Apoptosis is a physiological cell suicide process. It plays essential roles in development, tissue homeostasis, and protection against viral infection and formation of cancer. Apoptosis is controlled by a cell intrinsic death pathway, at the core of which are a group of aspartic acid specific cysteine proteases termed caspases. Caspases normally exist in the cytoplasm as inactive precursors and are activated during apoptosis through proteolytic processing. Once activated, caspases cleave various cellular proteins, which leads to dismantling of cells. The conversion of caspase precursors to mature caspases is a key regulatory step in apoptosis, and is subject to intricate regulation by other anti and proapoptotic proteins. In this proposal, we will investigate three interrelated aspects of caspase activation: 1) the mechanism by which caspases are activated, 2) the inhibition of caspase activation by a family of apoptosis inhibitors termed IAPs, and 3) the regulation of the caspase activator Apaf1 and CED4. These studies would lead to an improved understanding of the regulation of apoptosis and may identify new therapeutic targets for the treatment of related diseases, ranging from cancer and autoimmune disorders to neurodegenerative diseases, immunodeficiency, and ischemic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060911-04
Application #
6649298
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$261,525
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Cuiping; Stonestrom, Aaron J; Christian, Thomas et al. (2016) Molecular Basis and Consequences of the Cytochrome c-tRNA Interaction. J Biol Chem 291:10426-36
Guo, Lili; Prall, Wil; Yang, Xiaolu (2016) Assays for the Degradation of Misfolded Proteins in Cells. J Vis Exp :
Guo, Lili; Giasson, Benoit I; Glavis-Bloom, Alex et al. (2014) A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol Cell 55:15-30
Hou, Ya-Ming; Yang, Xiaolu (2013) Regulation of cell death by transfer RNA. Antioxid Redox Signal 19:583-94
Du, Wenjing; Jiang, Peng; Mancuso, Anthony et al. (2013) TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol 15:991-1000
Jiang, Peng; Du, Wenjing; Wang, Xingwu et al. (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310-6
Mei, Yide; Hahn, Allison Alcivar; Hu, Shimin et al. (2011) The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. J Biol Chem 286:35380-7
Chu, Y; Yang, X (2011) SUMO E3 ligase activity of TRIM proteins. Oncogene 30:1108-16
Mei, Yide; Yong, Jeongsik; Liu, Hongtu et al. (2010) tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell 37:668-78
Mei, Yide; Stonestrom, Aaron; Hou, Ya-Ming et al. (2010) Apoptotic regulation and tRNA. Protein Cell 1:795-801

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