Abstract
Following TGFbeta receptor-mediated phosphorylation and association with Smad4, Smad2 moves into the nucleus, binds to target promoters in association with DNA-binding cofactors, and recruits coactivators such as p300/CBP to activate transcription. We identified the homeodomain protein TGIF as a Smad2-binding protein and a repressor of transcription. A TGFbeta-activated Smad complex can recruit TGIF and histone deacetylases (HDACs) to a Smad target promoter, repressing transcription. Thus, upon entering the nucleus, a Smad2-Smad4 complex may interact with coactivators, forming a transcriptional activation complex, or with TGIF and HDACs, forming a transcriptional repressor complex. Formation of one of these two mutually exclusive complexes is determined by the relative levels of Smad corepressors and coactivators within the cell.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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COS Cells
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Epithelial Cells
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Forkhead Transcription Factors
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Histone Deacetylases / metabolism
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Histone Deacetylases / physiology
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Homeodomain Proteins / physiology*
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Lung
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Macromolecular Substances
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Mink
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Nuclear Proteins / physiology
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Repressor Proteins / physiology*
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Signal Transduction
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Smad2 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transcription Factors / physiology
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Transcription, Genetic
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Transforming Growth Factor beta / physiology
Substances
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxh1 protein, mouse
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Homeodomain Proteins
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Macromolecular Substances
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Nuclear Proteins
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Repressor Proteins
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Smad2 Protein
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Histone Deacetylases