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J. Biol. Chem., Vol. 275, Issue 50, 39762-39766, December 15, 2000
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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-
The Interaction of the Carboxyl Terminus-binding Protein with the
Smad Corepressor TGIF Is Disrupted by a Holoprosencephaly Mutation in
TGIF*
-activated Smads, thereby repressing genes normally activated by
TGF-
. 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-
-activated gene responses by
TGIF is dependent on interaction with CtBP, and we show that TGIF is able to recruit CtBP to a TGF-
-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.
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.
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