Tumor-derived p53 Mutants Induce Oncogenesis by Transactivating Growth-Promoting Genes

Oncogene. 2004 May 27;23(25):4430-43. doi: 10.1038/sj.onc.1207553.

Abstract

We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-derived mutants. Using a colony formation assay, we found that the majority of the mutants increased the number of colonies formed compared to the vector. Expression of tumor-derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have 'gain of function' properties. We have studied the gene expression profile of cells expressing tumor-derived p53-D281G to identify genes transactivated by mutant p53. We report the transactivation of two genes, asparagine synthetase and human telomerase reverse transcriptase. Quantitative real-time PCR confirms this upregulation. Transient transfection promoter assays verify that tumor-derived p53 mutants transactivate these promoters significantly. An electrophoretic mobility shift assay shows that tumor-derived p53-mutants cannot bind to the wild-type p53 consensus sequence. The results presented here provide some evidence of a possible mechanism for mutant p53-mediated transactivation.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Aspartate-Ammonia Ligase / biosynthesis
  • Aspartate-Ammonia Ligase / genetics
  • Cell Division
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Consensus Sequence
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Genes, p53*
  • Humans
  • Mutation, Missense
  • Neoplasms / genetics*
  • Nuclear Proteins / metabolism
  • Point Mutation
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / physiology
  • Structure-Activity Relationship
  • Telomerase / biosynthesis
  • Telomerase / genetics
  • Transcriptional Activation / genetics*
  • Tumor Protein p73
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Proteins

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Telomerase
  • Aspartate-Ammonia Ligase