The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation.
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.
Feng
X H
XH
Departments of Growth and Development and Anatomy, and Programs in Cell Biology and Developmental Biology, University of California, San Francisco, California 94143-0640 USA.
Zhang
Y
Y
Wu
R Y
RY
Derynck
R
R
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009698:Nucleoproteins / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009698:Nucleoproteins; D017395:Plasminogen Activator Inhibitor 1; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D050882:CREB-Binding Protein; C494363:CREBBP protein, human