BRCA1 physically associates with p53 and stimulates its transcriptional activity.
Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer. Although BRCA1 is required for normal mouse development, the molecular basis for its tumor suppressive function remains poorly understood. We show here that BRCA1 increases p53-dependent transcription from the p21WAF1/CIP1 and bax promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224-500 of BRCA1 and the C-terminal domain of p53. Tumor-derived transactivation-deficient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription. BRCA1 and p53 cooperatively induce apoptosis of cancer cells. The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.
Zhang
H
H
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Somasundaram
K
K
Peng
Y
Y
Tian
H
H
Zhang
H
H
Bi
D
D
Weber
B L
BL
El-Deiry
W S
WS
D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016296:Mutagenesis; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D019313:BRCA1 Protein; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53