BRCA1 signals ARF-dependent stabilization and coactivation of p53.
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 p14ARF-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 p14ARF 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.
Somasundaram
K
K
Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
MacLachlan
T K
TK
Burns
T F
TF
Sgagias
M
M
Cowan
K H
KH
Weber
B L
BL
el-Deiry
W S
WS
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019313:BRCA1 Protein; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D020727:ADP-Ribosylation Factors