Natural resistance of pigment cells to sunlight may make deadly skin cancer tough to treat

screen cells, the melanocytes, are continuously bombarded by ultraviolet solar radiation as they generate pigment which protects underlying skin cells. Ordinarily, the melanocytes would become damaged from the radiation and apoptosis may be initiated, unless there were some countervailing force. And there is: During human evolution, melanocytes appear to have acquired at least one such mechanism that neutralizes apoptosis and enables the cells to survive. The main players in this apoptosis-blocking game are MITF and another gene with which it interacts, BCL2.

The MITF gene, dubbed by scientists as the master melanocyte regulator, is found in melanocytes and is critical for their proper development and their long-term survival. In addition MITF is thought to play a key role in production of pigment by these cells. BCL2 is a cell-death suppressor, many of whose actions were discovered by Dana-Farber researcher Stanley J. Korsmeyer, MD.

When either the MITF or BCL2 gene is mutated or missing, the whiskers and fur of mice turn from black to gray or white because melanocytes have died. A mutant MITF gene is involved in a human genetic disorder that causes, among other abnormalities, locks of white hair from birth.

The investigators used microarrays, or DNA chips, to determine what genes are turned on when the MITF gene is active, i.e., what genes are targets of MITF within normal melanocytes. The microarray experiments showed that the protein produced by MITF links up with the BCL2 gene both in normal melanocytes and in melanoma cells, increasing the amount of BCL2 protein being made, and activating cell survival.

McGill and others in the Fisher lab also inhibited the activity of MITF in melanocytes and melanoma cells by infecting them with genetically engineered viruses. When the viruses blocked the action of MITF, the cells died. By the same token, the researchers could artificially rev up the activity of BCL2 in MITF-inhibited melano

Contact: Bill Schalaler
Dana-Farber Cancer Institute

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