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

The p73 protein, a homologue of the tumour-suppressor protein p53, can acti vate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactiv ate p73. The binding of such mutants is influenced by whether TP53 (encodin g 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 enhan ced 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 c ontribute to the biological properties of a subset of p53 mutants, and a po lymorphic residue within p53 affects mutant behaviour.