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Originally published In Press as doi:10.1074/jbc.C000416200 on September 19, 2000

J. Biol. Chem., Vol. 275, Issue 50, 39762-39766, December 15, 2000
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The Interaction of the Carboxyl Terminus-binding Protein with the Smad Corepressor TGIF Is Disrupted by a Holoprosencephaly Mutation in TGIF*

Tiffany A. Melhuish and David WottonDagger

From the Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908

The homeodomain protein TGIF represses transcription in part by recruiting histone deacetylases. TGIF binds directly to DNA to repress transcription or interacts with TGF-beta -activated Smads, thereby repressing genes normally activated by TGF-beta . Loss of function mutations in TGIF result in holoprosencephaly (HPE) in humans. One HPE mutation in TGIF results in a single amino acid substitution in a conserved PLDLS motif within the amino-terminal repression domain. We demonstrate that TGIF interacts with the corepressor carboxyl terminus-binding protein (CtBP) via this motif. CtBP, which was first identified by its ability to bind the adenovirus E1A protein, interacts both with gene-specific transcriptional repressors and with a subset of polycomb proteins. Efficient repression of TGF-beta -activated gene responses by TGIF is dependent on interaction with CtBP, and we show that TGIF is able to recruit CtBP to a TGF-beta -activated Smad complex. Disruption of the PLDLS motif in TGIF abolishes the interaction of CtBP with TGIF and compromises the ability of TGIF to repress transcription. Thus, at least one HPE mutation in TGIF appears to prevent CtBP-dependent transcriptional repression by TGIF, suggesting an important developmental role for the recruitment of CtBP by TGIF.


* 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.

Dagger To whom correspondence should be addressed: Center for Cell Signaling, University of Virginia, Hospital West, Box 800577, HSC, Charlottesville, VA 22908. Tel.: 804-243-6752; Fax: 804-924-1236; E-mail: dw2p@virginia.edu.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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