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

Tamara Terzian, Young Ah Suh, Tomoo Iwakuma, Sean M. Post, Manja Neumann, Gene A. Lang, Carolyn S. Van Pelt, Guillermina Lozano

Research output: Contribution to journalArticle

237 Scopus citations

Abstract

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 p16INK4a, 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.

Original languageEnglish (US)
Pages (from-to)1337-1344
Number of pages8
JournalGenes and Development
Volume22
Issue number10
DOIs
StatePublished - May 15 2008

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Keywords

  • Gain of function
  • Metastasis
  • Mouse models
  • p53 stability

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Terzian, T., Suh, Y. A., Iwakuma, T., Post, S. M., Neumann, M., Lang, G. A., Van Pelt, C. S., & Lozano, G. (2008). The inherent instability of mutant p53 is alleviated by Mdm2 or p16 INK4a loss. Genes and Development, 22(10), 1337-1344. https://doi.org/10.1101/gad.1662908