CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor.

The estrogen receptor (ER) protects against debilitating effects of the inflammatory response by inhibiting the proinflammatory transcription factor nuclear factor-kappaB (NFkappaB). Heretofore cAMP response element-binding protein (CREB)-binding protein (CBP) has been suggested to mediate inhibitory cross talk by functioning either as a scaffold that links ER and NFkappaB or as ...
a required cofactor that competitively binds to one or the other transcriptional factor. However, here we demonstrate that ER is recruited to the NFkappaB response element of the MCP-1 (monocyte chemoattractant protein-1) and IL-8 promoters and displaces CBP, but not p65, in the MCF-7 breast cancer cell line. In contrast, ER displaced p65 and associated coregulators from the IL-6 promoter, demonstrating a gene-specific role for CBP in integrating inflammatory and steroid signaling. Further, RNA interference and overexpression studies demonstrated that CBP dosage regulates estrogen-mediated suppression of MCP-1 and IL-8, but not IL-6, gene expression. This work further demonstrates that CBP dosage is a critical regulator of gene-specific signal integration between the ER- and NFkappaB-signaling pathways.
Mesh Terms:
Blotting, Northern, CREB-Binding Protein, Cell Line, Tumor, Chemokine CCL2, Chromatin Immunoprecipitation, Electrophoretic Mobility Shift Assay, Estradiol, Estrogen Receptor alpha, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Immunoprecipitation, Interleukin-6, Interleukin-8, Models, Biological, NF-kappa B, Polymerase Chain Reaction, Protein Binding, Transcription Factor RelA, Tumor Necrosis Factor-alpha
Mol. Endocrinol.
Date: Feb. 01, 2008
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