title: Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors.
abstract: αβ and γδ 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 αβ lineage T cells. Germline ablation of Rpl22 impairs development of αβ lineage, but not γδ 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, p21(waf), 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 (p21(waf)) and apoptosis (PUMA) actually abrogated the partial rescue caused by loss of PUMA alone, suggesting that the G1 checkpoint protein p21(waf) facilitates thymocyte development in some contexts.
authors.affiliation: Immune Cell Development and Host Defense Program, Blood Cell Development and Cancer Keystone, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Stadanlick
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Lee
authors.forename: Mike
authors.initials: M
authors.lastname: Hemann
authors.forename: Matthew
authors.initials: M
authors.lastname: Biery
authors.forename: Michael O
authors.initials: MO
authors.lastname: Carleton
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Anderson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000172:deficiency; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018390:Gene Targeting / Q000379:methods; D006131:Growth Inhibitors / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000172:deficiency; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D006131:Growth Inhibitors; D008565:Membrane Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein