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Detailed studies reveal how key cancer-fighting protein is held in check
Date:5/15/2014

enables p53 to attach to DNA in the cell's nucleus, helping the cell repair genetic damage. The same domain also acts as an attachment point for BCL-xL in the cytosol.

"The structural details that we report are novel," Kriwacki said. "And they provide the key insights for really dissecting the dual roles of BCL-xl in inhibiting apoptosis. Those roles are inhibiting the BH3-containing proteins on the one side, and p53 on the other. Also, through these studies we solidified the mechanistic understanding for how p53 functions in the cytosol, which complements its pro-apoptotic role in the nucleus."

The findings will help scientists design cancer-fighting drugs, Kriwacki said. In many cancers, p53 is prevented from triggering apoptosis by its attachment to BCL-xL. Drugs are currently being tested that bind to BCL-xL to free BH3 proteins to trigger apoptosis. However, Kriwacki said, new drugs could be developedbased on knowledge of p53's attachment to BCL-xLthat also block BCL-xL from binding p53.

"Our hypothesis is that many cancers have normal p53, but it is being tied up by BCL-xL," he said. "If it could be released, it could play its role in triggering apoptosis. A drug that could block both of BCL-xL's anti-apoptotic functions could potentially more profoundly induce apoptosis in cancer cells."

Kriwacki also said that the paper was significant because it emphasizes the importance of the role that p53 plays in the cytosol of the cell, in addition to its role in the nucleus; his further studies are seeking to map that molecular machinery in great detail.


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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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