A common gain of function of p53 cancer mutants in inducing genetic instability

D. P. Liu, Hoseok Song, Y. Xu

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

The critical tumor suppressor p53 is mutated in over half of all human cancers. The majority of p53 cancer mutations are missense mutations, which can be classified into contact mutations that directly disrupt the DNA-binding of p53 but have modest impact on p53 conformation and structural mutations that greatly disrupt p53 conformation. Many p53 cancer mutants, including the hot spot mutations (R175H, R248W and R273H), not only lose p53-dependent tumor-suppressor activities, but also acquire new oncogenic activities to promote cancer. Therefore, it is critical to elucidate the gain of oncogenic function of p53 cancer mutants. Using humanized p53-mutant knock-in mouse models, we have identified a gain of oncogenic function shared by the most common p53 contact mutants (R273H and R248W) and structural mutant (R175H). This gain of function inactivates Mre11/ATM-dependent DNA damage responses, leading to chromosomal translocation and defective G2/M checkpoint. Considering the critical roles of ATM in maintaining genetic stability and therapeutic responses to many cancer treatments, the identification of this common gain of function of p53 cancer mutants will have important implication on the drug resistance of a significant portion of human cancers that express either the contact or structural p53 cancer mutants.

Original languageEnglish
Pages (from-to)949-956
Number of pages8
JournalOncogene
Volume29
Issue number7
DOIs
Publication statusPublished - 2010 Feb
Externally publishedYes

Keywords

  • Gain of function
  • Genetic instability
  • P53
  • Tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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