Cables and the colonocyte

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DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer in men and women combined, and the overall lifetime risk in the general population is six percent. A stepwise model of colon cancer includes mutations of the adenomatous polyposis tumor suppressor gene and oncogenic KRAS mutations as early events. These are followed by deletions on human chromosome 18q and mutation of the p53 tumorsuppressor gene. The gene targeted by chromosome 18q deletions has not been well defined. Our recent studies have demonstrated that Cables, a novel regulatory protein, maps to human chromosome 18q and is lost at a high frequency in colon cancer. We find decreased or loss of Cables in approximately 60% of colon cancer and one-third of colonic adenomas. Cables appear to act as a cable or link between important proteins involved in cell proliferation and tumorigenesis. Cyclin dependent kinase (cdk) 2 is a serine/threonine protein kinase that regulates progression through the cell cycle and ultimately cell proliferation. Cables interacts with cdk2 and enhances an inhibitory cdk2 tyrosine phosphorylation, which leads to decreased kinase activity and decreased cell proliferation. Cables also interacts with the p53 tumor-suppressor gene and augments p53 induced apoptosis. Conversely, loss of Cables may cause uncontrolled cell growth and enhance tumor formation. The hypothesis for this proposal is that loss of or reduced levels of Cables is one of the important events in the pathways to colon cancer formation. To study the role of Cables in colon cancer we plan to: 1) define the tumor-suppressor function of Cables in primary colonic epithelial cells and in mouse models of colonic tumorigenesis; 2) determine the mechanism of Cables gene inactivation in primary colon tumors. We have already created a Cables deficient mouse, which is viable and is prone to the development of colon cancer. The studies in this proposal will help determine what genetic alterations lead to Cables loss and if Cables is a key target of the chromosome 18q deletions commonly seen in colon cancer. If this is true than therapeutics to restore Cables function could be developed and the prognostic implications and/or response to treatment of tumors with or without Cables loss could be studied.