Gain of function of mutant p53 by coaggregation with multiple tumor suppressors

Nat Chem Biol. 2011 May;7(5):285-95. doi: 10.1038/nchembio.546. Epub 2011 Mar 27.

Abstract

Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.

MeSH terms

  • Animals
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Genes, p53
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Conformation
  • Spectrometry, Mass, Electrospray Ionization
  • Spectroscopy, Fourier Transform Infrared
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human