Abstract
Smad3 is a direct mediator of transcriptional activation by the TGFbeta receptor. Its target genes in epithelial cells include cyclin-dependent kinase inhibitors that generate a cytostatic reponse. We defined how, in the same context, Smad3 can also mediate transcriptional repression of the growth-promoting gene c-myc. A complex containing Smad3, the transcription factors E2F4/5 and DP1, and the corepressor p107 preexists in the cytoplasm. In response to TGFbeta, this complex moves into the nucleus and associates with Smad4, recognizing a composite Smad-E2F site on c-myc for repression. Previously known as the ultimate recipients of cdk regulatory signals, E2F4/5 and p107 act here as transducers of TGFbeta receptor signals upstream of cdk. Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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Animals
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Binding Sites
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COS Cells
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Cell Cycle / physiology
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology
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Chlorocebus aethiops
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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E2F4 Transcription Factor
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E2F5 Transcription Factor
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Gene Silencing*
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Humans
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-myc / genetics*
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Receptors, Transforming Growth Factor beta / metabolism*
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Retinoblastoma-Like Protein p107
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Smad3 Protein
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transcription Factor DP1
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcription, Genetic
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
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Tumor Cells, Cultured
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F4 Transcription Factor
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E2F5 Transcription Factor
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E2F5 protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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RBL1 protein, human
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Receptors, Transforming Growth Factor beta
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Retinoblastoma-Like Protein p107
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SMAD3 protein, human
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Smad3 Protein
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TFDP1 protein, human
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TFDP2 protein, human
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Trans-Activators
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Transcription Factor DP1
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Transcription Factors
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Transforming Growth Factor beta