Altered Subcellular Distribution of MSK1 Induced by Glucocorticoids Contributes to NF-kappaB Inhibition

EMBO J. 2008 Jun 18;27(12):1682-93. doi: 10.1038/emboj.2008.95. Epub 2008 May 29.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cytokines / genetics
  • Cytoplasm / enzymology
  • Enzyme Induction / drug effects
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology*
  • Histones / metabolism
  • Humans
  • Inflammation / genetics
  • Isoquinolines / pharmacology
  • Karyopherins / metabolism
  • Ligands
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Transport
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Serine / metabolism
  • Subcellular Fractions / enzymology
  • Sulfonamides / pharmacology
  • Transcription Factor RelA / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • Glucocorticoids
  • Histones
  • Isoquinolines
  • Karyopherins
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Sulfonamides
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • exportin 1 protein
  • Serine
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide