P53 MUTATIONS ISOLATED IN YEAST BASED ON LOSS OF TRANSCRIPTION FACTORACTIVITY - SIMILARITIES AND DIFFERENCES FROM P53 MUTATIONS DETECTED IN HUMAN TUMORS

p53 is a transcriptional activator that plays a key role in the integr ation of signals inducing cell division arrest and programed cell deat h, Moreover, p53 is a tumor suppressor gene, mutations of which are th e most commonly detected mutations in diverse malignancies. In order t o better understand the significance of p53 mutations to human cancer, me isolated mutant alleles of p53 that had lost transcription factor activity in yeast. These mutant alleles mere evaluated for their preci se changes, their activity against three different p53 responsive enha ncers and their ability to act in a transdominant fashion to the wild type allele, While many of the mutations isolated in yeast resembled t hose found in human tumors, consistent with the importance of transcri ption factor activity for p53 in mammalian cells, the mutational spect rum obtained was dependent upon the p53 enhancer employed for the sele ction. Some mutations specifically inactivated p53 in yeast for a sing le enhancer element. Virtually all missense mutations tested had a dom inant inhibitory effect on wild type p53 in yeast, Since some of these transdominant mutations are virtually unknown in human tumors me conc lude that transdominance, per se, fails to predict which mutations occ ur frequently in cancer.