Repression of BRCA1 through a Feedback Loop Involving p53

• Published in: The Journal of biological chemistry 2000-10, Vol.275 (41), p.31869-31875
• Main Authors: MacLachlan, Timothy K., Dash, Bipin C., Dicker, David T., El-Deiry, Wafik S.
• Format: Article
• Language: English
• Subjects: adriamycin; Ataxia Telangiectasia Mutated Proteins; BRCA1 gene; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Cell Cycle Proteins; DNA Damage - drug effects; DNA-Binding Proteins; Down-Regulation - drug effects; Doxorubicin - pharmacology; Feedback; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Genes, BRCA1 - genetics; Genes, Reporter; Humans; mitomycin; Mitomycin - pharmacology; mitomycin C; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Promoter Regions, Genetic - genetics; Protein-Serine-Threonine Kinases - genetics; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M003338200

The BRCA1 and p53 tumor suppressors have been shown to interact and cooperate to activate transcription of p53-responsive genes. In this study, we show that BRCA1 is initially up-regulated, followed by a reduction to below basal levels in response to treatment with the DNA-damaging agents adriamycin and mitomycin C, and that the reduction of BRCA1 expression is dependent on the presence of wild-type p53. Elimination of p53 by expression of human papilloma virus E6 resulted in an inability to down-regulate BRCA1 in response to adriamycin. Ectopic expression of p53 resulted in a rapid decrease in BRCA1 protein and RNA levels and BRCA1promoter-driven luciferase activity even in null p21 cells deficient in p53-dependent G1 arrest. ATM−/− lymphoblastoid cells were deficient in their ability to reduce BRCA1 protein in response to DNA damage, whereas the wild-type counterparts reduced BRCA1 protein levels after exposure to adriamycin. These results, in conjunction with others, suggest a loop wherein BRCA1 initially participates in accumulation of p53 protein, whereas later p53 acts to reduce BRCA1 expression.