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 #
5R01CA098172-03
Application #
6918636
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$300,280
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yuan, Hua; Rossetto, Dorine; Mellert, Hestia et al. (2012) MYST protein acetyltransferase activity requires active site lysine autoacetylation. EMBO J 31:58-70
Sussman, Robyn T; Zhang, Xiao-Yong; McMahon, Steven B (2011) Enzymatic assays for assessing histone deubiquitylation activity. Methods 54:339-47
Zhang, Xiao-Yong; Pfeiffer, Harla K; Mellert, Hestia S et al. (2011) Inhibition of the single downstream target BAG1 activates the latent apoptotic potential of MYC. Mol Cell Biol 31:5037-45
Sotillo, E; Laver, T; Mellert, H et al. (2011) Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. Oncogene 30:2587-94
Mellert, Hestia S; Stanek, Timothy J; Sykes, Stephen M et al. (2011) Deacetylation of the DNA-binding domain regulates p53-mediated apoptosis. J Biol Chem 286:4264-70
Aggarwal, Priya; Vaites, Laura Pontano; Kim, Jong Kyong et al. (2010) Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell 18:329-40
Van Dang, Chi; McMahon, Steven B (2010) Emerging Concepts in the Analysis of Transcriptional Targets of the MYC Oncoprotein: Are the Targets Targetable? Genes Cancer 1:560-567
Dent, Paul; Grant, Steven; Fisher, Paul B et al. (2009) PI3K: A rational target for ovarian cancer therapy? Cancer Biol Ther 8:27-30
Sykes, Stephen M; Stanek, Timothy J; Frank, Amanda et al. (2009) Acetylation of the DNA binding domain regulates transcription-independent apoptosis by p53. J Biol Chem 284:20197-205
Park, Margaret A; Walker, Teneille; Martin, Aditi Pandya et al. (2009) MDA-7/IL-24-induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK-dependent mechanism. Mol Cancer Ther 8:1280-91

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