Affiliations GYN-Pathology Research Laboratory
GYN-Pathology Research Laboratory
Lawrence Zukerberg, MD
Massachusetts General Hospital
Associate Professor of Pathology
Harvard Medical School
In the United States, the overall lifetime risk of colorectal cancer in the general population is 6%, but it ranks as the second leading cause of cancer-related deaths in men and women combined.
A stepwise model of colorectal tumorigenesis was developed that includes mutations in the adenomatous polyposis coli tumor-suppressor gene (APC) and oncogenic KRAS mutations as early events. These are followed by deletions on human chromosome 18q (LOH) and mutations of TP53 with the transition to malignancy. This model has been generally validated. However the genes targeted by chromosome 18q deletions in colon cancers have not been well defined and it appears that there may be more than one important tumor suppressor gene on 18q that is altered in many cancers.
We have recently cloned a novel protein, Cables, which maps to human chromosome 18q and inhibits growth of cells in culture and tumor formation in nude mice. Cables interacts with multiple cyclin dependent kinases (cdks), including cdk2, and links the cdks and non-receptor tyrosine kinases (Src, Abl, and Wee1). Cdk2 regulates the G1/S phase transition and is essential for cell cycle progression. Enhanced cdk2 tyrosine phosphorylation occurs in the presence of Cables, which leads to decreased kinase activity and diminished cell proliferation. Cables also interacts with p53 and potentiates p53-induced cell death.
Loss of Cables is found in up to 60% of primary colon cancers, 90% of endometrial cancers, and 50% of ovary, lung, bladder and head and neck cancers. Thus, we believe that Cables may be a target of the chromosome 18q deletions commonly seen in colon and other cancers and may act as a tumor suppressor gene. We have already created a Cables deficient mouse which is viable. The loss of Cables enhances tumors of the endometrium and colon. In addition, Cables plays a role in oocyte loss and infertility. Our studies will define a novel target for the deletions commonly seen on chromosome 18q. Ultimately, these studies will lay the foundation for new therapeutic approaches.