertaken in an attempt to clarify the mechanism of viral RNA duplication.", "issn": "0021-9258", "publisher": "American Society for Biochemistry and Molecular Biology", "publication": "Journal of Biological Chemistry", "publication_date": "1963-10-01", "series_number": "10", "volume": "238", "issue": "10", "pages": "3395-3400" }, { "id": "authors:vpnpz-30796", "collection": "authors", "collection_id": "vpnpz-30796", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120815-095821900", "type": "article", "title": "Poliovirus-Induced RNA Polymerase and the Effects of Virus-Specific Inhibitors on Its Production", "author": [ { "family_name": "Baltimore", "given_name": "David", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Eggers", "given_name": "Hans J.", "clpid": "Eggers-Hans-J" }, { "family_name": "Franklin", "given_name": "Richard M.", "clpid": "Franklin-Richard-M" }, { "family_name": "Tamm", "given_name": "Igor", "clpid": "Tamm-Igor" } ], "abstract": "In the last few years new experimental approaches have been found to the study of virus-specific biosynthesis in animal virus reproduction. This report describes recent results obtained in the study of the mechanism of action of two virus-specific inhibitors, and provides evidence which bears on the virus-specific nature of the virus-induced RNA polymerase.", "doi": "10.1073/pnas.49.6.843", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1963-06-01", "series_number": "6", "volume": "49", "issue": "6", "pages": "843-849" }, { "id": "authors:w0bbh-4tv38", "collection": "authors", "collection_id": "w0bbh-4tv38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120809-151252748", "type": "article", "title": "The Effect of Mengovirus Infection on the Activity of the DNA-Dependent RNA Polymerase of L-Cells", "author": [ { "family_name": "Baltimore", "given_name": "D.", "orcid": "0000-0001-8723-8190", "clpid": "Baltimore-D" }, { "family_name": "Franklin", "given_name": "R. M.", "clpid": "Franklin-Richard-M" } ], "abstract": "Mengovirus is a small RNA virus, approximately 27 m\u00b5 in diameter, containing\nonly RNA and protein, according to the analyses of Faulkner et al. on the closely\nrelated encephalomyocarditis (EMC) virus. It is a member of the Columbia SK\ngroup of viruses which we have been studying in detail in recent years.", "doi": "10.1073/pnas.48.8.1383", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "1962-08-01", "series_number": "8", "volume": "48", "issue": "8", "pages": "1383-1390" } ]