BRCA1 augments transcription by the NF-κB transcription factor by binding to the rel domain of the p65/RelA subunit

被引:60
作者
Benezra, M
Chevallier, N
Morrison, DJ
MacLachlan, TK
El-Deiry, WS
Licht, JD
机构
[1] CUNY Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA
[2] Univ Penn, Sch Med, Howard Hughes Med Inst, Lab Mol Oncol & Cell Cycle Regulat, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M303076200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BRCA1 is a tumor suppressor gene mutated in cases of hereditary breast and ovarian cancer. BRCA1 protein is involved in apoptosis and growth/tumor suppression. In this study, we present evidence that p65/RelA, one of the two subunits of the transcription factor NF-kappaB, binds to the BRCA1 protein. Treatment of 293T cells with the cytokine tumor necrosis factor-alpha induces an interaction between endogenous p65/RelA and BRCA1. GST-protein affinity assay experiments reveal that the Rel homology domain of the p65/RelA subunit of NF-kappaB interacts with multiple sites within the N-terminal region of BRCA1. Transient transfection of BRCA1 significantly enhances the ability of the tumor necrosis factor-alpha or interleukin-1beta to activate transcription from the promoters of NF-kappaB target genes. Mutation of the NF-kappaB-binding sites in the NF-kappaB reporter blocks the effect of BRCA1 on transcription. Also the ability of BRCA1 to activate NF-kappaB target genes is inhibited by a super-stable inhibitor of NF-kappaB and by the chemical inhibitor SN-50. These data indicate that BRCA1 acts as a co-activator with NF-kappaB. In addition, we show that cells infected with an adenovirus expressing BRCA1 up-regulate the endogenous expression of NF-kappaB target genes Fas and interferon-beta. Together, this information suggests that BRCA1 may play a role in cell life-death decisions following cell stress by modulation of the activity of NF-kappaB.
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页码:26333 / 26341
页数:9
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