Physical and Functional Interaction of SMADs and p300/CBP*
- From the Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Abstract
SMADs are transforming growth factor β (TGF-β) receptor substrates and mediators of TGF-β 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-β. 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-β action.
Footnotes
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↵* This work was supported by National Institutes of Health Grant CA34610.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ These authors are equal contributors.
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↵§ Recipient of a postdoctoral fellowship from the International Agency for Research on Cancer when this work was initiated. Research Associate of the Howard Hughes Medical Institute.
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↵¶ Research Associate of the Howard Hughes Medical Institute.
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↵‖ To whom correspondence should be addressed: Memorial Sloan-Kettering Cancer Center, Box 116, 1275 York Ave., New York, NY 10021. Tel.: 212-639-8975; Fax: 212-717-3298; E-mail:j-massague{at}ski.mskcc.org.
- Abbreviations:
- TGF-β
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transforming growth factor β
- CBP
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CREB-binding protein
- FAST1
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forkhead activated signal transducer
- ARE
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activin responsive element
- BMP
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bone morphogenetic protein.
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- Received June 18, 1998.
- Revision received June 30, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
