Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-kappaB inhibition.
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.
Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Gent University, Gent, Belgium.
Ilse M E
IM
Beck
Wim
W
Vanden Berghe
Linda
L
Vermeulen
Nadia
N
Bougarne
Bert
B
Vander Cruyssen
Guy
G
Haegeman
Karolien
K
De Bosscher
D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097606:Exportin 1 Protein
D016207:Cytokines; D005938:Glucocorticoids; D006657:Histones; D007546:Isoquinolines; D028884:Karyopherins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D012694:Serine; D013449:Sulfonamides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000097606:Exportin 1 Protein; C116919:mitogen and stress-activated protein kinase 1; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide