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CBP Is a Dosage-Dependent Regulator of Nuclear Factor-B Suppression by the Estrogen Receptor

Department of Cancer Biology (K.W.N., G.G., J.N.), The Scripps Research Institute, Jupiter, Florida 33458; Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6026 (Intéractions Cellulaires et Moléculaires) (R.M.), Equipe Spatio-Temporal Regulation of Transcription in Eukaryotes, Université de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France; Division of Oncology (V.B.S.), Stanford University School of Medicine, Stanford, California 94305; Ben May Institute for Cancer Research and Department of Biochemistry (G.L.G.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Kendall W. Nettles, Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida 33458. E-mail: knettles{at}scripps.edu; or Geoffrey L. Greene, Ben May Institute for Cancer Research and Department of Biochemistry, University of Chicago, Chicago, Illinois 60637. E-mail: ggreene{at}uchicago.edu.

The estrogen receptor (ER) protects against debilitating effects of the inflammatory response by inhibiting the proinflammatory transcription factor nuclear factor-B (NFB). 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 NFB 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 NFB 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 NFB-signaling pathways.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   CBP

Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  Diethylstilbestrol  |  4-Hydroxytamoxifen

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