There are catastrophic consequences of defects in T cell function, and it is probably for this reason that T lymphocytes are among the most sensitive cells in the body to the induction of apoptosis in response to stress. In this application we propose to continue our research into the mechanisms of stress-induced apoptosis in T cells by investigating how p53 and its family members participate in this process. The p53 protein is activated in response to signals initiated by DNA damage, oncogenesis, and T cell activation. While p53 clearly acts as a transcription factor to orchestrate cell cycle arrest and apoptosis, there is accumulating evidence that it also functions in a transcription-independent manner. Here, we propose to dissect and integrate the transcription dependent and independent mechanisms of p53-mediated apoptosis and to explore how the downstream apoptotic pathways contribute to the regulation of T cell survival. In particular we propose (1) to determine the transcription-independent mechanisms whereby p53 triggers apoptosis, (2) to determine how do p53 and p73 regulate apoptosis in T cells at the transcriptional level, and (3) to delineate the roles of p53-induced apoptotic pathways in T cell apoptosis. Our studies exploit anumber of novel systems and approaches we have developed for this purpose. Using a pSSER""""""""? chimeric construct, which encodes a p53 protein that is activated by tamoxifen, we will explore p53 function in cell lines, in a novel cell-free system, and in primary T cells from a pSSER12""""""""1 knock-in mouse. The expression and regulation of p53 by its family member, ANp73, and by survival factors, will be examined in the context of p53-regulated Bcl-2 family proteins that control the mitochondrial pathway of apoptosis. Components of this pathway, downstream or independently of mitochondria will be investigated for their contributions to T cell apoptosis under a variety of circumstances. In this integrated approach to the problem of p53 function in apoptosis, we will elucidate the roles of p53 in the context of stress-induced apoptosis in mature and developing T cells.
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