Evidence for a role of MSK1 in transforming growth factor-beta-mediated responses through p38alpha and Smad signaling pathways.
Smad proteins are central mediators of the transforming growth factor-beta (TGF-beta) superfamily signaling. The mitogen-activated protein kinase (MAPK) p38 is also one of the downstream targets required for TGF-beta-mediated responses. Although the interplay between the p38 and Smad signaling pathways might allow cells to display diverse patterns of responses to TGF-beta, the mechanism of this cross-talk is not well established. We report here that inhibition of the p38alpha isoform suppressed the ability of Smad3 to mediate TGF-beta-induced transcriptional responses. The inhibition of p38 activity blocked TGF-beta-mediated phosphorylation of the MSK1 kinase, a substrate of p38 that plays an important role in the remodeling of chromatin. Moreover, we observed that expression of dominant-interfering mutants of MSK1 blocked the binding of Smad3 to the coactivator p300 in response to TGF-beta signaling. These data reveal a new mechanism whereby the Smad signaling pathway and the p38 cascade are integrated in the nucleus to activate gene expression.
Abécassis
Lucile
L
INSERM U542, Bâtiment Lavoisier, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94807 Villejuif, France.
Rogier
Edith
E
Vazquez
Aimé
A
Atfi
Azzedine
A
Bourgeade
Marie-Françoise
MF
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D018613:Microscopy, Confocal; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D011725:Pyridines; D011994:Recombinant Proteins; C497790:SMAD3 protein, human; D051785:Smad Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580