Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor

Abstract

N-CoR (nuclear hormone receptor corepressor) was identified originally as a corepressor that binds to, and mediates transcriptional repression by, nuclear hormone receptors (Hö rlein et al. 1995). Thyroid-hormone and retinoic-acid receptors (TR and RAR) of the nuclear hormone receptor family actively repress the transcription of target genes in the absence of ligand (Chambon 1994;Mangelsdorf et al. 1995). Transcriptional repression is mediated by a conserved region in the aminoterminal part of the ligand-binding domain of TR (Baniahmad et al. 1995). N-CoR binds to the ligand-binding domain, termed the Co-R box, and, thereby, mediates transcriptional repression (Hö rlein et al. 1995). N-CoR is a large protein with a molecular mass of 270,000 (Mr 270K), and contains three repressor domains in its amino-terminal region (Hö rlein et al. 1995). Another corepressor, SMRT, which also binds to the Co-R box, shows striking homology to N-CoR (Chen and Evans 1995). N-CoR also forms a complex with mammalian Sin3 orthologs (mSin3A and mSin3B), which bind to another repressor, Mad (Alland et al. 1997;Hassing et al. 1997;Heinzel et al. 1997;Laherty et al. 1997;Nagy et al. 1997). The basic helix-loop-helix (bHLH) proteins of the Mad family act as transcriptional repressors after heterodimerization with Max (Ayer et al. 1993). N-CoR is required for Mad-induced transcriptional repression. The same target sequence of Mad/Max, the so-called E-box, is also recognized by a heterodimer of Myc/Max that activates transcription. It is believed that transcriptional activation of a group of target genes by Myc/Max enhances cellular proliferation or transformation, whereas transcriptional repression of the same target genes by Mad/Max leads to suppression of proliferation or induction of terminal differentiation in a wide range of cell types Chin et al. 1995;Roussel et al. 1996)

NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor

“…SnoN is a transcriptional co-repressor that interacts with Smad2/3 and Smad4, and represses TGF-β signalling through recruitment of HDAC (histone deacetylase) to Smads [40][41][42]. Bonni et al [21] have reported that Smurf2 associates with SnoN via Smad2, and induces ubiquitin-mediated degradation of SnoN, but not that of Smad2.…”

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

“…Ski has been shown to be involved in certain distinct signaling pathways including nuclear receptors (Dahl et al, 1998;Nomura et al, 1999;Ueki and Hayman, 2003b;Ritter et al, 2006), transforming growth factor-b (TGF-b) (Akiyoshi et al, 1999;Luo et al, 1999;Sun et al, 1999;Xu et al, 2000;Ueki and Hayman, 2003a) and tumor suppressors Tokitou et al, 1999;Khan et al, 2001) where Ski can act as a transcriptional corepressor. This is in part due to its direct and indirect interactions with histone deacetylase (HDAC) complexes including nuclear receptor-corepressor/silencing mediator for retinoid and thyroid hormone receptors (N-CoR/SMRT) and Sin3A corepressors Jepsen and Rosenfeld, 2002).…”

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome

“…SKI is dependent on interactions with other cellular partners, such as SMAD proteins, and transcriptional co-regulators including N-CoR, mSin3A, and histone deacetylases. 14,16 Remarkably, all SKI mutations described so far cluster into two domains: the R-SMAD binding domain, involved in TGFb signaling, and the DHD domain, which mediates binding to SNW1 and N-Cor proteins. The latter are essential for the transforming activity of SKI and for the recruitment of transcriptional corepressors.…”

“…[13][14][15] Additionally, the SKI protein can recruit transcriptional corepressors including SNW1, N-CoR, and mSIN3 and forms a complex with histone deacetylases. 16,17 In vivo studies in Xenopus embryos, zebrafish, and mice have shown that SKI has a critical role in the development of neuronal and muscle cells or tissues. [18][19][20] Homozygous Ski-targeted mice show a major reduction in skeletal muscle mass and defects in cranial neural tube closure, manifestations that resemble those observed in SGS patients.…”