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.
Nettles
Kendall W
KW
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA. knettles@scripps.edu
Gil
German
G
Nowak
Jason
J
Métivier
Raphaël
R
Sharma
Vandana B
VB
Greene
Geoffrey L
GL
D015152:Blotting, Northern; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D047628:Estrogen Receptor alpha; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D050882:CREB-Binding Protein; C494363:CREBBP protein, human