Increased apoptosis induction by 121F mutant p53

p53 mutants in tumours have a reduced affinity for DNA and a reduced abilit y to induce apoptosis, We describe a mutant with the opposite phenotype, an increased affinity for some p53-binding sites and an increased ability to induce apoptosis, The apoptotic function requires transcription activation by p53, The mutant has an altered sequence specilicity and selectively fail s to activate MDM2 transcription. Loss of MDM2 feedback results in overexpr ession of the mutant, but the mutant kills better than wild-type p53 even i n MDM2-null cells. Thus the apoptotic phenotype is due to a combination of decreased MDM2 feedback control and increased or unbalanced expression of o ther apoptosis-inducing p53 target genes. To identify these genes, DNA chip s were screened using RNA from cells expressing the apoptosis-inducing muta nt, 121F, and a sequence-specificity mutant with the reciprocal phenotype, 277R. Two potential new mediators of p53-dependent apoptosis were identifie d, Rad and PIR121, which are induced better by 121F than wild-type p53 and not induced by 277R, The 121F mutant kills untransformed MDM2-null but not wild-type mouse embryo fibroblasts and kills tumour cells irrespective of p 53 status. It may thus expand the range of tumours which can be treated by p53 gene therapy.