In a test-tube study, the scientists discovered how both beta-catenin and cyclin D1 are involved in causing colon cancer.
First, the levels of beta-catenin increase to excessively high levels in one of two different scenarios. In one case, the beta-catenin gene itself is mutated. In the second case, a mutation is found in adenomatous polyposis coli (APC), a well-known tumor-suppressor gene that is mutated in about 90% of colon cancers. APC's major role in the cell is to reduce the level of beta-catenin. When the APC gene is mutated, beta-catenin accumulates to high levels and enters the nucleus.
Upon entering the nucleus, beta-catenin can directly activate the cyclin D1 gene, leading to an abnormal surge in the production of the cyclin D1 protein. Since cyclin D1 is a major regulator of cell growth, the result is uncontrolled cell proliferation. This contributes to abnormal tissue growth and the creation of a tumor.
"In most cases, tumor formation is triggered by mutated genes. Therefore, it was unclear how completely normal copies of the cyclin D1 gene could be involved in colon cancer," Ben-Ze'ev says. "Now we have shown that the 'guilty' mutation doesn't have to appear in cyclin D1 itself, but may be found in other molecules by which it is affected.
"As for beta-catenin, we and other researchers have long wanted to know what kind of signals it conveys to the nuclei of cancer cells. Our study has made it possible to 'eavesdrop' on one of these signals, and to show how certain colon cancers may develop."
Ben-Ze'ev and his colleagues have also demonstrated how this signaling mechanism can be blocked, a finding that may some day be of use in the development of cancer therapy.
In one approach, cyclin D1 activity was diminished by introducing a nonmutated
copy of the tumor-suppressor APC gene into colon cancer cells. The "good" APC
lowered beta-catenin levels, stopping the abnormal stimulation of the cyclin D1
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American Committee for the Weizmann Institute of Science
11-May-1999