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 breast and ovarian cancer. Here we report that BRCA1 stimulates artificial and genomic promoter constructs containing p53-responsive elements. This activity of BRCA1 depends on the presence of wild-type p53, which was shown by using mouse fibroblasts expressing temperature-sensitive forms of p53, or p53(+/+) and p53(-/-) fibroblasts obtained from p53 knockout mice. Furthermore, mutant forms of BRCA1 lacking the C-terminal second BRCA1 C-terminal (BRCT) domain showed reduced p53-mediated transcriptional activation. Finally, we found that BRCA1 coimmunoprecipitates with p53, in vitro and in vivo. These findings suggest a function of BRCA1 as a p53 coactivator.
Ouchi
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Laboratory of Molecular Oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Monteiro
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August
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Aaronson
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Hanafusa
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D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001940:Breast; D002460:Cell Line; D004847:Epithelial Cells; D005260:Female; D005786:Gene Expression Regulation; D019398:Genes, BRCA1; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D007680:Kidney Neoplasms; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019313:BRCA1 Protein; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D005982:Glutathione Transferase