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The inherent instability of mutant p53 is alleviated by Mdm2 or p16^INK4a loss

¹ Department of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; ² Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA; ³ Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

The p53 tumor suppressor is often disrupted in human cancers by the acquisition of missense mutations. We generated mice with a missense mutation at codon 172 that mimics the p53R175H hot spot mutation in human cancer. p53 homozygous mutant mice have unstable mutant p53 in normal cells and stabilize mutant p53 in some but not all tumors. To investigate the significance of these data, we examined the regulation of mutant p53 stability by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation, and p16^INK4a, a member of the Rb tumor suppressor pathway. Mice lacking Mdm2 or p16^INK4a stabilized mutant p53, and revealed an earlier age of tumor onset than p53 mutant mice and a gain-of-function metastatic phenotype. Analysis of tumors from p53 homozygous mutant mice with stable p53 revealed defects in the Rb pathway. Additionally, ionizing radiation stabilizes wild-type and mutant p53. Thus, the stabilization of mutant p53 is not a given but it is a prerequisite for its gain-of-function phenotype. Since mutant p53 stability mimics that of wild-type p53, these data indicate that drugs aimed at activating wild-type p53 will also stabilize mutant p53 with dire consequences.

[Keywords: Metastasis; mouse models; gain of function; p53 stability]

Received February 13, 2008; revised version accepted March 31, 2008.

E-MAIL gglozano{at}mdanderson.orgU; FAX (713) 834-6380.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1662908.

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