Overexpression of MYC is among the most common genetic events in human cancer. Current models suggest that high levels of MYC, which is a sequence-specific transcription factor, regulate a transcription network that ultimately leads to malignant transformation. Despite intensive study, the essential genes that lie downstream of MYC, and the mechanism by which MYC regulates these genes, remains only partially understood. We have performed an expression profiling screen aimed selectively at the identification of MYC targets that are critical to the transformation process. Of the 629 genes previously reported as MYC targets, only 6 have documented roles in MYC mediated transformation. Our screen identified 20 novel MYC targets and validation studies are beginning to confirm their importance in MYC driven tumorigenesis. We have recently reported that shRNA mediated depletion of one of the novel targets, MTA1, blocks the ability of MYC to induce growth of cells in soft agar. Additional targets from the screen (POLRMT and CD30), have been thoroughly characterized at the molecular level.
The first Aim of the new funding cycle is the characterization of the biological role these three targets play during MYC mediated transformation. Based on the success of our screen for essential, MYC activated targets, we propose in the second Aim to perform the first screen focused specifically on the identification of genes repressed by MYC. A great deal of evidence suggests that repressed targets are of particular importance during MYC induced transformation. As part of this Aim, we will define the co-repressor(s) that function with MYC to mediate transcriptional silencing. These studies will combine biochemical, molecular and genetic techniques and should ultimately provide a deeper understanding of the pathway regulated by MYC in human cancer.

Public Health Relevance

Overexpression of the MYC oncogene plays a causal role in up to 100,000 cancer cases in U.S. each year. Understanding the cellular changes induced by MYC will provide us with novel targets for therapeutic intervention in these patients. The studies proposed here are aimed at a precise mechanistic delineation of the MYC pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090465-11
Application #
8220785
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
2001-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2012
Total Cost
$268,305
Indirect Cost
$94,645
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
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
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
Sotillo, E; Laver, T; Mellert, H et al. (2011) Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. Oncogene 30:2587-94
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
Mellert, Hestia S; McMahon, Steven B (2009) Biochemical pathways that regulate acetyltransferase and deacetylase activity in mammalian cells. Trends Biochem Sci :
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

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