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.
|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|
|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|
|Cowling, Victoria H; Cole, Michael D (2010) Myc Regulation of mRNA Cap Methylation. Genes Cancer 1:576-579|
|Wright, Jason B; Brown, Seth J; Cole, Michael D (2010) Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol Cell Biol 30:1411-20|
|Chandriani, Sanjay; Frengen, Eirik; Cowling, Victoria H et al. (2009) A core MYC gene expression signature is prominent in basal-like breast cancer but only partially overlaps the core serum response. PLoS One 4:e6693|
|Brown, Seth J; Cole, Michael D; Erives, Albert J (2008) Evolution of the holozoan ribosome biogenesis regulon. BMC Genomics 9:442|
|Cowling, V H; Cole, M D (2007) E-cadherin repression contributes to c-Myc-induced epithelial cell transformation. Oncogene 26:3582-6|
|Cowling, Victoria H; D'Cruz, Celina M; Chodosh, Lewis A et al. (2007) c-Myc transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol Cell Biol 27:5135-46|
|Goodliffe, Julie M; Cole, Michael D; Wieschaus, Eric (2007) Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1. BMC Mol Biol 8:40|
|Obaya, Alvaro J; Kotenko, Iulia; Cole, Michael D et al. (2002) The proto-oncogene c-myc acts through the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) to facilitate the activation of Cdk4/6 and early G(1) phase progression. J Biol Chem 277:31263-9|