Characterization of CNOT1 and CNOT2, candidate colorectal cancer genes identified in a transposon-based genetic screen in mice.

Abstract

Colorectal cancer (CRC) is currently the third most common form of cancer worldwide, with approximately 639,000 deaths per year. In the United States, it is the second leading cause of cancer-related death, with just under 53,000 deaths per year. CRC is thought to arise predominantly from benign, epithelial-derived tumors (adenomatous polyps), which, over time, become cancerous. This shift from normal epithelium to adenoma to carcinoma is the result of a number of genetic and epigenetic changes that occur within the tumor. To determine which genes play a role in oncogenesis, a recent study performed an unbiased, forward genetic screen using Sleeping Beauty transposon-mediated mutagenesis in mice. The current challenge is to functionally validate the greater than 100 candidate cancer genes identified in the screen. To achieve this goal the strategy of our lab is to knockdown or overexpress candidate cancer genes in cancer cell lines and then measure the effect of this manipulation on cancer cell processes such as proliferation, apoptosis, invasion and modulation of cell signaling pathways. Collectively, these data will help us characterize the role of our candidate genes as either oncogenes or tumor suppressors in gastrointestinal cancer. Here we report the characterization of CNOT1 and CNOT2, individual subunits of the CCR4-NOT complex, as potential oncogenes. In addition, the progress on the development and optimization of a β-catenin transcriptional activity assay will be reported