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Stabilizing cancer-fighting p53 can also shield a metastasis-promoter
Date:5/22/2008

HOUSTON - Efforts to protect the tumor-suppressor p53 could just as easily shelter a mutant version of the protein, causing cancer cells to thrive and spread rather than die, according to research by scientists at The University of Texas M. D. Anderson Cancer Center reported in the current issue of the journal Genes and Development.

"As we develop therapies to restore the function of p53, we need to make sure we first know what version of this gene is present in a patient's tumor and then decide how to treat it," said senior author Guillermina Lozano, Ph.D., professor and chair of M. D. Anderson's Department of Cancer Genetics.

The research shows that attempting to restore normal expression of p53 protein by blocking another protein that normally degrades p53 can have the perverse effect of protecting mutated p53 and promoting metastasis.

The p53 gene is inactivated in many types of cancer. Its normal role is to halt the division of a defective cell and then force the cell to kill itself or deprive the cell of its ability to reproduce. As such, reactivation of p53 is thought to have great therapeutic potential.

Normally, p53 levels are low, but it springs into action in response to DNA damage or activation of cancer-promoting genes, or oncogenes.

Lozano, an expert on mouse models of human cancer, and colleagues developed mice with a specific mutation of p53 that mimics a common genetic mutation in human cancers. The mutated gene, called p53H, expresses a defective version of the p53 protein.

When mice had the p53H mutation on both genes (p53 H/H), the researchers found that the p53 protein was not detectable in normal tissue but was present in 79 percent of tumors. However, tumors in these mice did not metastasize.

Enter Mdm2, a protein whose normal job is to degrade p53 when it's no longer needed. Mdm2 also degrades the mutated version of the p53 protein.

The researchers developed
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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