We are interested in determining the function of the c-myc proto-oncogene in normal cells and how misregulation or overexpression of the c-Myc protein can induce cell transformation. Functional studies have demonstrated that a segment from the N-terminus of Myc (called Myc homology box II or MBII) is essential for oncogenic transformation. In the last granting period, we were able to purify and characterize a nuclear cofactor, called TRRAP, for TRansformation/tRansactivation Associated Protein, that binds to Myc through MBII. The discovery of TRRAP has proven to be a seminal discovery in the Myc field because it provided a link between Myc and chromatin modifying complexes that acetylate histones. Localized histone acetylation has been shown both biochemically and genetically to facilitate gene activation. This project will address the functional consequences of TRRAP complex recruitment by c-Myc. We will also explore the more global function of TRRAP itself and the growing number of TRRAP containing nuclear complexes.
The specific aims are as follows: 1) We will characterize the structure and function of DNA Methyltransferase Associated Protein (DMAP1), a newly discovered protein associated with both Myc and TRRAP. We will test the hypothesis that DMAP1 is a critical Myc-associated histone acetyltransferase. 2) We will explore the function of the nuclear actin-related protein BAF53 and its role in chromatin modifying complexes. Specifically, we will determine the biochemical basis for the dominant inhibitory activity of a BAF53 mutant protein with a small deletion in a critical functional domain. 3) We will explore the function of the Enhancer of polycomb protein, which marks a unique set of HAT complexes. We will try to determine how complexes between TRRAP and Epc1 differ from those containing TRRAP and DMAP1, and we will examine the role of these complexes in gene regulation. 4) We will determine the role of individual HATs and cofactors in the activation of specific cellular target genes. The role of each protein in the activation of the silent TERT gene will be addressed. We will test for synergism between Myc and the Sp1 transcription factor in the activation of the silent telomerase reverse transcriptase (TERT) gene.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055248-16
Application #
7247977
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
1992-08-12
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
16
Fiscal Year
2007
Total Cost
$485,411
Indirect Cost
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Smits, Nicole C; Kobayashi, Takashi; Srivastava, Pratyaksh K et al. (2017) HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. Matrix Biol 63:69-90
Weyburne, Emily S; Wilkins, Owen M; Sha, Zhe et al. (2017) Inhibition of the Proteasome ?2 Site Sensitizes Triple-Negative Breast Cancer Cells to ?5 Inhibitors and Suppresses Nrf1 Activation. Cell Chem Biol 24:218-230
Posternak, Valeriya; Ung, Matthew H; Cheng, Chao et al. (2017) MYC Mediates mRNA Cap Methylation of Canonical Wnt/?-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase. Mol Cancer Res 15:213-224
Posternak, Valeriya; Cole, Michael D (2016) Strategically targeting MYC in cancer. F1000Res 5:
Cowling, V H; Turner, S A; Cole, M D (2014) Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis. Oncogene 33:3519-27
Cole, Michael D (2014) MYC association with cancer risk and a new model of MYC-mediated repression. Cold Spring Harb Perspect Med 4:a014316
Kaur, Mandeep; Cole, Michael D (2013) MYC acts via the PTEN tumor suppressor to elicit autoregulation and genome-wide gene repression by activation of the Ezh2 methyltransferase. Cancer Res 73:695-705
Doe, Megan R; Ascano, Janice M; Kaur, Mandeep et al. (2012) Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res 72:949-57
Savino, Mauro; Annibali, Daniela; Carucci, Nicoletta et al. (2011) The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLoS One 6:e22284
Choi, Seung H; Wright, Jason B; Gerber, Scott A et al. (2010) Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells. Genes Dev 24:1236-41

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