BRCA1 Augments Transcription by the NF-κB Transcription Factor by Binding to the Rel Domain of the p65/RelA Subunit

Abstract 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-κB, binds to the BRCA1 protein. Treatment of 293T cells with the cytokine tumor necrosis factor-α 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-κB interacts with multiple sites within the N-terminal region of BRCA1. Transient transfection of BRCA1 significantly enhances the ability of the tumor necrosis factor-α or interleukin-1β to activate transcription from the promoters of NF-κB target genes. Mutation of the NF-κB-binding sites in the NF-κB reporter blocks the effect of BRCA1 on transcription. Also the ability of BRCA1 to activate NF-κB target genes is inhibited by a super-stable inhibitor of NF-κB and by the chemical inhibitor SN-50. These data indicate that BRCA1 acts as a co-activator with NF-κB. In addition, we show that cells infected with an adenovirus expressing BRCA1 up-regulate the endogenous expression of NF-κB target genes Fas and interferon-β. 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-κB.