DOMINANCE OF WILD-TYPE P53-MEDIATED TRANSCRIPTIONAL ACTIVATION IN BREAST EPITHELIAL-CELLS

The p53 gene is a recessive oncogene whose loss of function can result in cell transformation, Approximately 25% of human breast cancers con tain missense mutations in one p53 allele, leading to inactivation of the mutated protein. In almost all of these cases, the wild-type allel e is also lost, However, it remains uncertain whether mutant p53 acts in a dominant negative fashion over the wild-type protein, Two paramet ers of p53 function, transcriptional activation and transcriptional re pression, were studied under a variety of experimental conditions with in malignant and normal breast epithelial cells, Transient transfectio n of DNA encoding wild-type p53 was able to transactivate p53-responsi ve promoters, Wild-type p53 functioned equally wed in malignant cells which harbored an endogenous mutation in p53, in malignant cells conta ining normal p53 and in normal mammary epithelial cells, Co-transfecti on of cDNAs encoding mutant p53 proteins mere unable to inhibit the ab ility of wild-type p53 to transactivate the reporter constructs, Repre ssion of viral promoters by normal p53 protein was not inhibited trans fected mutant p53 proteins, regulated gene WBF1/CIP1/p21 was induced f ollowing gamma irradiation in normal mammary cells, containing endogen ous wild-type p53 and in the same cells transfected with mutant p53 ge nes, From these experiments me conclude that mutant p53 proteins do no t inactivate the transactivating (or repressing) function of a co-expr essed normal p53 protein in these cells implying that complete loss of mild-type p53 is required to eliminate these functions in breast epit helium.