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

M C Marin1, C A Jost, L A Brooks

  • 1Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

Nature Genetics
|May 10, 2000
PubMed

Insights

Tumor-derived p53 mutants can inactivate the related p73 protein. A common genetic variation in TP53 (p53 gene) influences this interaction, affecting cancer development in some patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The p73 protein, a homolog of the tumor suppressor p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells.
  • Tumor-derived p53 mutants are frequently found in various cancers, and their mechanisms of action are crucial for understanding tumorigenesis.

Purpose of the Study:

  • To investigate the interaction between tumor-derived p53 mutants and the p73 protein.
  • To determine the role of the common TP53 codon 72 polymorphism (Arg vs. Pro) in this interaction and its functional consequences.

Main Methods:

  • Co-immunoprecipitation assays to assess binding between p53 mutants and p73.
  • Apoptosis assays to evaluate the functional impact of p53-p73 interaction on cell death.
  • Cell transformation assays in cooperation with EJ-Ras.
  • Analysis of TP53 mutation and allele retention in patient tumor samples.

Main Results:

  • Certain tumor-derived p53 mutants bind to and inactivate p73.
  • The binding affinity and inactivating capacity of p53 mutants towards p73 are influenced by the codon 72 polymorphism, with Arg-encoding alleles showing enhanced effects.
  • Mutant p53's ability to neutralize p73-induced apoptosis and cooperate with EJ-Ras for cell transformation is enhanced when codon 72 encodes Arg.
  • The Arg-containing allele was preferentially mutated and retained in squamous cell tumors from individuals heterozygous for the Arg/Pro polymorphism.

Conclusions:

  • Inactivation of p53 family members by mutant p53 contributes to the biological properties of a subset of p53 mutants.
  • A polymorphic residue within p53 significantly affects the behavior of p53 mutants, influencing their interaction with p73 and potentially impacting cancer progression.

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