A Smad Transcriptional Corepressor

Abstract

Following TGFbeta receptor-mediated phosphorylation and association with Smad4, Smad2 moves into the nucleus, binds to target promoters in association with DNA-binding cofactors, and recruits coactivators such as p300/CBP to activate transcription. We identified the homeodomain protein TGIF as a Smad2-binding protein and a repressor of transcription. A TGFbeta-activated Smad complex can recruit TGIF and histone deacetylases (HDACs) to a Smad target promoter, repressing transcription. Thus, upon entering the nucleus, a Smad2-Smad4 complex may interact with coactivators, forming a transcriptional activation complex, or with TGIF and HDACs, forming a transcriptional repressor complex. Formation of one of these two mutually exclusive complexes is determined by the relative levels of Smad corepressors and coactivators within the cell.

TGIF, a gene associated with human brain defects, regulates neuronal development

“…In addition, in vitro studies have demonstrated that TGIF can regulate transforming growth factor-␤ (TGF-␤) -responsive gene expression (Wotton et al, 1999a). TGIF can bind Smads, intracellular components of TGF-␤ signaling Wrana and Attisano, 2000;ten Dijke et al, 2002).…”

Expression and functional analysis of Tgif during mouse midline development

“…Tgif encodes a homeodomain protein that was originally identified by its ability to bind a retinoid X receptor (RXR) responsive element and inhibit activation of transcription (Bertolino et al, 1995). Subsequent studies disclosed that TGIF contains multiple transcription repression domains and plays an important role as a negative regulator of Activin/TGF-␤ signaling by binding to Smad2 (Wotton et al, 1999a). Briefly, the binding of TGIF to Smad2 leads to the recruitment of general transcription repressors such as histone deacetylases (HDACs) (Wotton et al, 1999a) and Sin3 ) into the Smad2-Smad4 complex.…”

“…Subsequent studies disclosed that TGIF contains multiple transcription repression domains and plays an important role as a negative regulator of Activin/TGF-␤ signaling by binding to Smad2 (Wotton et al, 1999a). Briefly, the binding of TGIF to Smad2 leads to the recruitment of general transcription repressors such as histone deacetylases (HDACs) (Wotton et al, 1999a) and Sin3 ) into the Smad2-Smad4 complex. The recruited transcriptional repressors compete out the transcriptional activators, such as p300, and suppress the Smad2-Smad4 mediated transcription (Wotton et al, 1999a).…”

“…Briefly, the binding of TGIF to Smad2 leads to the recruitment of general transcription repressors such as histone deacetylases (HDACs) (Wotton et al, 1999a) and Sin3 ) into the Smad2-Smad4 complex. The recruited transcriptional repressors compete out the transcriptional activators, such as p300, and suppress the Smad2-Smad4 mediated transcription (Wotton et al, 1999a). This repression is independent of DNA binding.…”

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

“…MH1 and MH2, which are separated by a proline-rich linker region of variable length, have distinct functions. The MH2 domain is important for homo-and heteromeric complex formation and for transcriptional activation and repression (Feng et al, 1998;Janknecht et al, 1998;Kawabata et al, 1998;Luo et al, 1999;Wotton et al, 1999). In addition, the MH2 domains of Smad2 and Smad3, but not Smad4, interact with type I receptors (Lo et al, 1998;MacõÂ as-Silva et al, 1996;Zhang et al, 1996).…”