p53 mediates repression of the BRCA2 promoter and down-regulation of BRCA2 mRNA and protein levels in response to DNA damage.
Adriamycin and other DNA-damaging agents have been shown to reduce BRCA2 mRNA levels in breast cancer cell lines, but the mechanism by which this occurs is unknown. In this study, we show that adriamycin and mitomycin C, but not other DNA-damaging agents, repress BRCA2 promoter activity in a dose- and time-dependent manner. We demonstrate that the effect is dependent on wild type p53 and that adriamycin and p53 mediate repression of the BRCA2 promoter by inhibiting binding of an upstream stimulatory factor protein complex to the promoter. In addition, we present evidence indicating that adriamycin and other DNA-damaging agents reduce BRCA2 mRNA and protein levels by altering both BRCA2 mRNA stability and protein stability. Thus, BRCA2 levels in the cell are regulated by three independent mechanisms in a p53-dependent manner.
Wu
Kangjian
K
Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, 1001 Guggenheim Building, 200 First Street SW, Rochester, MN 55905, USA.
Jiang
Shi-Wen
SW
Couch
Fergus J
FJ
D024682:BRCA2 Protein / Q000032:analysis*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D024522:Genes, BRCA2; D006801:Humans; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051720:Upstream Stimulatory Factors
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051720:Upstream Stimulatory Factors; D004317:Doxorubicin