Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators.
Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in many autoimmune and inflammatory diseases. Transcriptional control of IL-6 gene expression is exerted by various compounds, among which glucocorticoids are the most potent antiinflammatory and immunosuppressive agents currently in use. Glucocorticoids exert their transrepressive actions by negatively interfering with transcription factors, such as nuclear factor-kappaB (NF-kappaB) and AP-1. Both factors make use of the coactivator cAMP response element-binding protein (CREB)-binding protein (CBP) to enhance their transcriptional activities, which led to the hypothesis that a mutual antagonism between p65 or c-Jun and activated glucocorticoid receptor (GR) results from a limited amount of CBP. Recently, we showed that glucocorticoid repression of NF-kappaB-driven gene expression occurs irrespective of the amount of coactivator levels in the cell. In the current study, we extend this observation and demonstrate that also AP-1-targeted gene repression by glucocorticoids is refractory to increased amounts of nuclear coactivators. From results with Gal4 chimeric proteins we conclude that glucocorticoid repression occurs by a promoter-independent mechanism involving a nuclear interplay between activated GR and AP-1, independently of CBP levels in the cell.
De Bosscher
K
K
Department of Molecular Biology, University of Gent-VIB, K.L. Ledeganckstraat 35, 9000 Gent, Belgium.
Vanden Berghe
W
W
Haegeman
G
G
D001667:Binding, Competitive; D050882:CREB-Binding Protein; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005656:Fungal Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000502:physiology; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D005938:Glucocorticoids; D015850:Interleukin-6; D016328:NF-kappa B; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases