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 contain missense mutations in one p53 allele, leading to inactivation of the mutated protein. In almost all of these cases, the wild-type allele is also lost. However, it remains uncertain whether mutant p53 acts in a dominant negative fashion over the wild-type protein. Two parameters of p53 function, transcriptional activation and transcriptional repression, were studied under a variety of experimental conditions within malignant and normal breast epithelial cells. Transient transfection of DNA encoding wild-type p53 was able to transactivate p53-responsive promoters. Wild-type p53 functioned equally well in malignant cells which harbored an endogenous mutation in p53, in malignant cells containing normal p53 and in normal mammary epithelial cells. Co-transfection of cDNAs encoding mutant p53 proteins were unable to inhibit the ability of wild-type p53 to transactivate the reporter constructs. Repression of viral promoters by normal p53 protein was not inhibited by endogenous or co-transfected mutant p53 -proteins. Finally, the p53 regulated gene WAF1/CIP1/p21 was induced following gamma irradiation in normal mammary cells, containing endogenous wild-type p53 and in the same cells transfected with mutant p53 genes. From these experiments we conclude that mutant p53 proteins do not inactivate the transactivating (or repressing) function of a co-expressed normal p53 protein in these cells implying that complete loss of wild-type p53 is required to eliminate these functions in breast epithelium.
Davis
P
P
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Bazar
K
K
Huper
G
G
Lozano
G
G
Marks
J
J
Iglehart
J D
JD
D000328:Adult; D000483:Alleles; D001940:Breast / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000502:physiology; D005260:Female; D005799:Genes, Dominant; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53