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. From a very different perspective, inherited Single Nucleotide Polymorphisms (SNPs) that predispose to various cancers have frequently been mapped within or near the c-MYC gene. Beyond these overt mutations and polymorphisms, it is estimated that up to 70% of all cancers overexpress c-MYC in response to disruptions in various signaling pathways such as Wnt. A major question confronting the cancer field is how these mutations and polymorphisms target c-MYC and its downstream cellular targets to mediate oncogenic transformation, cell cycle progression or apoptosis. Of broader interest is how the c-MYC gene itself is regulated in response to diverse oncogenic signaling pathways. The specific goals of this project are to:
Aim 1 : Characterize the missense mutations frequently found in the c-MYC protein in Burkitt's and AIDS-associated lymphomas. Our hypothesis is that these mutations cluster at sites that enhance oncogenic activity and dramatically shift the profiles of c-MYC target genes.
Aim 2 : Characterize the function of a novel direct target of c-MYC, the nol5a gene, that is hyperactivated by Burkitt's lymphoma associated c-MYC mutations. Our hypothesis is that the Nol5a protein potentiates c-MYC function through its role in ribosome biogenesis.
Aim 3 : Characterize the function of SNPs that map over a large domain on chromosome 8q24, a huge region (>2 Mb) that harbors only a single functional gene, i.e. c-MYC. Our hypothesis is that these SNPs map to very distal regulatory elements that control c-MYC gene expression in specific tissues and predispose (or protect) individuals from colon, prostate and breast cancer, dependent on the particular inherited allele.
Certain cellular genes are frequently mutated or misregulated to cause the abnormal growth of cancer cells. One of the most commonly mutated genes is called c-myc, and this gene is known to be an important regulatory of growth. The goal of the project is to understand how mutations change c-myc function in some cancers and how inherited variations near c-myc in the human genome can increase the risk of cancer.
|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|
|Cole, Michael D (2014) MYC association with cancer risk and a new model of MYC-mediated repression. Cold Spring Harb Perspect Med 4:a014316|
|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|
|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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