Abstract
Glucocorticoids are widely used anti-inflammatory and immunomodulatory agents, of which the action mechanism is mainly based on interference of hormone-activated glucocorticoid receptor (GR) with the activity of transcription factors, such as nuclear factor-kappaB (NF-kappaB). In addition to the well described interaction-based mutual repression mechanism between the GR and NF-kappaB, additional mechanisms are at play, which help to explain the efficacy of glucocorticoid-mediated gene repression. In this respect, we found that glucocorticoids counteract the recruitment of activated Mitogen- and Stress-activated protein Kinase-1 (MSK1) at inflammatory gene promoters resulting in the inhibition of NF-kappaB p65 transactivation and of concurrent histone H3 phosphorylation. Additionally, we observed that activated GR can trigger redistribution of nuclear MSK1 to the cytoplasm through a CRM1-dependent export mechanism, as a result of an interaction between liganded GR and activated MSK1. These findings unveil a novel aspect within the GR-mediated NF-kappaB-targeting anti-inflammatory mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Cytokines / genetics
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Cytoplasm / enzymology
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Enzyme Induction / drug effects
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Exportin 1 Protein
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Gene Expression Regulation / drug effects
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Glucocorticoids / pharmacology*
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Histones / metabolism
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Humans
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Inflammation / genetics
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Isoquinolines / pharmacology
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Karyopherins / metabolism
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Ligands
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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Protein Transport
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Glucocorticoid / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Serine / metabolism
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Subcellular Fractions / enzymology
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Sulfonamides / pharmacology
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Transcription Factor RelA / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cytokines
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Glucocorticoids
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Histones
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Isoquinolines
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Karyopherins
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Ligands
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Receptors, Cytoplasmic and Nuclear
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Receptors, Glucocorticoid
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Sulfonamides
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Serine
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide