Abstract
Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor beta-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiation of Smad signaling. Conversely, few studies have suggested the possible nuclear functions of inhibitory Smads. Here, we present compelling evidence demonstrating that Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). A consensus CtBP-binding motif, PLDLS, was identified in the linker region of Smad6. Our findings show that mutation in the motif abolished the Smad6 binding to CtBP and subsequently its repressor activity of transcription. We conclude that the nuclear functions and physical interaction of Smad6 and CtBP provide a novel mechanism for the transcriptional regulation by inhibitory Smads.
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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Alcohol Oxidoreductases
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Base Sequence
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism*
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Cell Line
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DNA / genetics
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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HeLa Cells
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Humans
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Inhibitor of Differentiation Protein 1
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Mice
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Models, Biological
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Molecular Sequence Data
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Mutation
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Promoter Regions, Genetic
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Sequence Homology, Amino Acid
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Signal Transduction
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Smad6 Protein
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Smad7 Protein
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Trans-Activators / chemistry
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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 Factors / metabolism
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Transcription, Genetic
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Transforming Growth Factor beta*
Substances
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BMP2 protein, human
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Bmp2 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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DNA-Binding Proteins
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ID1 protein, human
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Idb1 protein, mouse
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Inhibitor of Differentiation Protein 1
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Phosphoproteins
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Repressor Proteins
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SMAD6 protein, human
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SMAD7 protein, human
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Smad6 Protein
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Smad6 protein, mouse
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Smad7 Protein
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Smad7 protein, mouse
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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DNA
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Alcohol Oxidoreductases
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C-terminal binding protein