The p53 tumor suppressor regulates the cellular response to genetic damage through its function as a sequence-specific transcription factor. Among the most well-characterized transcriptional targets of p53 is the mdm2 oncogene, which is overexpressed in a number of common human cancers. Transcriptional activation of mdm2 is critical in the p53 pathway because its protein product marks p53 for proteosome-mediated degradation, thereby providing a negative feedback loop. We have shown that recruitment of the ATM-related TRRAP protein is essential for p53-mediated activation of mdm2 transcription. TRRAP is a component of several, multi-protein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair. Among the goals of this study are: a.) defining which of the distinct TRRAP complexes is required for p53 function, b.) assessing other p53 target genes for TRRAP dependence, c.) defining the molecular consequences of TRRAP recruitment to the mdm2 promoter, d.) mapping the unique elements within the mdm2 promote which confer its TRRAP dependence. Understanding the role that the TRRAP complexes play in the biochemical activity of p53 should provide us with a deeper molecular insight into the pathway mutated most frequently in human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098172-01
Application #
6558414
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mietz, Judy
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$291,055
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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