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This version published online on October 11, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0324
A more recent version of this article appeared on February 1, 2008
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Submitted on June 26, 2007
Accepted on October 1, 2007

CBP is a dosage dependent regulator of NF{kappa}B suppression by the estrogen receptor

Kendall W. Nettles*, German Gil, Jason Nowak, Raphaël Métivier, Vandana B. Sharma, and Geoffrey L. Greene*

Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA; UMR CNRS 6026 (ICM), Equipe SPARTE, Université de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France; Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Ben May Institute for Cancer Research, and Department of Biochemistry, University of Chicago, Chicago, IL 60637, USA

* To whom correspondence should be addressed. E-mail: knettles{at}scripps.edu or ggreene{at}uchicago.edu.

The estrogen receptor (ER) protects against debilitating effects of the inflammatory response by inhibiting the pro-inflammatory transcription factor NF{kappa}B. Heretofore CBP has been suggested to mediate inhibitory cross-talk by functioning either as a scaffold that links ER and NF{kappa}B 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 NF{kappa}B response element of the MCP-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 over-expression 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 NF{kappa}B signaling pathways.
Key words: Estrogen receptor • NF{kappa}B • CBP • transcriptional repression

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Coregulators:   CBP
Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  Diethylstilbestrol  |  4-Hydroxytamoxifen



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