c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity.
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.
Mesh Terms:
Animals, COS Cells, Cercopithecus aethiops, DNA-Binding Proteins, Forkhead Transcription Factors, Gene Expression Regulation, Homeodomain Proteins, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, MAP Kinase Kinase Kinase 1, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Protein-Serine-Threonine Kinases, Repressor Proteins, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta, Tumor Cells, Cultured
Animals, COS Cells, Cercopithecus aethiops, DNA-Binding Proteins, Forkhead Transcription Factors, Gene Expression Regulation, Homeodomain Proteins, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, MAP Kinase Kinase Kinase 1, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Protein-Serine-Threonine Kinases, Repressor Proteins, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta, Tumor Cells, Cultured
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 22, 2001
PubMed ID: 11371641
View in: Pubmed Google Scholar
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