title: The role of CBP in estrogen receptor cross-talk with nuclear factor-kappaB in HepG2 cells.
abstract: Functional interactions or cross-talk between ligand-activated nuclear receptors and the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB function. In the current study 17beta-estradiol-bound ERalpha interfered with cytokine-induced activation of a NF-kappaB reporter in HepG2 cells. The estrogen metabolite, 17alpha-ethinyl estradiol, and the phytoestrogen, genistein, were also effective inhibitors of NF-kappaB activation, whereas tamoxifen, 4-hydroxytamoxifen, and raloxifene were inactive. This inhibition was reciprocal, as NF-kappaB interfered with the trans-activation properties of ERalpha. Ligand-bound ERalpha did not inhibit NF-kappaB binding to DNA, but it did decrease the histone acetyltransferase activity required for NF-kappaB transcriptional activity. Coexpression of the transcription coactivator CREB binding protein (CBP), but not steroid receptor coactivator 1a, reversed the ERalpha-mediated inhibition of NF-kappaB activity. Mammalian two-hybrid experiments also revealed that ligand-bound ERalpha can interact functionally with CBP-NF-kappaB complexes. We suggest that CBP targeting by ERalpha results in the inhibition of NF-kappaB and may occur through formation of transcriptionally inert multimeric complexes that are dependent upon the nature of the ERalpha ligand.
authors.affiliation: Women's Health Research Institute, Wyeth-Ayerst Laboratories, Inc, Radnor, Pennsylvania 19087, USA. harnisd@war.wyeth.com
authors.forename: D C
authors.initials: DC
authors.lastname: Harnish
authors.forename: M S
authors.initials: MS
authors.lastname: Scicchitano
authors.forename: S J
authors.initials: SJ
authors.lastname: Adelman
authors.forename: C R
authors.initials: CR
authors.lastname: Lyttle
authors.forename: S K
authors.initials: SK
authors.lastname: Karathanasis
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015153:Blotting, Western; D050882:CREB-Binding Protein; D002460:Cell Line; D004586:Electrophoresis; D004967:Estrogens / Q000494:pharmacology; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D004967:Estrogens; D056572:Histone Deacetylase Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D008156:Luciferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human