The c-myc gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15% of all cancers exhibit amplification of the c-myc gene and about 25% of breast cancers have similar mutations. Chromosomal translocations at c-myc occur in 100% of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. In addition to these gross rearrangements, missense mutations can also play a major role in the oncogenic activity of c-myc, and more than 60% of Burkitt's and AIDS associated lymphomas have mutations that alter the protein structure of the already translocated c-myc gene. The major question confronting the c-myc field (and nuclear oncogenes in general) is which cellular genes are targeted by the oncoprotein to mediate its function in oncogenic transformation, cell cycle progression or apoptosis. Of broader interest is how the c-myc gene itself is regulated in response to diverse signaling pathways. The specific goals of this project are to: 1) Dissect the functional role of individual target genes in mediating the proliferative activity of the Myc transcription factor. Research will involve functional screens to discover specific genes that contribute directly to the Myc pathway. 2) Dissect the apoptotic, proliferative and oncogenic response of the Myc transcription factor using specific mutants that are defective in each biological activity using a dedicated Myc target gene microarray. 3) Use Drosophila genetics to gain insight into the regulatory pathways that govern c-myc gene expression, with particular emphasis on understanding the unique features of c-myc gene auto-suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080320-07
Application #
6850786
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
1999-01-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
7
Fiscal Year
2005
Total Cost
$359,307
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin et al. (2016) An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Hum Mol Genet 25:3863-3876
Pattison, Jillian M; Posternak, Valeriya; Cole, Michael D (2016) Transcription Factor KLF5 Binds a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk. Mol Cancer Res 14:1078-1086
Pattison, Jillian M; Wright, Jason B; Cole, Michael D (2015) Retroviruses hijack chromatin loops to drive oncogene expression and highlight the chromatin architecture around proto-oncogenic loci. PLoS One 10:e0120256
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
Hu, Ting; Pan, Qinxin; Andrew, Angeline S et al. (2014) Functional genomics annotation of a statistical epistasis network associated with bladder cancer susceptibility. BioData Min 7:5
Cole, Michael D (2014) MYC association with cancer risk and a new model of MYC-mediated repression. Cold Spring Harb Perspect Med 4:a014316
Schmucker, Adam C; Wright, Jason B; Cole, Michael D et al. (2012) Distal interleukin-1? (IL-1?) response element of human matrix metalloproteinase-13 (MMP-13) binds activator protein 1 (AP-1) transcription factors and regulates gene expression. J Biol Chem 287:1189-97
Cowper-Sal lari, Richard; Zhang, Xiaoyang; Wright, Jason B et al. (2012) Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 44:1191-8

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