Apr. 5, 1999 UC San Francisco researchers have determined how a protein already strongly associated with colon cancer actually exacts its toll, offering a potential new target for drug therapy.
In their study, published in the April 1 issue of Nature, the investigators report that a protein known as beta catenin gives colon cells the internal nudge they need to circumvent a molecular checkpoint that normally regulates the cycle of cell growth. By evading the checkpoint, known as retinoblastoma (Rb), colon cells proceed to divide uncontrollably and excessively, a hallmark of cancer.
"We've known for several years that colon cancers have high levels of this protein, and that it almost certainly drives the cancer," said the senior author of the study, Frank McCormick, Ph.D., F.R.S., director of the UCSF Cancer Research Institute. "The question has been, `how the heck it does it.'"
A conundrum for researchers has been the fact the retinoblastoma checkpoint remains intact in colon cancer cells.
"Probably every human cancer has a defect in the retinoblastoma checkpoint, and it is this defect that allows cells to grow under conditions that would be forbidden in normal cells," said McCormick. "In colon cancer, it's been known for years that the checkpoint is intact. We've determined that colon cancers have found a way around the checkpoint."
McCormick and Osamu Tetsu, M.D., Ph.D., a visiting postdoctoral fellow in McCormick's lab, determined that beta catenin disrupts cell regulation by synthesizing cyclin D1, a protein that prompts cells to enter S-phase, the point at which a cell duplicates its DNA, in preparation for cell division. "High levels of cyclin D1 override the checkpoint," said McCormick. "This explains how the cells proliferate out of control even though the checkpoint remains intact."
The finding, said McCormick, should fuel ongoing efforts by pharmaceutical companies to develop ways to block beta catenin, which plays a direct causal role in the development of most colon cancers, and a number of other cancers as well, including melanoma, gastric cancer, prostate cancer and hepatocellular carcinoma, said McCormick.
It has been known for years that a mutation in a tumor-suppressor gene known as adenomatous polyposis coli (APC) occurs in the majority of human colon cancers, and several years ago researchers discovered that the mutated gene leads to the activation of the beta catenin protein.
"Now we have identified at least one consequence of APC mutation," said McCormick. "We can now test the contribution that this makes to the initiation and progression of the disease. This should help us assess the potential of therapies based on our discovery."
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