A common polymorphism acts as an intragenic modifier of mutant p53 behaviour

Nat Genet. 2000 May;25(1):47-54. doi: 10.1038/75586.

Abstract

The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Arginine / genetics
  • Carcinoma, Squamous Cell / genetics
  • Cell Line
  • Codon / genetics
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology
  • Genes, Tumor Suppressor
  • Genes, p53
  • Genetic Carrier Screening
  • Germ-Line Mutation
  • Humans
  • Macromolecular Substances
  • Mutagenesis, Site-Directed*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • Polymorphism, Genetic*
  • Proline / genetics
  • Protein Binding / genetics
  • Protein Conformation
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Protein p53 / physiology
  • Tumor Suppressor Proteins

Substances

  • Codon
  • DNA-Binding Proteins
  • Macromolecular Substances
  • Nuclear Proteins
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human
  • Arginine
  • Proline