Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Blotting, Western
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COS Cells
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Cell Line, Tumor
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Chromatin / metabolism
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation
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Genes, Dominant
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Genes, Reporter
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Genetic Vectors
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Humans
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Imidazoles / pharmacology
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MAP Kinase Signaling System
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Microscopy, Confocal
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases / metabolism*
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Mutation
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Protein Isoforms
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Pyridines / pharmacology
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Recombinant Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Signal Transduction*
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Smad Proteins
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Smad3 Protein
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Time Factors
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Trans-Activators / metabolism*
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Transcription Factor AP-1 / metabolism
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Transfection
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Transforming Growth Factor beta / metabolism*
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p38 Mitogen-Activated Protein Kinases
Substances
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Chromatin
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DNA-Binding Proteins
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Enzyme Inhibitors
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Imidazoles
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Protein Isoforms
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Pyridines
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Recombinant Proteins
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SMAD3 protein, human
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Smad Proteins
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Smad3 Protein
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Trans-Activators
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Transcription Factor AP-1
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Transforming Growth Factor beta
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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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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580