We have isolated a novel transcriptional cofactor whose recruitment is essential for transformation by the c-MYC oncoprotein. This protein, TRRAP is a component of several histone acetyltransferase complexes that regulate transcription via chromatin modification. We also show for the first time that c-MYC itself is modified by acetylation in vitro and in vivo. Furthermore, both classes of TRRAP-associated acetyltransferase are capable of acetylating c-MYC in vivo. Guiding Hypothesis and Specific Aims: We hypothesize that the TRRAP cofactor complexes are critical for cellular transformation by c-MYC because together they regulate the expression of a subset of downstream target genes. The identification of this subset of genes is our primary goal. Once identified, we will define the mechanism by which these genes participate in c -MYC' s biological functions. In addition, we will biochemically characterized the c-MYC/TRRAP interaction. This will include defining the domain on the 434 kDa TRRAP protein bound by c-MYC and determining the role of TRRAP in the assembly and function of the acetyltransferase complexes themselves. Innovation and Significance: The identification of the TRRAP cofactor and the demonstration that it is recruited by c-MYC are novel observations that form the basis of this proposal. Because this recruitment appears critical for transformation, we will use specific mutants in c-MYC which are defective for TRRAP recruitment to probe the genetic cascade regulated by c-MYC in transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090465-02
Application #
6624323
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mietz, Judy
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$288,430
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Oran, Amanda R; Adams, Clare M; Zhang, Xiao-Yong et al. (2016) Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer. Oncotarget 7:72395-72414
McMahon, Steven B (2014) MYC and the control of apoptosis. Cold Spring Harb Perspect Med 4:a014407
Chen, Ke; Wu, Kongming; Gormley, Michael et al. (2013) Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer. Oncotarget 4:923-35
Blomain, Erik S; McMahon, Steven B (2012) Dynamic regulation of mitochondrial transcription as a mechanism of cellular adaptation. Biochim Biophys Acta 1819:1075-9
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

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