title: Mitogen- and stress-activated protein kinase 1 MSK1 regulates glucocorticoid response element promoter activity in a glucocorticoid concentration-dependent manner.
abstract: The glucocorticoid receptor is a nuclear receptor, and can be activated by glucocorticoid ligands. Mitogen- and stress-activated protein kinase (MSK1), when activated by p38 and ERK mitogen-activated protein kinases (MAPKs), plays a major role in chromatin relaxation via phosphorylation of histone H3 S10. The glucocorticoid receptor can target MSK1 as part of its anti-inflammatory mechanism. Here, we studied the converse mechanism, i.e. the impact of MSK1 on glucocorticoid receptor-mediated transactivation. Upstream MSK1-activating kinases concentration-dependently enhanced glucocorticoid response element (GRE)-regulated promoter activity. Correspondingly, MSK1 inhibition, via H89, or combined p38 and ERK MAPK inhibition, via SB203580 and U0126, diminished maximally stimulated GRE-regulated promoter activity using high concentrations of glucocorticoids. Concomitantly, the combination of these agents does not seem to alter site-specific phosphorylations of murine glucocorticoid receptor S212 or S220. Paradoxically, we reveal that a sub-maximally activated GRE-mediated promoter activity, by using lower concentrations of glucocorticoids, is consistently enhanced by H89 or a combination of SB203580 and U0126, irrespective of the GRE promoter context. Furthermore, we show that the glucocorticoid-induced nucleocytoplasmic translocation of MSK1 occurs in a glucocorticoid concentration-dependent manner. The observed glucocorticoid concentration-dependent effect of MSK1 or MAPK inhibition on glucocorticoid receptor transactivation warrants further research into the applicability of combined glucocorticoid and kinase inhibitor strategies for anti-inflammatory purposes.
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Therapy & Experimental Cancer Research, Ghent University, UZ 1P7, De Pintelaan 185, B-9000 Gent, Belgium. Ilse.Beck@UGent.be
authors.forename: Ilse M
authors.initials: IM
authors.lastname: Beck
authors.forename: Dorien
authors.initials: D
authors.lastname: Clarisse
authors.forename: Nadia
authors.initials: N
authors.lastname: Bougarne
authors.forename: Sam
authors.initials: S
authors.lastname: Okret
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007546:Isoquinolines; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Concentration-dependent effect; Glucocorticoid receptor; MAPK (Mitogen-activated protein kinase); MSK1 (Mitogen- and stress-activated protein kinase 1); Transactivation