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Developmental arrest of T cells in RpL22-deficient mice is dependent upon multiple p53 effectors

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dc.contributor.author Stadanlick, Jason E.
dc.contributor.author Zhang, Zhiqiang
dc.contributor.author Lee, Sang-Yun
dc.contributor.author Hemann, Michael
dc.contributor.author Biery, Matthew
dc.contributor.author Carleton, Michael O.
dc.contributor.author Zambetti, Gerard P.
dc.contributor.author Anderson, Stephen J.
dc.contributor.author Oravecz, Tamas
dc.contributor.author Wiest, David L.
dc.date.accessioned 2012-10-05T18:16:50Z
dc.date.available 2012-10-05T18:16:50Z
dc.date.issued 2011-06
dc.identifier.issn 0022-1767
dc.identifier.issn 1550-6606
dc.identifier.uri http://hdl.handle.net/1721.1/73658
dc.description available in PMC 2012 July 15 en_US
dc.description.abstract alpha beta and gamma delta lineage T cells are thought to arise from a common CD4–CD8– progenitor in the thymus. However, the molecular pathways controlling fate selection and maturation of these two lineages remain poorly understood. We demonstrated recently that a ubiquitously expressed ribosomal protein, Rpl22, is selectively required for the development of alpha beta lineage T cells. Germline ablation of Rpl22 impairs development of alpha beta lineage, but not gamma delta lineage, T cells through activation of a p53-dependent checkpoint. In this study, we investigate the downstream effectors used by p53 to impair T cell development. We found that many p53 targets were induced in Rpl22−/− thymocytes, including miR-34a, PUMA, p21waf, Bax, and Noxa. Notably, the proapoptotic factor Bim, while not a direct p53 target, was also strongly induced in Rpl22−/− T cells. Gain-of-function analysis indicated that overexpression of miR-34a caused a developmental arrest reminiscent of that induced by p53 in Rpl22-deficient T cells; however, only a few p53 targets alleviated developmental arrest when individually ablated by gene targeting or knockdown. Co-elimination of PUMA and Bim resulted in a nearly complete restoration of development of Rpl22−/− thymocytes, indicating that p53-mediated arrest is enforced principally through effects on cell survival. Surprisingly, co-elimination of the primary p53 regulators of cell cycle arrest (p21waf) and apoptosis (PUMA) actually abrogated the partial rescue caused by loss of PUMA alone, suggesting that the G1 checkpoint protein p21[superscript waf] facilitates thymocyte development in some contexts. en_US
dc.description.sponsorship National Institutes of Health (U.S.) ( (NIH) Grant R01AI073920) en_US
dc.description.sponsorship National Institutes of Health (U.S.) (NIH Core Grant P01CA06927) en_US
dc.description.sponsorship National Institutes of Health (U.S.) ( (NIH) Grant R21CA141194) en_US
dc.description.sponsorship National Institutes of Health (U.S.) ( NIH Center Grant P30-DK-50306) en_US
dc.description.sponsorship Pennsylvania (appropriation) en_US
dc.description.sponsorship Fox Chase Cancer Center (NIH Postdoctoral Training Grant T32 CA00903534) en_US
dc.description.sponsorship Fox Chase Cancer Center (NIH Postdoctoral Training Grant F32 AI089077-01A1) en_US
dc.language.iso en_US
dc.publisher American Association of Immunologists en_US
dc.relation.isversionof http://dx.doi.org/10.4049/jimmunol.1100029 en_US
dc.rights Creative Commons Attribution-Noncommercial-Share Alike 3.0 en_US
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/ en_US
dc.source PMC en_US
dc.title Developmental arrest of T cells in RpL22-deficient mice is dependent upon multiple p53 effectors en_US
dc.type Article en_US
dc.identifier.citation Stadanlick, J. E. et al. “Developmental Arrest of T Cells in Rpl22-Deficient Mice Is Dependent Upon Multiple P53 Effectors.” The Journal of Immunology 187.2 (2011): 664–675. Web. en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biology en_US
dc.contributor.mitauthor Hemann, Michael
dc.relation.journal Journal of Immunology en_US
dc.identifier.mitlicense OPEN_ACCESS_POLICY en_US
dc.eprint.version Author's final manuscript en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Stadanlick, J. E.; Zhang, Z.; Lee, S.-Y.; Hemann, M.; Biery, M.; Carleton, M. O.; Zambetti, G. P.; Anderson, S. J.; Oravecz, T.; Wiest, D. L. en


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