Abstract
Smads regulate transcription of defined genes in response to TGF-beta receptor activation, although the mechanisms of Smad-mediated transcription are not well understood. We demonstrate that the TGF-beta-inducible Smad3 uses the tumor suppressor Smad4/DPC4 and CBP/p300 as transcriptional coactivators, which associate with Smad3 in response to TGF-beta. The association of CBP with Smad3 was localized to the carboxyl terminus of Smad3, which is required for transcriptional activation, and a defined segment in CBP. Furthermore, CBP/p300 stimulated both TGF-beta- and Smad-induced transcription in a Smad4/DPC4-dependent fashion. Smad3 transactivation and TGF-beta-induced transcription were inhibited by expressing E1A, which interferes with CBP functions. The coactivator functions and physical interactions of Smad4 and CBP/p300 with Smad3 allow a model for the induction of gene expression in response to TGF-beta.
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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Adenovirus E1A Proteins / metabolism
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Animals
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Binding Sites
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COS Cells
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CREB-Binding Protein
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Genes, Tumor Suppressor*
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Humans
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleoproteins / metabolism
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Plasminogen Activator Inhibitor 1 / genetics
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Promoter Regions, Genetic
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription, Genetic
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Transcriptional Activation*
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
Substances
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Adenovirus E1A Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Nucleoproteins
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Plasminogen Activator Inhibitor 1
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SMAD2 protein, human
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SMAD3 protein, human
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SMAD4 protein, human
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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CREB-Binding Protein
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CREBBP protein, human