It is now apparent that there exist an abundance of genes that can mediate p53-dependent cell death; yet, it is unclear whether specific subsets of these genes are required for death in different cell types, or in response to different signals. During the previous funding period, we have identified the ASC gene as a novel p53-target gene. ASC protein belongs to a large family of proteins that contain Pyrin, AIM and death domain-like (PAAD) domains. ASC consists of a N-terminal Pyrin followed by a C-terminal caspase-recruitment domain (CARD), representing one of only two genes in the human genome that encodes proteins combining these two protein interaction domains. Although its potential role in the regulation of apoptosis, cancer and inflammatory responses appear to be intriguing, there is limited information available concerning the biological role of ASC. We propose here that ASC utilizes a novel mechanism to regulate the intrinsic apoptosis pathway by regulating caspase-2-mediated apoptosis through a p53-Bax mitochondrial pathway. This is the first evidence that ASC acts as an adaptor of the proapoptotic protein Bax and an up-stream effector of caspase 2 in p53-mediated apoptosis. Our proposal presents a novel mechanism connecting upstream mediators of the mitochondrial apoptosis program and a network involving the p53-->ASC-->Bax apoptosis module. ASC is also known as TMS1 (target of methylation-induced silencing), and becomes inactive in 40% of breast cancers, suggesting ASC involvement in breast tumor development. Better understanding of the role(s) of ASC should offer the unique opportunity to study a novel mechanism of p53-mediated apoptosis. In addition, ASC may be an appropriate target for induction of apoptosis in tumor cells through potential chemical compounds, which can be developed for more effective treatments of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078356-10
Application #
7367002
Study Section
Special Emphasis Panel (ZRG1-PTHB (04))
Program Officer
Blair, Donald G
Project Start
1999-04-01
Project End
2010-02-28
Budget Start
2008-03-26
Budget End
2010-02-28
Support Year
10
Fiscal Year
2008
Total Cost
$273,706
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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