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1.
J Immunol ; 187(2): 664-75, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21690328

ABSTRACT

αß 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 αß lineage T cells. Germline ablation of Rpl22 impairs development of αß 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.


Subject(s)
Cell Differentiation/immunology , Gene Targeting , Growth Inhibitors/immunology , Ribosomal Proteins/deficiency , T-Lymphocyte Subsets/immunology , Tumor Suppressor Protein p53/physiology , Animals , Apoptosis/genetics , Apoptosis/immunology , Apoptosis Regulatory Proteins/biosynthesis , Apoptosis Regulatory Proteins/deficiency , Bcl-2-Like Protein 11 , Cell Differentiation/genetics , Cell Line , Cell Lineage/genetics , Cell Lineage/immunology , Down-Regulation/genetics , Down-Regulation/immunology , Gene Targeting/methods , Growth Inhibitors/genetics , Membrane Proteins/biosynthesis , Membrane Proteins/deficiency , Mice , Mice, Knockout , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/deficiency , Ribosomal Proteins/biosynthesis , Ribosomal Proteins/genetics , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Thymus Gland/immunology , Thymus Gland/metabolism , Thymus Gland/pathology , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/deficiency , bcl-2-Associated X Protein/biosynthesis
2.
Mol Cell Biol ; 23(21): 7909-19, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14560033

ABSTRACT

Maturation of Trypanosoma brucei mitochondrial mRNA involves massive posttranscriptional insertion and deletion of uridine residues. This RNA editing utilizes an enzymatic complex with seven major proteins, band I through band VII. We here use RNA interference (RNAi) to examine the band II and band V proteins. Band II is found essential for viability; it is needed to maintain the normal structure of the editing complex and to retain the band V ligase protein. Previously, band III was found essential for certain activities, including maintenance of the editing complex and retention of the band IV ligase protein. Thus, band II and band V form a protein pair with features analogous to the band III/band IV ligase pair. Since band V is specific for U insertion and since band IV is needed for U deletion, their parallel organization suggests that the editing complex has a pseudosymmetry. However, unlike the essential band IV ligase, RNAi to band V has only a morphological but no growth rate effect, suggesting that it is stimulatory but nonessential. Indeed, in vitro analysis of band V RNAi cell extract demonstrates that band IV can seal U insertion when band V is lacking. Thus, band IV ligase is the first activity of the basic editing complex shown able to serve in both forms of editing. Our studies also indicate that the U insertional portion may be less central in the editing complex than the corresponding U deletional portion.


Subject(s)
Mitochondria/genetics , Polynucleotide Ligases/metabolism , RNA Editing , RNA, Protozoan/metabolism , Trypanosoma brucei brucei/metabolism , Amino Acid Sequence , Animals , Base Sequence , Genes, Protozoan , Macromolecular Substances , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Molecular Sequence Data , Polynucleotide Ligases/genetics , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , RNA Interference , Sequence Alignment , Trypanosoma brucei brucei/cytology , Trypanosoma brucei brucei/genetics
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