"The Cables gene may be an important tumor suppressor gene located on chromosome 18," says principal investigator Lawrence Zukerberg, MD, of the MGH Department of Pathology. "People have known that a region of that chromosome is often missing in cancer cells, and they've been searching for cancer genes around that area for some time now."
Zukerberg and his colleagues found that the Cables gene is located on a chromosomal region that is frequently lost in colon, pancreatic, and squamous cancers. They also discovered that expression of the Cables protein is missing in these cancer cells. "We stained human tumor tissues such as colon and head and neck squamous cell carcinomas ? and found that 50 to 60 percent seem to be missing this protein," Zukerberg says.
The Cables protein normally acts to inhibit cell growth through a chain reaction effect. Cables prompts a protein called Wee1 to interact with another protein called cdk2, which plays a key role in encouraging cells to divide and grow. When it interacts with the Wee1 protein, however, cdk2's activity is diminished. So ultimately, expression of the Cables protein leads to decreased cell division.
Zukerberg's recent findings indicate that expression of the Cables protein may be important for thwarting the uncontrolled cell growth that is indicative of cancer. Without the protein, cells may be able to divide faster and could eventually become cancerous if they have a growth advantage over neighboring cells.
The next step for the MGH researchers is to try to prove that the Cables gene is a true tumor suppressor. They plan to knock out the gene in a mouse model to see if the effect leads to tumor development. They will also sequence the Cables gene from primary human tumor tissues to look for any potential mutations.
Other scientists involved in the study include Chin-Lee Wu, MD, PhD, Hua Xiao, MD, PhD, Daniel Chung, MD, Yenning Chuang, and Sandra Kirley. Laboratory support was provided by Scott McDougal, MD, Chief of Urology at MGH.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, photomedicine, transplantation biology. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and non acute and home health services.
Journal
Cancer Research