Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways

Hoseok Song, Yang Xu

Research output: Contribution to journalReview article

33 Citations (Scopus)

Abstract

Loss of the tumor suppression activity of p53 is required for the progression of most human cancers. In this context, p53 gene is somatically mutated in about half of all human cancers; in the rest human cancers, p53 is mostly inactivated due to the disruption of pathways important for its activation. Most p53 cancer mutations are missense mutations within the core domain, leading to the expression of full-length mutant p53 protein. The expression of p53 mutants is usually correlated with the poor prognosis of the cancer patients. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumor suppression activity of WT p53, but also gain novel oncogenic activities to promote tumorigenesis and drug resistance. Therefore, to improve current cancer therapy, it is critical to elucidate the gain-of-functions of p53 cancer mutants. By analyzing the humanized p53 mutant knock-in mouse models, we have identified a new gain of function of the common p53 cancer mutants in inducing genetic instability by disrupting ATM-mediated cellular responses to DNA double-stranded break (DSB) damage. Considering that some current cancer therapies such as radiotherapy kills the cancer cells by inducing DSBs in their genome DNA, our findings will have important implications on the treatment of human cancers that express common p53 mutants.

Original languageEnglish
Pages (from-to)1570-1573
Number of pages4
JournalCell Cycle
Volume6
Issue number13
DOIs
Publication statusPublished - 2007 Jul 1
Externally publishedYes

Keywords

  • ATM
  • Gain of function
  • Genetic stability
  • Tumor suppression
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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