Ser276 phosphorylation of NF-kB p65 by MSK1 controls SCF expression in inflammation.
Transcription of the mast cell growth factor SCF (stem cell factor) is upregulated in inflammatory conditions, and this is dependent upon NF-kappaB, as well as the MAP kinases p38 and ERK activation. We show here that the MAPK downstream nuclear kinase MSK1 induces NF-kappaB p65 Ser276 phosphorylation upon IL-1beta treatment, which was inhibited in cells transfected with a MSK1 kinase-dead (KD) mutant compared to the WT control. In addition, we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP, and of MSK1 itself to the kappaB intronic enhancer site of the SCF gene. We show that interaction between NF-kappaB and CBP is prevented in cells transfected by a p65 S276C mutant. Finally, we demonstrate that both transfections of MSK1-KD and MSK1 siRNA -- but not the WT MSK1 or control siRNA -- downregulate the expression of SCF induced by IL-1ss. Our study provides therefore a direct link between MSK1-mediated phosphorylation of Ser276 p65 of NF-kappaB, allowing its binding to the SCF intronic enhancer, and pathophysiological SCF expression in inflammation.
Reber
Laurent
L
EA3771, Inflammation and Environment in Asthma, Université Louis Pasteur-Strasbourg-I, Faculté de Pharmacie, Illkirch, France.
Vermeulen
Linda
L
Haegeman
Guy
G
Frossard
Nelly
N
D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D051996:Transcription Factor RelA; D010768:Phosphoserine; D050882:CREB-Binding Protein; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1