The Smad transcriptional corepressor TGIF recruits mSin3.
The homeodomain protein TG-interacting factor (TGIF) represses transcription by histone deacetylase-dependent and -independent means. Heterozygous mutations in human TGIF result in holoprosencephaly, a severe genetic disorder affecting craniofacial development, suggesting that TGIF is critical for normal development. After transforming growth factorbeta (TGFbeta) stimulation, Smad proteins enter the nucleus and form transcriptional activation complexes or interact with TGIF, which functions as a corepressor. The relative levels of Smad corepressors and coactivators present within the cell may determine the outcome of a TGFbeta response. We show that TGIF interacts directly with the paired amphipathic alpha-helix 2 domain of the mSin3 corepressor, and TGIF recruits mSin3 to a TGFbeta-activated Smad complex. The mSin3 interaction domain of TGIF has been shown to be essential for repression of a TGFbeta transcriptional response. Thus, TGIF represents a targeting component of the mSin3 corepressor complex.
Wotton
D
D
Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, 800577 HSC, University of Virginia, Charlottesville, Virginia 22908, USA. dw2p@virginia.edu
Knoepfler
P S
PS
Laherty
C D
CD
Eisenman
R N
RN
Massagué
J
J
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; C497782:SMAD2 protein, human; D029701:Saccharomyces cerevisiae Proteins; D051899:Smad2 Protein; C097504:TGIF1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D006655:Histone Deacetylases