Abstract
The Sma and Mad related (Smad) family proteins are critical mediators of the transforming growth factor-beta (TGF-beta) superfamily signaling. After TGF-beta-mediated phosphorylation and association with Smad4, Smad2 moves to the nucleus and activates expression of specific genes through cooperative interactions with DNA-binding proteins, including members of the winged-helix family of transcription factors, forkhead activin signal transducer (FAST)-1 and FAST2. TGF-beta has also been described to activate other signaling pathways, such as the c-Jun N-terminal Kinase (JNK) pathway. Here, we show that activation of JNK cascade blocked the ability of Smad2 to mediate TGF-beta-dependent activation of the FAST proteins. This inhibitory activity is mediated through the transcriptional factor c-Jun, which enhances the association of Smad2 with the nuclear transcriptional corepressor TG-interacting factor (TGIF), thereby interfering with the assembly of Smad2 and the coactivator p300 in response to TGF-beta signaling. Interestingly, c-Jun directly binds to the nuclear transcriptional corepressor TGIF and is required for TGIF-mediated repression of Smad2 transcriptional activity. These studies thus reveal a mechanism for suppression of Smad2 signaling pathway by JNK cascade through transcriptional repression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Chlorocebus aethiops
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Forkhead Transcription Factors
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Gene Expression Regulation*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4*
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MAP Kinase Kinase Kinase 1*
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction / physiology*
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Smad2 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription, Genetic
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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FOXH1 protein, human
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Forkhead Transcription Factors
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Foxh1 protein, mouse
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Homeodomain Proteins
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Repressor Proteins
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SMAD2 protein, human
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Smad2 Protein
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TGIF1 protein, human
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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MAP Kinase Kinase 4
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MAP2K4 protein, human
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Mitogen-Activated Protein Kinase Kinases