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The Role of CBP in Estrogen Receptor Cross-Talk with Nuclear Factor-B in HepG2 Cells

Women’s Health Research Institute, Wyeth-Ayerst Laboratories, Inc., Radnor, Pennsylvania 19087

Address all correspondence and requests for reprints to: Dr. Douglas C. Harnish, Women’s Health Research Institute, Wyeth-Ayerst Laboratories, Inc., 145 King of Prussia Road, Radnor, Pennsylvania 19087. E-mail: harnisd{at}war.wyeth.com

Functional interactions or cross-talk between ligand-activated nuclear receptors and the proinflammatory transcription factor nuclear factor-B (NF-B) may play a major role in ligand-mediated modification of diseases processes. In particular, the cardioprotective effects of estrogen replacement therapy are thought to be due in part to the ability of ligand-bound estrogen receptor (ER) to inhibit NF-B function. In the current study 17ß-estradiol-bound ER interfered with cytokine-induced activation of a NF-B reporter in HepG2 cells. The estrogen metabolite, 17-ethinyl estradiol, and the phytoestrogen, genistein, were also effective inhibitors of NF-B activation, whereas tamoxifen, 4-hydroxytamoxifen, and raloxifene were inactive. This inhibition was reciprocal, as NF-B interfered with the trans-activation properties of ER. Ligand-bound ER did not inhibit NF-B binding to DNA, but it did decrease the histone acetyltransferase activity required for NF-B transcriptional activity. Coexpression of the transcription coactivator CREB binding protein (CBP), but not steroid receptor coactivator 1a, reversed the ER-mediated inhibition of NF-B activity. Mammalian two-hybrid experiments also revealed that ligand-bound ER can interact functionally with CBP-NF-B complexes. We suggest that CBP targeting by ER results in the inhibition of NF-B and may occur through formation of transcriptionally inert multimeric complexes that are dependent upon the nature of the ER ligand.

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