This is a proposal to study the ribosomal protein RPL22 in T cell development. The premise for the proposed studies is the extraordinary preliminary data showing that RPL22 deficient mice have a severe and selective defect in ??, but not ???, T cell development. RPL22 protein is induced as cells go through beta selection, so this selectivity makes some sense. They also show that RPL22 deficiency results in an increase in p53 in thymocytes and that p53 knock-down can rescue??? T cell development. The proposed aims will explore this further by: 1) investigating the basis for the arrest by testing if a TCR transgene can rescue and testing the effect of PUMA and p21waf1, as deficiency in these genes abrogates p53-induced apoptosis, 2) determine how pre-TCR signaling increases RPL22 protein expression, and 3) examine why RPL22 deficiency triggers this p53 checkpoint. They show that global protein synthesis is not impaired, but the production of a CAP-independent IRES based protein (p27kip) is. Ultimately these studies will test the central idea is that a ubiquitously expressed ribosome subunit, while not required for general CAP-dependent translation, is required for translation of certain CAP-independent transcripts, and will reveal how ribosome biogenesis and translation can regulate specific biological processes.
