BRCA1 REGULATES P53-DEPENDENT GENE-EXPRESSION

Mutations in BRCA1 are present in 45% of families that segregate with susceptibility for breast cancer and in 80-90% of families with both b reast and ovarian cancer, sere we report that BRCA1 stimulates artific ial and genomic promoter constructs containing p53-responsive elements , This activity of BRCA1 depends on the presence of wild-type p53, whi ch was shown by using mouse fibroblasts expressing temperature-sensiti ve forms of p53, or p53(+/+) and p53(-/-) fibroblasts obtained from p5 3 knockout mice, Furthermore, mutant forms of BRCA1 lacking the C-term inal second BRCA1 C-terminal (BRCT) domain showed reduced p53-mediated transcriptional activation, Finally, we found that BRCA1 coimmunoprec ipitates with p53, in vitro and in vivo. These findings suggest a func tion of BRCA1 as a p53 coactivator.