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Turning a cellular sentinel into a cancer killer

Howard Hughes Medical Institute researchers have developed two strategies to reactivate the p53 gene in mice, causing blood, bone and liver tumors to self destruct. The p53 protein is called the "guardian of the genome" because it triggers the suicide of cells with damaged DNA.

Inactivation of p53 can set the stage for the development of different types of cancer. The researchers' findings show for the first time that inactivating the p53 gene is necessary for maintaining tumors. While the researchers caution that cancers can mutate to circumvent p53 reactivation, they believe their findings offer ideas for new approaches to cancer therapy.

The research was carried out independently by two Howard Hughes Medical Institute (HHMI) research teams led by Tyler Jacks at the Massachusetts Institute of Technology and Scott Lowe at Cold Spring Harbor Laboratory. Both papers were published online January 24, 2007, in advance online publication articles in the journal Nature. Although researchers have long known that p53 inactivation plays a central role in the development of cancer, little was known about whether p53 inactivation played a role in maintaining cancers. And researchers were not sure whether switching p53 back on in tumor cells would have any therapeutic effect.

"It had been demonstrated that overexpressing p53 at very high levels could arrest or kill tumors, said Lowe. "But at such high levels, p53 might not be working through a physiological mechanism. So, it was an open question whether restoring the p53 pathway would have any anti-tumor effect." For one thing, the high mutation rate in cancers might enable a cancer to switch the p53 pathway back off, or to circumvent the pathway in some other fashion. For those reasons, researchers were not sure whether the pathway would be a useful therapeutic target.

To reactivate p53, Lowe and his colleagues used a genetic technique they had developed to induce an aggressive form of liver cancer i
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
24-Jan-2007


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