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Reviving a foe of cancer
Date:4/25/2013

April 25, 2013, New York, NY and Oxford, UK Cancer cells are a problem for the body because they multiply recklessly, refuse to die and blithely metastasize to set up shop in places where they don't belong. One protein that keeps healthy cells from behaving this way is a tumor suppressor named p53. This protein stops potentially precancerous cells from dividing and induces suicide in those that are damaged beyond repair. Not surprisingly, p53's critical function is disrupted in most cancers.

In the April 25 issue of Cancer Cell, a research team, led by Xin Lu, PhD, Ludwig director and member at the University of Oxford and a team of scientists from both institutions, describes how p53 is silenced in advanced melanomas by a protein named iASPP, and applies that information to restore p53 function in such cells.

Lu's research team first identified iASPP as an inhibitor of p53 in 2003. In the current study, Lu and her colleagues show that a protein complex named cyclin B1/cdk1, which is expressed at high levels in the cytoplasm of advanced melanomas, induces a pair of precise chemical modifications on iASPP to activate the protein. When activated, iASPP is shuttled into the nucleus, binds to p53 and ultimately inhibits its ability to induce cell suicide. "This is the first time that such a mechanism of p53 inactivation has been described," says Lu.

Lu and her colleagues explored whether they could restore p53's function in advanced melanomas by scuttling iASPP activation. To do so, they treated melanoma cells with a panel of small molecules and identified JNJ-7706621 (JNJ) as the best inhibitor of cyclinB1/cdk1. Lu's study showed that p53 is inhibited by two proteins in melanoma cells, iASPP and MDM2. The activity of the latter protein is known to be blocked by a small molecule called Nutlin-3. When JNJ and the Nutlin-3 were combined, the full function of p53 was restored in metastatic melanoma cells. Further, such treatment sig
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Contact: Rachel Steinhardt
rsteinhardt@licr.org
212-450-1582
Ludwig Institute for Cancer Research
Source:Eurekalert

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