: Apoptosis is a form of cell death in animals that is executed by intrinsic cellular biochemical programs. Initiated by inter, and intracellular signals, apoptosis plays essential roles in animal development, maintaining normal tissue homeostasis, and elimination of tumorigenic and viral infected cells. Cancer and autoimmunity may arise when normal apoptosis is defective, resulting in excess numbers of cells. Conversely, apoptosis may be prematurely activated in diseases including neurodegenerative diseases, and neuron and cardiomyocyte death during stroke. Caspases are a group of intracellular proteases that carry out apoptosis. Caspases are synthesized as inactive zymogens that become activated when cells are committed to apoptosis. Caspase-3 is one of the major caspases that are responsible for generating many characteristic biochemical and morphological features of apoptosis. One of the major caspase activation pathways is initiated by mitochondria through the release of apoptotic protease activating factors such as cytochrome c and Smac. These factors trigger the activation of caspase-3 through a cascade of caspases. The cytochrome c-initiated caspase-3 activating pathway is negatively regulated by IAPs, another family of proteins that bind and inhibit caspase activities. Smac neutralizes IAP activity and ensure apoptosis to proceed when cells are damaged beyond repair. This grant proposes to continue the biochemical studies on the caspase-3 activating process focusing on the regulation by IAPs and Smac. The results generated should provide mechanistic insights into how a cell's sensitivity to a certain apoptotic stimulus is determined. Such knowledge should provide guidance to the diagnosis and therapy of the common human diseases listed above.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057158-07
Application #
6606908
Study Section
Biochemistry Study Section (BIO)
Program Officer
Ikeda, Richard A
Project Start
1997-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
7
Fiscal Year
2003
Total Cost
$260,520
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Zhong, Qing; Gao, Wenhua; Du, Fenghe et al. (2005) Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121:1085-95
Hao, Zhenyue; Duncan, Gordon S; Chang, Chia-Che et al. (2005) Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell 121:579-91
Nijhawan, Deepak; Fang, Min; Traer, Elie et al. (2003) Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 17:1475-86
Jiang, Xuejun; Kim, Hyun-Eui; Shu, Hongjun et al. (2003) Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science 299:223-6
Jiang, X; Wang, X (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 275:31199-203
Du, C; Fang, M; Li, Y et al. (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33-42
Rodriguez, A; Oliver, H; Zou, H et al. (1999) Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nat Cell Biol 1:272-9
Zou, H; Li, Y; Liu, X et al. (1999) An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 274:11549-56
Luo, X; Budihardjo, I; Zou, H et al. (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481-90