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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM052735-21
Application #
8137074
Study Section
Special Emphasis Panel (NSS)
Program Officer
Marino, Pamela
Project Start
1994-09-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
21
Fiscal Year
2011
Total Cost
$403,410
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Verbist, Katherine C; Guy, Cliff S; Milasta, Sandra et al. (2016) Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532:389-93
Follis, Ariele Viacava; Chipuk, Jerry E; Fisher, John C et al. (2013) PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nat Chem Biol 9:163-8
Moldoveanu, Tudor; Grace, Christy R; Llambi, Fabien et al. (2013) BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol 20:589-97
Green, Douglas R; Victor, Bernadette (2012) The pantheon of the fallen: why are there so many forms of cell death? Trends Cell Biol 22:555-6
Wang, Ruoning; Green, Douglas R (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13:907-15
Wang, Ruoning; Green, Douglas R (2012) Metabolic reprogramming and metabolic dependency in T cells. Immunol Rev 249:14-26
Green, Douglas R; Galluzzi, Lorenzo; Kroemer, Guido (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109-12
Llambi, Fabien; Green, Douglas R (2011) Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev 21:12-20
Wang, Ruoning; Dillon, Christopher P; Shi, Lewis Zhichang et al. (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871-82
Shi, Lewis Z; Wang, Ruoning; Huang, Gonghua et al. (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367-76

Showing the most recent 10 out of 25 publications