Abstract
The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53-dependent gene expression. We show here that BRCA1 increases p53 protein levels through a post-transcriptional mechanism. BRCA1-stabilized p53 has increased sequence-specific DNA-binding and transcriptional activity. BRCA1 does not stabilize p53 in p14(ARF)-deficient cells. A deletion mutant of BRCA1 which inhibits p53-dependent transcription confers resistance to topoisomerase II-targeted chemotherapy. Our results suggest that BRCA1 may trigger the p53 pathway through two potentially separate mechanisms: accumulation of p53 through a direct or indirect induction of p14(ARF) as well as direct transcriptional coactivation of p53. BRCA1 may also enhance chemosensitivity and repair of DNA damage through binding to and coactivation of p53.
Original language | English (US) |
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Pages (from-to) | 6605-6614 |
Number of pages | 10 |
Journal | Oncogene |
Volume | 18 |
Issue number | 47 |
DOIs | |
State | Published - Nov 11 1999 |
Keywords
- BRCA1
- p14(ARF)
- p53
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research