Physical and functional interaction of SMADs and p300/CBP.
SMADs are transforming growth factor beta (TGF-beta) receptor substrates and mediators of TGF-beta transcriptional responses. Here we provide evidence that the coactivators p300 and CBP interact with Smads 1 through 4. The biological relevance of this interaction is shown in vivo by overexpression of the adenovirus E1A protein and mutant forms of E1A that lack p300-binding sites. Wild-type E1A, but not the mutants, inhibits SMAD-dependent transcriptional responses to TGF-beta. E1A also inhibits the intrinsic transactivating function of the Smad4 MH2 domain. In addition, overexpression of p300 enhances SMAD-dependent transactivation. Our results suggest a role for p300/CBP in SMAD-mediated transcriptional activation and provide an explanation for the observed ability of E1A to interfere with TGF-beta action.
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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Pouponnot
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Jayaraman
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Massagué
D000123:Acetyltransferases / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000494:pharmacology; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000123:Acetyltransferases; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D056921:Nuclear Receptor Coactivator 3