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Genome-wide survey nets key melanoma gene
Date:2/7/2008

prompting cells to multiply abnormally. In some melanocytes with this mutation, the proliferation cannot be stopped, and cancer develops.

But sometimes when the mutated BRAF gene is expressed in melanocytes, those cells go into a state of permanent hibernation via a process known as senescence. These cells form nevi, not melanoma. This, according to Green, indicates that the genetic checks and balances within those cells are working correctly. The cell has sensed this oncogenic influenceactivated BRAFand that induces an anti-cancer mechanism to throw the cell into this frozen state, he said. Green added that sometimes cells simply commit suicide instead of senescing.

Cancer results when something blocks this failsafe mechanism, said Green. While this phenomenon was known, the components and the pathways involved were not, he said.

Green, his postdoctoral fellow Narendra Wajapeyee, and their colleagues did a genome-wide search for the proteins involved. They used engineered retroviruses to insert short bits of RNA to selectively turn off individual genes in a series of melanocytes. Some of the cells progressed to cancer, while others did not. After testing thousands of genes, they found 17 that were required for activated BRAF to induce either senescence or suicide. Together, Green said, the proteins made by these genes make up the bodys melanoma defense pathway.

Greens group found that three of those proteins are required for both the senescence and programmed cell death pathways. The identity of one of those proteins, insulin-like growth factor binding protein 7 (IGFBP7), surprised the researchers. Not much was known about IGFBP7, except that it was secreted, said Green. A secreted protein does not stay inside the cell that produces it, but instead is released from the cell and moves through the blood to other cells. Green said that a secreted proteins role in the pathway caught them off guard, because we would have thought this process would be p
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
Source:Eurekalert

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