BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit.
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.
Mesh Terms:
BRCA1 Protein, Base Sequence, Binding Sites, Breast Neoplasms, Carrier Proteins, Cell Line, DNA Primers, Female, Humans, Models, Biological, Mutagenesis, Site-Directed, NF-kappa B, Promoter Regions, Genetic, Protein Structure, Tertiary, Recombinant Proteins, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
BRCA1 Protein, Base Sequence, Binding Sites, Breast Neoplasms, Carrier Proteins, Cell Line, DNA Primers, Female, Humans, Models, Biological, Mutagenesis, Site-Directed, NF-kappa B, Promoter Regions, Genetic, Protein Structure, Tertiary, Recombinant Proteins, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Jul. 18, 2003
PubMed ID: 12700228
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