Fly Genetics Point To Potential Cancer-Causing Gene; Mutated Variants Found In Human Cancer Cell Lines

"We've used fly genetics to successfully dissect cellular pathways and find a gene relevant to human cancer," says principal investigator Iswar Hariharan, MD, PhD of the MGH Cancer Center. Hariharan and his laboratory team found that a gene called archipelago, or ago, is involved in destroying a protein called cyclin E. When cyclin E is present, cells keep dividing. When it is destroyed, cells lie in a resting state.

Hariharan says that some cancer cells may have irregular cyclin E regulation that can lead to uncontrolled growth. The protein encoded by the ago gene may be crucial for this regulation. "The ago protein takes cyclin E to the destruction machinery in the cell. Cells that have mutated, inactive forms of the ago protein may have a growth advantage over neighboring cells because their cyclin E isn't degraded," says Hariharan.

Hariharan and his group identified the ago protein as a cyclin E regulator in the Drosophila fruit fly. "We screened about 50,000 flies to look for mutations that gave cells a growth advantage during development of the eye," says Ken Moberg, PhD, the study's lead author who isolated the gene. "Essentially, we were looking at cancer in the eye of the fly."

Moberg says it was exciting news when he discovered the identity and role of the ago protein. "Researchers have known that the protein that triggers cyclin E destruction must be out there, but nothing definitive had been found," he says. "Our study, together with the two others coming out now, presents a pretty strong case that the ago protein is it."

The researchers next wanted to see whether the ago gene is mutated in cancer cell lines derived from human patients. To do this, they collaborated with Daniel Haber, MD, PhD, also a co-author of the report and a researcher at the MGH Cancer Center. As documented in this study, Haber has indeed found that the ago gene is mutated in several human cancer cell lines.

"Now we're looking at primary tumors from patients to see if any of them have a mutated ago gene. If they do, we'd like to know if that gives any indication of cyclin E levels and, ultimately, implications for patients with respect to clinical outcome and response to treatments," says Haber.

Haber stresses that the teamwork at the MGH Cancer Center has been crucial in the success of discovering important cancer genes like ago. "Using fly genetics is faster than using human genetics and family studies," he says. "Most cancer centers have faculty studying mammalian systems, but we also have a large number of researchers studying other genetic systems. It validates the focus we have for our research at MGH because we can go back and forth between different model systems."

The MGH team says that the ago protein may also be involved in degrading other proteins and therefore may play roles in other cellular processes besides cell division. They hope to discover which proteins these might be.

Other scientists involved in the study include Daphne Bell, PhD, and Doke Wahrer, also of the MGH Cancer Center. The research was supported by the National Institutes of Health and the American Cancer Society.

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.