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SKI (SKI proto-oncogene)

Written2021-02Miriam Frech, Andreas Neubauer
Clinic for Hematology, Oncology, Immunology and Center for Tumor Biology and Immunology, Philipps University Marburg, Germany / frechm@staff.uni-marburg.de, neubauer@staff.uni-marburg.de

Abstract SKI gene is located on chromosome 1 (1p36.33-p36.32) and encodes a predominantly nuclear co-regulator of several transcription factors. SKI is also a proto-oncogene. SKI was initially found as the viral protein v-Ski of the Sloan-Kettering viruses, which are able to transform avian cells in vitro. SKI is a well described inhibitor of TGFβ signalling and is further involved in essential cellular mechanisms like proliferation and differentiation. As an oncogene SKI is further overexpressed in various tumours promoting transformation and tumour progression, but in some tumours SKI is also described as a tumour suppressor.

Keywords SKI, TGFbeta signalling, oncoprotein

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Identity

Alias (NCBI)SGS
SKV
HGNC (Hugo) SKI
HGNC Previous namev-ski avian sarcoma viral oncogene homolog
LocusID (NCBI) 6497
Atlas_Id 42303
Location 1p36.33-p36.32  [Link to chromosome band 1p36]
Location_base_pair Starts at 2228319 and ends at 2310213 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SKI.png]
Local_order 2228319-2310213 (GRCh38/hg38), plus strand
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Figure 1. Scheme of the SKI gene consisting of 7 exons. There are three MYB binding sites in exon 1 and intron 1 as well as interaction sites for serum-response factor (SRF) and PPARD in the SKI regulatory region contributing to the induction of SKI expression. Inhibition of SKI can be mediated via hypermethylation of the SKI regulatory region or micro RNAs (miRs) interacting with the 3'UTR of SKI transcript.
Description SKI is a protein coding gene that encompasses about 81.9 kb of genomic DNA and comprises 7 exons. It is located on the short arm of human chromosome 1 (1p36.33-p36.32).
Transcription SKI has 4 transcripts of which only one is protein coding (SKI-201, ENST00000378536.5), 237 orthologues, 3 paralogues ( SKIL, SKOR1, SKOR2) and is associated with 39 phenotypes. So far only a few factors are identified, which are involved in the regulation of SKI gene expression. In murine cardiac cells, serum-response factor ( SRF) is able to interact with CArG and CArG-like boxes in the 5'UTR and induces Ski expression (Zhang et al., 2005). Moreover, PPARD induces Ski expression by binding to a direct repeat-1 (DR1) response element (-865~-853) in the Ski promoter region in rat skin fibroblasts (Li et al., 2012). Also as part of a negative feedback loop, retinoic acid seems to induce SKI gene expression in Xenopus embryos and in immortalised human keratinocytes (HaCaT) (Melling et al., 2013). In human leukemic cells, SKI expression is further dependent on MYB, which interacts with MYB binding sites in the SKI regulatory region (Frech et al., 2018). It was also reported that SKI expression is inhibited by hypermethylation of the SKI promoter region in human lung cancer cells (Xie et al., 2017). Laidlaw et al. (2020) showed in a mouse model that the transcription factor Hhex induces Ski expression in memory B cells. Post-transcriptionally SKI mRNA levels are also regulated by several microRNAs (miRs), like MIR155, MIR29A, MIR21, MIR-127-3p, MIR1908, MIR17-5p, MIR34A, MIR93, MIR339 all interacting with the 3'UTR (s. Figure 1).

Protein

Note The SKI family consists of SKI, SKIL (alias SnoN, SnoN2, SnoI, SnoA), SKOR1 (alias CORL1, FUSSEL15, LBXCOR1), SKOR2 (alias CORL2, FUSSEL18) DACH1, DACH2.
Description SKI consists of 728 amino acids (aa) and contains three main domains. The DHD (dachshund homology domain, aa 91-192), also characterising the SKI family, is highly conserved and located near the N-terminus. It also contains Leu127, which is important for the stabilization of the DHD domain and thereby its interaction with NCOR and SMAD2 / SMAD3 (Ueki & Hayman, 2003, Wilson et al., 2004). The second conserved domain is the SAND-L (SAND-like, aa 219-312) domain. Both domains show homologies with DNA-interacting proteins but have lost the ability to bind DNA. They serve as domains for the interaction with transcription factors, transcriptional coregulators, kinases or other factors (s. Figure 2)(Bonnon & Atanasoski, 2012, Tecalco-Cruz et al., 2018). Via the interaction with other factors, SKI is recruited to the DNA and can act as co-regulator. The C-terminal part is more variable and comprises two coiled-coil (CC) regions mainly enabeling SKI homodimerization and heterodimerization with its paralog SnoN (Heyman & Stavnezer, 1994). The N-terminus further contains a proline-rich part (aa 61-89). Also, the region responsible for SKI's transformational activity lies in the N-terminal part (1-304) (Teclaco-Cruz, 2018). The degradation of SKI is regulated via PTM. For degradation via the ubiquitin-proteasome system (UPS) SKI is polyubiquitinylated at so far unidentified lysine residues by RNF111 (the E3 ligase ARKADIA). For the polyubiquitination SKI needs not only to interact with ARKADIA via aa 211-490 but also with SMAD2/3 (Nagano et al., 2007, Nagano et al., 2010). SKI is further a phosphoprotein (Struave et al., 1990). During mitosis SKI seems to be phosphorylated by CDK1 / CCNB1 (Cyclin B) and is localised at the centrososmes and mitotic spindle (Marcelain & Hayman, 2005). Furthermore, SKI phosphorylation and subsequent destabalization is mediated by the kinases AKT and AURKA. SKI phosphorylation by AKT at T458 is induced by insulin ( INS), insulin-like growth factor-1 ( IGF1R and IGF2R) and hepatocyte growth factor ( HGF) (Band et al., 2009). In contrast, AURKA phosphorylates SKI at S326 and S383 causing its degradation as well as centrosomes amplification and multipolar spindles formation (Mosquera et al, 2011, Rivas et al., 2016). S515 was described as another SKI phosphorylation site, which has no influence on SKI stability or activity. Also, the responsible kinase has not yet been identified (Nagata et al., 2010).
 
  Figure 2. SKI protein domains and interaction partners (adapted from Bonnon & Atanasoski, 2012, Tecalco-Cruz et al., 2018).
Expression Under physiological conditions SKI is expressed at low levels in most tissues. Higher expression levels can be found in the brain, lung, male and female reproductive organs as well as bone marrow and lymphoid tissue (Human Protein Atlas v20.0 available from www.proteinatlas.org). As published in a study of Pearson-White et al. (1995), Ski is expressed in mature B and T lymphocytes as well as mature macrophages and mast cells. Further, Ski expression can be found in megakaryocyte-erythroid progenitor cells. Often mRNA levels do not correspond with protein levels (Nagano et al., 2010). Also, SKI expression was reported to be cell-cycle dependent showing the lowest protein levels in G0/G1 phase and an upregulation during mitosis (Marcelaine & Hayman, 2005). Furthermore, SKI was reported to be overexpressed in several tumor entities acting mostly oncogenic (Bonnon & Atanasoski 2012, Tecalco-Cruz et al., 2018, Liao et al., 2020).
Localisation SKI is predominantly localised in the nucleus (Colmenares et al., 1991). The NLS consists of the sequence PRKRKLT (s. Figure 2; aa 452-458) (Nagata et al., 2006). Aberrant cytoplasmic localisation of SKI was reported in primary invasive and metastatic melanomas preventing TGFB1 -induced SMAD3 nuclear translocation (Reed et al., 2001), primary esophageal squamous cell carcinoma (Fukuchi et al., 2004), colorectal cancer (Bravou et al., 2009), Barrett's esophagus (Villanacci et al., 2008) and cervical cancer (Chen et al., 2013). In hepatocytes SKI also was reported to be localised in the cytoplasm, where it co-localises with CD63- and ALIX-positive vesicles. Here, SKI stability is dependent on actin dynamics (Vázquez-Victorio et al., 2015). Cellular function seems to differ between cytoplasmic and nuclear SKI (Nagata et al., 2006). In Schwann cells SKI was reported to partially co-localise with phosphorylated RB1 in the cytoplasm affecting TGFB-induced cell proliferation (Jacob et al., 2008).
Function SKI is a well described inhibitor of TGFβ signalling but has also influence on the associated BMP signalling and other cellular pathways relevant for cancer development including nuclear hormone receptor signalling, Sonic hedgehog ( SHH) signalling, Hippo signalling, PI3K/Akt signalling and Wnt/β-catenin signalling (Bonnon & Atanasoski, 2012, Liao et al., 2020). SKI acts as a corepressor for SMAD proteins thereby inhibiting TGFβ signalling. Via the interaction with SMAD complexes SKI blocks the interaction with co-activator molecules like EP300 (CBP/P300) and additionally recruits co-repressor complexes to SMAD target genes (Luo et al., 1999, Akiyoshi et al., 1999). SKI is also able to suppress BMP signalling via weak interactions with BMP-specific SMAD complexes and inhibition of BMP target gene expression by interacting with homologous domain interaction protein kinase 2 ( HIPK2) (Wang et al., 2000, Takeda et al., 2004, Harada et al., 2003). The presence of SKI is also needed for the inhibition of nuclear hormone receptor signalling. SKI is an essential part of the NCOR1 / NCOR2, SIN3A and HDAC-recruiting co-repressor complex and contributes to the inhibition of thyroid hormone receptors ( THRA and THRB), RARA and VDR signalling (Nomura et al., 1999, Dahl et al., 1998, Ritter et al., 2006, Ueki & Hayman, 2003). SKI further is involved in the inhibition of SHH signalling by binding to GLI3 protein and recruiting HDAC1 to SHH-induced genes like GLI1 (Dai et al., 2002). In contrast, in pancreatic cancer cells SKI was reported to augment pluripotency of pancreatic cancer stem cells via induction of SHH signalling (Song et al., 2016). SKI can also act as a tumor suppressor and was reported to inhibit breast and lung cancer progression via blocking Hippo/TAZ signalling by increasing TAZ phosphorylation or recruiting co-repressors to TAZ (Rashidian et al., 2015, Xie et al., 2017). SKI is not only a repressor but also activates certain pathways. It was published by Zhao et al. (2020) that SKI knockdown in osteosarcoma (OS) cells causes dephosphorylation of PI3K and AKT leading to decreased OS cell proliferation and migration. Furthermore, in melanoma cells SKI together with FHL2 promotes Wnt/β-catenin signalling and induces the expression of the tumorigenic genes MITF and NRCAM (Chen et al., 2003). In colorectal cancer SKI also significantly correlates with Wnt/β-catenin signalling (Bravou et al., 2009).
SKI interacts with several PU.1 different factors (s. Figure 2) and functions as a co-regulator. SKI was reported to inhibit i.a. GATA1 (Ueki et al., 2004), SPI1 (PU.1) (Ueki et al., 2008), TP53, together with SIRT1 or via MDM2 sumoylation, (Inoue et al., 2011, Ding et al., 2012) and RUNX1 (Feld et al., 2018). It also acts as a co-activator for factors like nuclear factor I (NFI) (Tarapore et al., 1997) or MYOD1, SIX1 and EYA3 during myogenesis (Kobayashi et al., 2007, Zhang & Stavnezer, 2009).
As in mature tissues, also during murine embryonic development low levels of SKI are expressed in most tissues. Highest expression levels can be found in brain and lung (Lyons et al., 1994, Namciu et al., 1995). SKI is crucial for the neuronal development, myogenesis and limb formation. In murine models, SKI downregulation causes aberrant neural tube closure leading to exencephaly, aberrant craniofacial, ocular, skeletal and muscle development (Berk et al., 1997, McGannon et al., 2006, Shinagawa and Ishii, 2003, Colmenares et al., 2002). SKI is further involved in the myelination of Schwann cells (Atanasoski et al., 2004). Even though SKI is relevant for myogenesis, it was reported that ectopic expression of SKI causes hypertrophy of fast skeletal muscle fibers (Lana et al., 1996, Leferovich et al., 1995, Sutrave et al., 1990, 2000). In humans SKI also may be relevant for neuronal and craniofacial development, since patients with the 1p36 deletion syndrome show similar symptoms like mice with a Ski deletion including developmental delay, orofacial clefting and congenital heart defects (Colmenares et al., 2002, Jordan et al., 2015). Moreover, SKI plays a role in hematopoietic differentiation (Namciu et al., 1994, Pearson-White et al., 1995, Dahl et al., 1998, Ueki et al., 2004, 2008, Singbrandt et al., 2014 Zhang et al., 2017). SKI is overexpressed in memory B cells (MBCs) and induces cell proliferation and differentiation (Bhattacharya et al., 2007, Laidlaw et al., 2020). Moreover, SKI is higher expressed in actively maintained quiescent tumour-infiltrating CD8+ T cells from liver tumours compared to natural quiescent T cells from the peripheral blood (Zhang et al., 2009). SKI is upregulated via T cell integrin leukocyte function-associated antigen-1(LFA-1) interacting with ICAM1 in T cells. Consequentially, SKI contributes to the inhibition of the TGFβ-mediated T cell quiescent state (Verma et al., 2012). In a mouse model, Ski inhibits CD103 (Itgae) expression in CD8+ T cells via histone hypoacetylation. This mechanism is dependent on SMAD4. The suppression of CD103+CD8+ T cell generation further leads to a higher susceptibility to secondary viral infections (Wu et al., 2020). In T cells, SKI and SMAD inhibit IL21 -induced differentiation into T helper 17 cells (Th17) via suppressing retinoic acid receptor-related orphan receptor γt (RORγt) expression (Zhang et al., 2017, 2019). SKI affects fibroblastic proliferation and development (Jinnin et al., 2007, Liu et al., 2008, Cunnington et al., 2011) and induces chondrocytic differentiation via inhibition of TGFβ signalling (Kim et al., 2012). The expression of SKI alters under many pathological conditions including demyelination or peripheral nerve damage (Atanasoski et al., 2004), wound healing (Liu et al., 2006, 2010, Li et al., 2011), liver regeneration (Macias-Silva et al., 2002), skeletal muscle regeneration (Soeta et al., 2001) and obstructive nephropathy (Fukasawa et al., 2006).
Homology SKI homologues have been identified in vertebrates from fish to human.

Mutations

Note Several coding and non-coding sequence variants of SKI were identified, also containing one coding non-synonymous variant, rs28384811 (White et al., 2008).
In patients with Shprintzen-Goldberg syndrome (SGS) mutations in exon 1 of SKI are responsible for ~90 % of the cases. The mutations can be found in the SMAD interaction domain and DHD domain resulting in the substitution or deletion of amino acids and leading to the induction of TGFβ signalling (Doyle et al., 2012, Carmignac et al., 2012, Au et al., 2014, Schepers et al., 2015, Polinska et al., 2016, Saito et al., 2017). However, it was proposed that during embryogenesis SKI mutations in the SMAD interaction domain or DHD domain effect TGFβ signalling differently, since a patient carrying a mutation in the SKI DHD domain developed lipomeningomyelocele, tethered cord and spina bifida but no SGS characteristics like intellectual disability, craniofacial or cardiovascular abnormalities (Zhang et al., 2019). Also, another mutation in the SKI DHD domain affecting the amino acid Thr180 was reported to be associated with marfanoid syndrome with thoracic aortic aneurysm but no intellectual disability (Arnaud et al., 2020).
A small deletion (576 kb) of 1p36.33-p36.32 encompassing SKI was found in a patient with limb malformations, congenital heart disease (CHD), epilepsy and mild development delay (Zhu et al., 2013).
In a paediatric case of de novo acute myeloid leukaemia with del(5q) a SKI out-of-frame fusion transcript with PRDM16, PRDM16(exon 1)/SKI(exon 2) t(1;1)(p36;p36) PRDM16/SKI, was identified together with another translocation, RUNX1(exon 6)/ USP42 (exon 3) t(7;21)(p22;q22) RUNX1/USP42 (Masetti et al., 2014).
SKI mutationAA changedomainWhite et al. (2008)Doyle et al. (2012)Carmignac et al. (2012)Au et al. (2014)Schepers et al. (2014)Poninska et al. (2016)Saito et al. (2017)Zhang et al. (2019)Arnaud et al. (2020)Total
c.59C>Gp.Thr20ArgSMAD      1  1
c.59C>Ap.Thr20LysSMAD     1   1
c.62T>Gp.Leu21ArgSMAD 1       1
c.82T>Ap.Ser28ThrSMAD    1    1
c.92C>Tp.Ser31LeuSMAD  1 1    2
c.94C>Gp.Leu32ValSMAD 2*3* 1    5*
c.95T>Cp.Leu32ProSMAD  1      1
c.100G>Ap.Gly34SerSMAD 11 1    3
c.100G>Tp.Gly34CysSMAD 11      2
c.101G>Ap.Gly34AspSMAD 1  1    2
c.101G>Tp.Gly34ValSMAD  1 1    2
c.101G>Cp.Gly34AlaSMAD    1    1
c.103C>Tp.Pro35SerSMAD 1112    5
c.104C>Ap.Pro35GlnSMAD  1      1
c.185C>Gp.Ala62GlySMAD3        3
c.280_291delp.Ser94_Ser97delDHD  1      1
c.283_291delp.Asp95_Ser97delDHD 11      2
c.289_300delp.Ser97_Arg100delDHD    1    1
c.336C>Gp.Cys112TrpDHD       1 1
c.347G>Ap.Gly116GluDHD 1 1     2
c.349G>Cp.Gly117ArgDHD 1       1
c.539C>Tp.Thr180MetDHD        55
c.539C>Ap.Thr180LysDHD        22
c.539C>Gp.Thr180ArgDHD        22
   389210111948

*one common patient
Table1. Overview of the published SKI mutations leading to AA changes or deletions (adapted from Schepers et al., 2015, Arnaud et al., 2020).

Implicated in

  
Entity Shprintzen-Goldberg Syndrome
Note Variations and mutations of SKI exon 1 cause ~90 % of the cases with Shprintzen-Goldberg syndrome (SGS). (see also section Mutations and Table 1).
  
  
Entity 1p36 Deletion Syndrome
Note 1p36 is the most common subtelomeric deletion syndrome and occurs in ~1 out of 5,000 cases (Heilstedt et al., 2003). SKI is one of the genes deleted in 1p36 deletion syndrome contributing to certain aspects of the disease. Also, SKI-deficient mice recapitulate aspects of the 1p36 deletion syndrome (Colmenares et al., 2002). Some but not all characteristics of 1p36 deletion syndrome overlap with Shprintzen-Goldberg syndrome like developmental delay, intellectual disability and a high, narrow palate. The differences were reported to be possibly due to the creation of loss-of-function alleles by the SKI mutations in 1p36 deletion syndrome but not in Shprintzen-Goldberg syndrome. In 1p36 deletion syndrome, deletion of SKI is supposed to contribute to developmental delay, intellectual disability, seizures, orofacial clefting and congenital heart defects (Jordan et al., 2015). In the development of cardiomyopathy, insufficiency of SKI and PRDM16, a gene also deleted in 1p36 deletion syndrome, may cooperate (Rosenfeld et al., 2010, Zaveri et al., 2014). Contrarily, it was published recently that not PRDM16 but the deletion of SKI and the congenital heart disease-associated genes RERE and UBE4B are the causing factors for Ebstein anomaly (EA) in 1p36 deletion syndrome patients (Miranda-Fernández et al., 2018).
  
  
Entity Cardiac Fibrosis
Note TGFβ induces cardiac fibrogenesis. Via inhibiting TGFβ signalling, SKI is able to inhibit cardiac fibrosis. Expression of SKI decreases the myofibroblast phenotype including reduced contractility, possibly by a decreased expression of α-smooth muscle actin (α-SMA: ACTA2) and less type I collagen secretion. SKI-induced decrease of myofibroblasts may be due to a redifferentiation to fibroblasts via SKI-induced repression of ZEB2 and reexpression of MEOX2 and/or inhibition of autophagy and induction of apoptosis (Cunnington et al., 2011, 2014, Zeglinski et al., 2016). Vice versa, ARKADIA induces SKI and SMAD7 degradation and thereby contributes to cardiac fibrosis (Cunnington et al., 2009). In diabetes, myocardial infarction can lead to cardiac fibrosis. Here, MIR155 is upregulated leading to SKI inhibition. PBMC transplantation causes the release of hepatocyte growth factor (HGF), which acts antifibrotic via inhibiting MIR155 and inducing SKI (Kishore et al., 2013). Besides MIR155 also MIR17, MIR34A and MIR93 inhibit SKI and contribute to development of cardiac fibrosis by inducing TGFβ signalling, cardiac fibroblast proliferation and extracellular matrix protein production (Wang et al., 2017, Zhang et al., 2018). The MIR155/SKI axis further plays a role in fibrogenic endothelial-mesenchymal transition (EndMT) of human coronary artery endothelial cells (HCAEC), which also supports cardiac fibrosis. Depletion of MIR155 reestablishes SKI expression leading to the downregulation of VIM (Vimentin), SNAI1, SNAI2 (Slug) and TWIST1 as well as the induction of PECAM1 (CD31) and in the end to the inhibition of EndMT (Wang et al., 2017). Downregulation of SKI in cardiac muscle cells also supports TGFβ-induced epithelial-mesenchymal transitions via inhibition of CDH1 (E-cadherin) and induction of ACTA2 and/or FN as well as SMAD3 phosphorylation (Ling et al., 2019). In myofibroblasts, SKI further induces MMP9 expression and associated gelatinase activity, which may enable cytoskeletal remodelling and may have an effect on extracellular matrix components (Landry et al., 2018).
  
  
Entity Haemangioma
Note SKI is overexpressed in haemangiomas, as shown in a study with 12 patients. SKI levels are high in actively proliferating haemangioma cells and lower in involuting haemangiomas (O et al., 2009).
  
  
Entity Myelodysplastic Syndrome (MDS)
Note Muench et al. (2018) showed that SKI protein is inhibited by elevated MIR21 expression in early stage MDS, supporting chronic induction of TGFβ signalling and deregulation of splicing factors. Moreover, SKI is crucial for hematopoietic stem cell (HSC) fitness, involving inhibition of TGFβ signalling and aberrant RNA splicing in mice.
  
  
Entity Acute Myeloid Leukaemia (AML)
Note In tumorigenic diseases SKI is rather overexpressed than mutated. Nevertheless, a PRDM16/SKI out-of-frame translocation was reported in a paediatric case of del(5q) AML, which is predicted not to be translated but to increase PRDM16 expression, which is already associated with leukemogenesis (Masetti et al., 2014).
Compared with CD34-positive stem cells of healthy donors, SKI is overexpressed in different acute myeloid leukaemia (AML) subgroups (Ritter et al., 2006). Overexpression of SKI in-7/del7q AML patients is due to deletion of the SKI-targeting MIR29A, encoded on chromosome 7q (Ritter et al., 2006, Teichler et al., 2011). Recently it was published that the oncogenic long non-coding RNA LINC00467 is upregulated and contributes to the AML phenotype. Downregulation of LINC00467 induces MIR339 expression and inhibition of the MIR337 target SKI (Lu et al., 2020). In AML, SKI expression is further dependent on the oncogenic haematopoietic transcription factor MYB and contributes to its inhibitory activity in myeloid differentiation (Frech et al., 2018). In avian bone marrow, Ski increases stem cell-ness of primary multipotential progenitor cells, what may be relevant for leukemogenesis (Beug et al., 1995). In a mouse model exogenous expression of Ski in hematopoietic stem and progenitor cells induces a stem cell gene expression signature and causes the development of a myeloproliferative disorder in vivo. Here, SKI-positive myeloid progenitor cells seem to depend on HGF signalling (cf. Kishore et al., 2013) but not on the inhibition of TGFβ signalling (Singbrant et al., 2014). SKI as part of the co-repressor complex was reported to interact with the nuclear body protein PML and may be involved in PML/RARα-inducedacute promyelocytic leukaemia (APL) (Khan et al., 2001). SKI contributes to the development of erythroleukemia via interacting with the erythroid transcription factor GATA1. SKI promotes erythroblastic proliferation and blocks GATA1 DNA binding ability, causing an erythroid differentiation block (Larsen et al., 1992, Ueki et al., 2004, Fagnan et al., 2020). A regulatory mechanism of SKI with the histone methyltransferase nuclear receptor SET domain protein 1 ( NSD1) may also play a role in erythroleukemia (Leonards et al., 2020). SKI may further contribute to leukemogenesis via blocking activity of the important hematopoietic transcription factor PU.1 by recruiting an HDAC3 -containing co-repressor complex to its target genes (Ueki et al., 2008). In AML, SKI inhibits the signalling pathway of the important retinoic acid receptor α (RARα) crucial for myeloid differentiation via interacting with the HDAC-recruiting NCOR co-repressor complex. The differentiation block can partially be released with the HDAC inhibitor valproic acid (Dahl et al., 1998, Ritter et al., 2006). SKI also seems to block RARα signalling and the response to all-trans retinoic acid (ATRA) treatment in AML patients, also treated with chemotherapy, in vivo (Teichler et al., 2008). Feld et al. (2018) further analysed the SKI-dependent cistrome and transcriptome in AML cells and showed that SKI blocks myeloid differentiation and acts as a co-repressor for the haematopoietic transcription factor RUNX1.
  
  
Entity Chronic Myelogenous Leukemia (CML)
Note SKI is upregulated in CD34-positive cells of patients with chronic myelogenous leukemia (CML) (n=5) compared to CD34-positive cells of healthy donors (n=10) (Kronenwett et al., 2005).
  
  
Entity Chronic Lymphocytic Leukemia (CLL)
Note SKI and SLAMF1 may be prognostic in CLL. In previously untreated CLL patients (n=133), a higher expression of SKI and SLAMF1 is associated with a longer time-to-treatment (Schweighofer et al., 2011).
  
  
Entity Melanoma
Note SKI is overexpressed in melanoma cell lines (Fumagalli et al., 1993) as well as in melanoma patients as shown by Reed et al. (2001, n=44) and Boone et al. (2009, n=120). In melanoma, SKI overexpression may be due to a downregulation of MIR155. Nevertheless, the inhibition of SKI is not the main cause for the MIR155-mediated suppression of proliferation and induction of apoptosis in melanoma cells (Levati et al., 2011). Furthermore, SKI expression is up-regulated by MAPK/ERK signalling, while a MEK inhibitor decreases SKI levels (Rothammer & Bosserhoff, 2006). SKI was further reported to increase cell cycle progression by inhibiting Smad-mediated induction of CDKN1A ("p21Waf-1"), thereby increasing CDK2 activity. SKI overexpression induces RB1 inactivation and increases colony size and formation in human melanoma cells (Medrano, 2003). The inhibition of TGFβ signalling by SKI also contributes to tumour growth and angiogenesis via increasing the level of oncogenic MYC and inducing expression of SERPINE1 (PAI-1) in melanoma cells (Reed et al., 2001, Chen et al., 2009). SKI also augments melanoma cell growth via acting as a co-activator for FHL2 and β-catenin to induce Wnt signalling. It thereby induces the expression of MITF and NRCAM, which are already associated with cell transformation, survival, growth and motility in melanoma (Chen et al., 2003). In primary invasive melanoma cells, SKI was predominantly found in the nucleus. In metastatic cells, SKI rather localises to the cytoplasm (Reed et al., 2001, Javelaud et al., 2011). Nuclear SKI was also found in ulcerated tumours but not in metastatic melanoma cells. Also, nuclear SKI is positively correlated with Breslow thickness (Boone et al., 2009). The role of SKI with melanoma malignancy is still under discussion. While Reed et al. (2001) showed that increased SKI levels correlate with increased melanoma malignancy, Boone et al. (2009) found no correlation of SKI levels with tumour progression, histogenetic subtype or patient survival. In mice, Javelaud et al. (2011) found Ski not to be correlated with melanoma cell growth or metastasis. Here, Ski levels even decreased upon treatment with increasing amounts of TGFβ.
  
  
Entity Osteosarcoma
Note Zhao et al. (2020) published that SKI is overexpressed in osteosarcoma cell lines. SKI knockdown inhibited PI3K/AKT signalling as well as cell proliferation and migration of the cell lines. Moreover, increased SKI levels were detected in patients with osteosarcoma (n=6) compared to osteochondroma tissue (n=6). The patients were not treated with radiotherapy or chemotherapy before surgery.
  
  
Entity Lung Cancer
Note In lung cancer, SKI rather acts as a tumour suppressor. SKI knockdown in lung cancer cells increases metastasis in a mouse model in vivo (Le Scolan et al., 2008). In turn, SKI overexpression inhibits TGFβ signalling in lung cancer cell lines, including translocation of SMAD2 to the nucleus and SMAD3 phosphorylation (Ferrand et al., 2010, Yang et al., 2015). Moreover, Makino et al. (2017) published that together with IL6 and STAT3, SKI may also mediate gefitinib drug resistance of lung cancer cells caused by inflammatory processes. Gefitinib is a tyrosin kinase inhibitor used for treatment of lung cancer with EGFR mutation. The proinflammatory cytokine IL6 induces STAT3 phosphorylation and STAT3 interacts with SKI and SKIL to inhibit TGFβ signalling and SMAD3 expression. Inhibition of SMAD3 expression inhibits gefitinib-induced apoptosis (Makino et al., 2017). SKI overexpression further inhibits epithelial-mesenchymal transition induced by TGFβ signalling (Yang et al., 2015). Yang et al. (2015) showed lower SKI transcript levels in metastatic (n=23) non-small lung cancer cells (NSCLCs) compared with non-metastatic (n=23) NSCLCs of lung cancer patients. The patients were not treated with radiotherapy or chemotherapy before sampling. Moreover, Xie et al. (2017) showed that a higher SKI expression in lung cancer is associated with a longer overall survival. In lung cancer cells, SKI is predominantly localised to the cytoplasm. Also, SKI is lower expressed in primary lung cancer tissues (n=168) compared to adjacent normal lung tissues (n=20). This is due to an increased SKI DNA methylation pattern in lung cancer cells. Treatment of the lung cancer cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine) reestablishes SKI expression. In lung cancer patients, SKI expression is positively correlated with differentiation and negatively associated with tumour stage. As in breast cancer cells (see below), SKI inhibits TGFβ-induced SMAD and TAZ signalling in lung cancer cell lines. TAZ inhibition by SKI suppresses growth, colony formation, migration and invasion of lung cancer cell lines (Xie et al., 2017).
  
  
Entity Gastric Cancer
Note In gastric cancer cells, SKI and another co-regulator PRDM16 (former MEL1) are co-amplified (Takahata et al., 2009). Both genes are encoded on chromosome 1p36, a locus which was reported to have an increased copy number in 22 % of gastric cancers (Sakakura et al., 1999). PRDM16 interacts with SKI and stabilises the SKI/SMAD3 complex, thereby inhibiting TGFβ target gene expression and inducing cell proliferation. In a mouse model, knockdown of Ski and Prdm16 in gastric tumour cells reduces tumour growth in vivo (Takahata et al., 2009). Vice versa, overexpression of SKI in diffuse-type gastric cancer cells inhibits TGFβ expression as well as signalling and induces tumour growth in a xenograft mouse model. SKI overexpression further leads to less fibrosis and inhibits expression of anti-angiogenic thrombospondin 1 ( THBS1), thereby promoting tumour angiogenesis (Kiyono et al., 2009). In contrast, Nakao et al. (2011) showed that THBS1 and SKI level are not associated in patients with advanced gastric cancer. Moreover, THBS1 expression correlates with increased angiogenesis and a better survival in advanced gastric cancer patients, while SKI expression is associated with a poorer survival in TGFβ-positive patients (Nakao et al., 2011). SKI is upregulated in gastric cancer patients' tissue and gastric cancer cell lines. Increased expression of SKI in gastric cancer-associated fibroblasts (CAFs) enhances cell viability, cell invasion and cell migration, probably by inhibiting SMAD3 activity in TGFβ signalling. SKI knockdown in CAFs reverses these effects (Zhang et al., 2019).
  
  
Entity Pancreatic Cancer
Note In pancreatic cancer, SKI is frequently overexpressed and was published to act as a proto-oncogene but also as a tumour suppressor. SKI knockdown in pancreatic cancer cells leads to reactivation of SMAD2/3-mediated TGFβ signalling and inhibition of tumour growth in mice, but to induction of metastasis to the lung (Heider et al., 2007, Wang et al., 2009). SKI is associated with a shorter overall survival in patients with pancreatic ductal adenocarcinoma (PDAC) (Wang et al., 2009). SKI overexpression further increases pluripotency of pancreatic cancer stem cells via activation of SHH signalling. In vitro and in an in vivo mouse model, SKI knockdown leads to a reduction of factors involved in stem cell maintenance ( CD24, CD44, POU5F1 (former OCT-4), SOX2) and SHH signalling (SHH, PTCH1, SMO, GLI1, GLI2), while SKI overexpression shows the reverse effects (Song et al., 2016). Ponath et al. (2020) showed that SKI suppresses NK cell-mediated killing of pancreatic cancer cells, probably by inhibiting the basal as well as HADCi-induced expression of KLRK1 (NKG2D) ligands.
  
  
Entity Colorectal Cancer
Note In early-stage colorectal cancer patients (n=159), SKI is overexpressed. Allelic amplification (10.1%) but not allelic loss (41.5%) of SKI is associated with a shorter disease-free survival and overall survival (Buess et al., 2004). Another analysis of 70 primary human colorectal adenomas/carcinomas (CRCs) as well as 21 lymph node metastases showed SKI overexpression in 75.7% or 71.4% of the cases, respectively. No or only weak SKI levels were detected in normal colon mucosa. In CRCs, SKI is predominantly localised in the cytoplasm and correlates with β-Catenin signalling (Bravou et al., 2009).
  
  
Entity Oesophageal Squamous Cell Carcinoma
Note SKI is overexpressed in oesophageal squamous cell carcinoma cell lines and patient cells (56.3%, n=80). Expression of SKI is correlated with invasion depth, tumour stage and a shorter overall survival after surgery in patients with TGFβ-negative tumours. SKI level further correlate with TGFβ and CDKN1A (P21) expression (Fukuchi et al., 2004).
  
  
Entity Barretts oesophagus
Note Evaluation of 37 patients with Barrets oesophagus (BE) show an overexpression of SKI in BE and a lower expression in BE with low-grade dysplasia, but no expression in normal oesophageal tissue and BE with high-grade dysplasia/adenocarcinoma. In BE, SKI may be involved in the suppression of TGFβ-mediated growth inhibition (Villanacci et al., 2008).
  
  
Entity Kidney Cancer
Note SKI is higher expressed in clear cell renal carcinoma (ccRCC) (n=31) compared to normal renal tissue of the same patients and localises to the nucleus. Overexpression of SKI in a mouse renal orthotopic tumour model inhibits TGFβ signalling as well as the TGFβ-associated growth inhibition and increases tumour growth in vivo (Taguchi et al., 2019).
  
  
Entity Breast Cancer
Note In breast cancer, SKI was published to act more as a tumour suppressor than a proto-oncogene. SKI overexpression inhibits breast cancer metastasis to lung and liver in a mouse model. This is dependent on the inhibition of TGFβ signalling by SKI (Azuma et al., 2005). Vice versa, SKI knockdown in a human breast cancer cell line augments metastasis in mice. Also, TGFβ treatment of these cells leads to a decrease of SKI protein levels (Le Scolan et al., 2008). However, SKI overexpression inhibits TGFβ-induced nuclear translocation of SMAD2 in the same breast cancer cell line (MDA-MB231) (Ferrand et al., 2010). Theohari et al. (2012) further analysed 119 patients with resectable invasive breast cancer and showed that SKI is localised in the cytoplasm (44.5%) and the nucleus (17.6%). Cytoplasmic SKI is inversely correlated with tumour size, stage and status of the lymph nodes and nuclear SKI is negatively associated with histological grade and nuclear phosphorylated SMAD2. Cytoplasmic SKI is further related to a longer overall survival and disease-free survival (Theohari et al., 2012). In breast cancer cell lines, SKI also activates the Hippo signalling-associated kinase LATS2, which leads to the phosphorylation and degradation of TAZ. TAZ signalling is associated with breast cancer progression. SKI also inhibits TAZ/TEAD target gene expression by recruitment of NCOR1 and induces TAZ degradation via a LATS2-independent mechanism. Furthermore, SKI suppresses TAZ-induced transformation and epithelial-mesenchymal transition in vitro as well as lung metastases in mice in vivo (Rashidian et al., 2015). A proto-oncogenic function of SKI in breast cancer progression was published by Wang et al. (2013). Here, SKI was described to be overexpressed in breast cancer-associated fibroblasts (CAFs) in the tumour microenvironment contributing to invasion and metastasis of breast cancer cells. SKI overexpression in normal fibroblasts induces transformation to CAFs with increased proliferation, migration, invasion and contraction.
  
  
Entity Cervical Cancer
Note In association with human papillomavirus (HPV)-derived cervical cancer, it was published that SKI and NFI cooperate in the induction of HPV16 early gene expression. A decrease of HPV16 early gene expression by TGFβ is accompanied by a reduction of SKI levels and suppressed NFI activity (Baldwin et al., 2004). Further studies showed that SKI is higher expressed in cervical cancer samples (n=42) compared to adjacent normal cervix tissue (n=38). In contrast to normal cervical tissue, where SKI is localised to the nuclei and less to the cytoplasm, in cervical cancer tissue SKI was predominantly localised to the cytoplasm. Moreover, SKI level increase during transformation of human keratinocytes immortalised with HPV16 DNA (HKc/HPV16), with highest levels in differentiation-resistant HKc/HPV16 (HKc/DR), which are also resistant to growth inhibition by TGFβ. Knockdown of SKI in HKc/DR further leads to a decrease in cell proliferation (Chen et al., 2013).
  
  
Entity Prostate Cancer
Note Vo et al. (2012) showed that SKI is overexpressed in prostate cancer cell lines and inhibits TGFβ signalling. Contrarily, SKI level were low to not detectable in prostate stem cells and normal prostate cell lines. In prostate cancer cell lines, SKI knockdown inhibits cell proliferation but increases cell migration. Also, patients with prostate adenocarcinomas and metastatic prostate cancer show a SKI overexpression, while SKI is not detectable in normal prostate tissues. In prostate cancer, localisation of SKI is predominantly cytoplasmic.
  

Bibliography

c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads
Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, Kawabata M
J Biol Chem 1999 Dec 3;274(49):35269-77.
PMID 10575014
 
A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis
Arnaud P, Racine C, Hanna N, Thevenon J, Alessandri JL, Bonneau D, Clayton-Smith J, Coubes C, Delobel B, Dupuis-Girod S, Gouya L, Odent S, Carmignac V, Thauvin-Robinet C, Le Goff C, Jondeau G, Boileau C, Faivre L
Hum Genet 2020 Apr;139(4):461-472.
PMID 31980905
 
The protooncogene Ski controls Schwann cell proliferation and myelination
Atanasoski S, Notterpek L, Lee HY, Castagner F, Young P, Ehrengruber MU, Meijer D, Sommer L, Stavnezer E, Colmenares C, Suter U
Neuron 2004 Aug 19;43(4):499-511.
PMID 15312649
 
De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review
Au PY, Racher HE, Graham JM, Kramer N, Lowry RB, Parboosingh JS, Innes AM,
Am J Med Genet A 2014 Mar;164A(3):676-84.
PMID 24357594
 
Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells
Azuma H, Ehata S, Miyazaki H, Watabe T, Maruyama O, Imamura T, Sakamoto T, Kiyama S, Kiyama Y, Ubai T, Inamoto T, Takahara S, Itoh Y, Otsuki Y, Katsuoka Y, Miyazono K, Horie S
J Natl Cancer Inst 2005 Dec 7;97(23):1734-46.
PMID 16333029
 
NFI-Ski interactions mediate transforming growth factor beta modulation of human papillomavirus type 16 early gene expression
Baldwin A, Pirisi L, Creek KE
J Virol 2004 Apr;78(8):3953-64.
PMID 15047811
 
The phosphatidylinositol 3-kinase/Akt pathway regulates transforming growth factor-{beta} signaling by destabilizing ski and inducing Smad7
Band AM, Björklund M, Laiho M
J Biol Chem 2009 Dec 18;284(51):35441-9.
PMID 19875456
 
Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development
Berk M, Desai SY, Heyman HC, Colmenares C
Genes Dev 1997 Aug 15;11(16):2029-39.
PMID 9284043
 
In vitro growth of factor-dependent multipotential hematopoietic cells is induced by the nuclear oncoprotein v-Ski
Beug H, Dahl R, Steinlein P, Meyer S, Deiner EM, Hayman MJ
Oncogene 1995 Jul 6;11(1):59-72.
PMID 7624132
 
Transcriptional profiling of antigen-dependent murine B cell differentiation and memory formation
Bhattacharya D, Cheah MT, Franco CB, Hosen N, Pin CL, Sha WC, Weissman IL
J Immunol 2007 Nov 15;179(10):6808-19.
PMID 17982071
 
c-Ski in health and disease
Bonnon C, Atanasoski S
Cell Tissue Res 2012 Jan;347(1):51-64.
PMID 21647564
 
Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma
Boone B, Haspeslagh M, Brochez L
J Dermatol Sci 2009 Jan;53(1):26-33.
PMID 18782659
 
TGF-beta repressors SnoN and Ski are implicated in human colorectal carcinogenesis
Bravou V, Antonacopoulou A, Papadaki H, Floratou K, Stavropoulos M, Episkopou V, Petropoulou C, Kalofonos H
Cell Oncol 2009;31(1):41-51.
PMID 19096149
 
Amplification of SKI is a prognostic marker in early colorectal cancer
Buess M, Terracciano L, Reuter J, Ballabeni P, Boulay JL, Laffer U, Metzger U, Herrmann R, Rochlitz C
Neoplasia May-Jun 2004;6(3):207-12.
PMID 15153332
 
In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome
Carmignac V, Thevenon J, Adès L, Callewaert B, Julia S, Thauvin-Robinet C, Gueneau L, Courcet JB, Lopez E, Holman K, Renard M, Plauchu H, Plessis G, De Backer J, Child A, Arno G, Duplomb L, Callier P, Aral B, Vabres P, Gigot N, Arbustini E, Grasso M, Robinson PN, Goizet C, Baumann C, Di Rocco M, Sanchez Del Pozo J, Huet F, Jondeau G, Collod-Beroud G, Beroud C, Amiel J, Cormier-Daire V, Rivière JB, Boileau C, De Paepe A, Faivre L
Am J Hum Genet 2012 Nov 2;91(5):950-7.
PMID 23103230
 
SKI knockdown inhibits human melanoma tumor growth in vivo
Chen D, Lin Q, Box N, Roop D, Ishii S, Matsuzaki K, Fan T, Hornyak TJ, Reed JA, Stavnezer E, Timchenko NA, Medrano EE
Pigment Cell Melanoma Res 2009 Dec;22(6):761-72.
PMID 19845874
 
SKI activates Wnt/beta-catenin signaling in human melanoma
Chen D, Xu W, Bales E, Colmenares C, Conacci-Sorrell M, Ishii S, Stavnezer E, Campisi J, Fisher DE, Ben-Ze', ev A, Medrano EE
Cancer Res 2003 Oct 15;63(20):6626-34.
PMID 14583455
 
Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer
Chen Y, Pirisi L, Creek KE
Virology 2013 Sep;444(1-2):100-8.
PMID 23809940
 
Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice
Colmenares C, Heilstedt HA, Shaffer LG, Schwartz S, Berk M, Murray JC, Stavnezer E
Nat Genet 2002 Jan;30(1):106-9.
PMID 11731796
 
Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility
Cunnington RH, Wang B, Ghavami S, Bathe KL, Rattan SG, Dixon IM
Am J Physiol Cell Physiol 2011 Jan;300(1):C176-86.
PMID 20943957
 
Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling
Dahl R, Kieslinger M, Beug H, Hayman MJ
Proc Natl Acad Sci U S A 1998 Sep 15;95(19):11187-92.
PMID 9736711
 
Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3
Dai P, Shinagawa T, Nomura T, Harada J, Kaul SC, Wadhwa R, Khan MM, Akimaru H, Sasaki H, Colmenares C, Ishii S
Genes Dev 2002 Nov 15;16(22):2843-8.
PMID 12435627
 
Overexpression of SKI oncoprotein leads to p53 degradation through regulation of MDM2 protein sumoylation
Ding B, Sun Y, Huang J
J Biol Chem 2012 Apr 27;287(18):14621-30.
PMID 22411991
 
Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm
Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, Gillis E, Mortier G, Homfray T, Sauls K, Norris RA, Huso ND, Leahy D, Mohr DW, Caulfield MJ, Scott AF, Destrée A, Hennekam RC, Arn PH, Curry CJ, Van Laer L, McCallion AS, Loeys BL, Dietz HC
Nat Genet 2012 Nov;44(11):1249-54.
PMID 23023332
 
Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers
Fagnan A, Bagger FO, Piqué-Borràs MR, Ignacimouttou C, Caulier A, Lopez CK, Robert E, Uzan B, Gelsi-Boyer V, Aid Z, Thirant C, Moll U, Tauchmann S, Kurtovic-Kozaric A, Maciejewski J, Dierks C, Spinelli O, Salmoiraghi S, Pabst T, Shimoda K, Deleuze V, Lapillonne H, Sweeney C, De Mas V, Leite B, Kadri Z, Malinge S, de Botton S, Micol JB, Kile B, Carmichael CL, Iacobucci I, Mullighan CG, Carroll M, Valent P, Bernard OA, Delabesse E, Vyas P, Birnbaum D, Anguita E, Garçon L, Soler E, Schwaller J, Mercher T
Blood 2020 Aug 6;136(6):698-714.
PMID 32350520
 
Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1
Feld C, Sahu P, Frech M, Finkernagel F, Nist A, Stiewe T, Bauer UM, Neubauer A
Nucleic Acids Res 2018 Apr 20;46(7):3412-3428.
PMID 29471413
 
The oncoprotein c-ski functions as a direct antagonist of the transforming growth factor-{beta} type I receptor
Ferrand N, Atfi A, Prunier C
Cancer Res 2010 Nov 1;70(21):8457-66.
PMID 20959473
 
MYB induces the expression of the oncogenic corepressor SKI in acute myeloid leukemia
Frech M, Teichler S, Feld C, Bouchard C, Berberich H, Sorg K, Mernberger M, Bullinger L, Bauer UM, Neubauer A
Oncotarget 2018 Apr 27;9(32):22423-22435.
PMID 29854289
 
Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury
Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Suzuki S, Kitagawa M, Hishida A
Kidney Int 2006 May;69(10):1733-40.
PMID 16625151
 
Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma
Fukuchi M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Sohda M, Manda R, Tsukada K, Kato H, Kuwano H
Int J Cancer 2004 Mar 1;108(6):818-24.
PMID 14712482
 
Expression of the c-ski proto-oncogene in human melanoma cell lines
Fumagalli S, Doneda L, Nomura N, Larizza L
Melanoma Res 1993 Feb;3(1):23-7.
PMID 8471834
 
Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation
Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim Y, Ishii S
J Biol Chem 2003 Oct 3;278(40):38998-9005.
PMID 12874272
 
Ski promotes tumor growth through abrogation of transforming growth factor-beta signaling in pancreatic cancer
Heider TR, Lyman S, Schoonhoven R, Behrns KE
Ann Surg 2007 Jul;246(1):61-8.
PMID 17592292
 
Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome
Heilstedt HA, Ballif BC, Howard LA, Lewis RA, Stal S, Kashork CD, Bacino CA, Shapira SK, Shaffer LG
Am J Hum Genet 2003 May;72(5):1200-12.
PMID 12687501
 
A carboxyl-terminal region of the ski oncoprotein mediates homodimerization as well as heterodimerization with the related protein SnoN
Heyman HC, Stavnezer E
J Biol Chem 1994 Oct 28;269(43):26996-7003.
 
Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1
Inoue Y, Iemura S, Natsume T, Miyazawa K, Imamura T
J Biol Chem 2011 Feb 25;286(8):6311-20.
PMID 21149449
 
Expression and localization of Ski determine cell type-specific TGFbeta signaling effects on the cell cycle
Jacob C, Grabner H, Atanasoski S, Suter U
J Cell Biol 2008 Aug 11;182(3):519-30.
PMID 18695043
 
Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression
Javelaud D, van Kempen L, Alexaki VI, Le Scolan E, Luo K, Mauviel A
Mol Cancer 2011 Jan 6;10(1):2.
PMID 21211030
 
Next generation sequencing analysis of miRNAs: MiR-127-3p inhibits glioblastoma proliferation and activates TGF-β signaling by targeting SKI
Jiang H, Jin C, Liu J, Hua D, Zhou F, Lou X, Zhao N, Lan Q, Huang Q, Yoon JG, Zheng S, Lin B
OMICS 2014 Mar;18(3):196-206.
PMID 24517116
 
Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts
Jinnin M, Ihn H, Mimura Y, Asano Y, Tamaki K
Arthritis Rheum 2007 May;56(5):1694-705.
PMID 17469184
 
1p36 deletion syndrome: an update
Jordan VK, Zaveri HP, Scott DA
Appl Clin Genet 2015 Aug 27;8:189-200.
PMID 26345236
 
Role of PML and PML-RARalpha in Mad-mediated transcriptional repression
Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S
Mol Cell 2001 Jun;7(6):1233-43.
PMID 11430826
 
Ski inhibits TGF-β/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes
Kim KO, Sampson ER, Maynard RD, O', Keefe RJ, Chen D, Drissi H, Rosier RN, Hilton MJ, Zuscik MJ
J Cell Biochem 2012 Jun;113(6):2156-66.
PMID 22461172
 
Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts
Kishore R, Verma SK, Mackie AR, Vaughan EE, Abramova TV, Aiko I, Krishnamurthy P
PLoS One 2013;8(4):e60161.
PMID 23560074
 
c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma
Kiyono K, Suzuki HI, Morishita Y, Komuro A, Iwata C, Yashiro M, Hirakawa K, Kano MR, Miyazono K
Cancer Sci 2009 Oct;100(10):1809-16.
PMID 19594546
 
c-Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases
Kobayashi N, Goto K, Horiguchi K, Nagata M, Kawata M, Miyazawa K, Saitoh M, Miyazono K
Genes Cells 2007 Mar;12(3):375-85.
PMID 17352741
 
Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia
Kronenwett R, Butterweck U, Steidl U, Kliszewski S, Neumann F, Bork S, Blanco ED, Roes N, Gräf T, Brors B, Eils R, Maercker C, Kobbe G, Gattermann N, Haas R
Oncogene 2005 Aug 11;24(34):5313-24.
PMID 15806158
 
The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
Laidlaw BJ, Duan L, Xu Y, Vazquez SE, Cyster JG
Nat Immunol 2020 Sep;21(9):1082-1093.
PMID 32601467
 
Selective expression of a ski transgene affects IIb fast muscles and skeletal structure
Lana DP, Leferovich JM, Kelly AM, Hughes SH
Dev Dyn 1996 Jan;205(1):13-23.
PMID 8770548
 
Ski drives an acute increase in MMP-9 gene expression and release in primary cardiac myofibroblasts
Landry N, Kavosh MS, Filomeno KL, Rattan SG, Czubryt MP, Dixon IMC
Physiol Rep 2018 Nov;6(22):e13897.
PMID 30488595
 
The v-ski oncogene cooperates with the v-sea oncogene in erythroid transformation by blocking erythroid differentiation
Larsen J, Beug H, Hayman MJ
Oncogene 1992 Oct;7(10):1903-11.
PMID 1408132
 
Transforming growth factor-beta suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation
Le Scolan E, Zhu Q, Wang L, Bandyopadhyay A, Javelaud D, Mauviel A, Sun L, Luo K
Cancer Res 2008 May 1;68(9):3277-85.
PMID 18451154
 
Regulation of c-ski transgene expression in developing and mature mice
Leferovich JM, Lana DP, Sutrave P, Hughes SH, Kelly AM
J Neurosci 1995 Jan;15(1 Pt 2):596-603.
PMID 7823166
 
Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia
Leonards K, Almosailleakh M, Tauchmann S, Bagger FO, Thirant C, Juge S, Bock T, Méreau H, Bezerra MF, Tzankov A, Ivanek R, Losson R, Peters AHFM, Mercher T, Schwaller J
Nat Commun 2020 Jun 12;11(1):2807.
PMID 32533074
 
MicroRNA-155 targets the SKI gene in human melanoma cell lines
Levati L, Pagani E, Romani S, Castiglia D, Piccinni E, Covaciu C, Caporaso P, Bondanza S, Antonetti FR, Bonmassar E, Martelli F, Alvino E, D', Atri S
Pigment Cell Melanoma Res 2011 Jun;24(3):538-50.
PMID 21466664
 
Upregulation of ski in fibroblast is implicated in the peroxisome proliferator--activated receptor δ-mediated wound healing
Li J, Li P, Zhang Y, Li GB, He FT, Zhou YG, Yang K, Dai SS
Cell Physiol Biochem 2012;30(4):1059-71.
PMID 23052247
 
MiR-21 inhibits c-Ski signaling to promote the proliferation of rat vascular smooth muscle cells
Li J, Zhao L, He X, Yang T, Yang K
Cell Signal 2014 Apr;26(4):724-9.
PMID 24388835
 
Ski, a modulator of wound healing and scar formation in the rat skin and rabbit ear
Li P, Liu P, Xiong RP, Chen XY, Zhao Y, Lu WP, Liu X, Ning YL, Yang N, Zhou YG
J Pathol 2011 Apr;223(5):659-71.
PMID 21341267
 
Ski: Double roles in cancers
Liao HY, Da CM, Wu ZL, Zhang HH
Clin Biochem 2021 Jan;87:1-12.
PMID 33188772
 
Silencing of c-Ski augments TGF-b1-induced epithelial-mesenchymal transition in cardiomyocyte H9C2 cells
Ling J, Cai Z, Jin W, Zhuang X, Kan L, Wang F, Ye X
Cardiol J 2019;26(1):66-76.
PMID 29570207
 
The essential role for c-Ski in mediating TGF-beta1-induced bi-directional effects on skin fibroblast proliferation through a feedback loop
Liu X, Li P, Liu P, Xiong R, Zhang E, Chen X, Gu D, Zhao Y, Wang Z, Zhou Y
Biochem J 2008 Jan 1;409(1):289-97.
PMID 17725545
 
Expression and possible mechanism of c-ski, a novel tissue repair-related gene during normal and radiation-impaired wound healing
Liu X, Zhang E, Li P, Liu J, Zhou P, Gu DY, Chen X, Cheng T, Zhou Y
Wound Repair Regen Mar-Apr 2006;14(2):162-71.
PMID 16630105
 
Long noncoding RNA LINC00467 facilitates the progression of acute myeloid leukemia by targeting the miR-339/SKI pathway
Lu J, Wu X, Wang L, Li T, Sun L
Leuk Lymphoma 2021 Feb;62(2):428-437.
PMID 33054480
 
The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling
Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q
Genes Dev 1999 Sep 1;13(17):2196-206.
PMID 10485843
 
Protooncogene c-ski is expressed in both proliferating and postmitotic neuronal populations
Lyons GE, Micales BK, Herr MJ, Horrigan SK, Namciu S, Shardy D, Stavnezer E
Dev Dyn 1994 Dec;201(4):354-65.
PMID 7894074
 
Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration
Macias-Silva M, Li W, Leu JI, Crissey MA, Taub R
J Biol Chem 2002 Aug 9;277(32):28483-90.
PMID 12023281
 
Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma
Makino Y, Yoon JH, Bae E, Kato M, Miyazawa K, Ohira T, Ikeda N, Kuroda M, Mamura M
Biochem Biophys Res Commun 2017 Mar 4;484(2):269-277.
PMID 28115165
 
The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis
Marcelain K, Hayman MJ
Oncogene 2005 Jun 23;24(27):4321-9.
PMID 15806149
 
Whole transcriptome sequencing of a paediatric case of de novo acute myeloid leukaemia with del(5q) reveals RUNX1-USP42 and PRDM16-SKI fusion transcripts
Masetti R, Togni M, Astolfi A, Pigazzi M, Indio V, Rivalta B, Manara E, Rutella S, Basso G, Pession A, Locatelli F
Br J Haematol 2014 Aug;166(3):449-52.
PMID 24673627
 
Ocular abnormalities in mice lacking the Ski proto-oncogene
McGannon P, Miyazaki Y, Gupta PC, Traboulsi EI, Colmenares C
Invest Ophthalmol Vis Sci 2006 Oct;47(10):4231-7.
PMID 17003410
 
Repression of TGF-beta signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis
Medrano EE
Oncogene 2003 May 19;22(20):3123-9.
PMID 12793438
 
Expression of Ski can act as a negative feedback mechanism on retinoic acid signaling
Melling MA, Friendship CR, Shepherd TG, Drysdale TA
Dev Dyn 2013 Jun;242(6):604-13.
PMID 23441061
 
Identification of a New Candidate Locus for Ebstein Anomaly in 1p36.2
Miranda-Fernández MC, Ramírez-Oyaga S, Restrepo CM, Huertas-Quiñones VM, Barrera-Castañeda M, Quero R, Hernández-Toro CJ, Tamar Silva C, Laissue P, Cabrera R
Mol Syndromol 2018 May;9(3):164-169.
PMID 29928183
 
Identification of Ski as a target for Aurora A kinase
Mosquera J, Armisen R, Zhao H, Rojas DA, Maldonado E, Tapia JC, Colombo A, Hayman MJ, Marcelain K
Biochem Biophys Res Commun 2011 Jun 10;409(3):539-43.
PMID 21600873
 
SKI controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness
Muench DE, Ferchen K, Velu CS, Pradhan K, Chetal K, Chen X, Weirauch MT, Colmenares C, Verma A, Salomonis N, Grimes HL
Blood 2018 Nov 22;132(21):e24-e34.
PMID 30249787
 
Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells
Nagano Y, Koinuma D, Miyazawa K, Miyazono K
J Biochem 2010 Apr;147(4):545-54.
PMID 19959502
 
Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling
Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T, Episkopou V, Miyazono K, Miyazawa K
J Biol Chem 2007 Jul 13;282(28):20492-501.
PMID 17510063
 
Nuclear and cytoplasmic c-Ski differently modulate cellular functions
Nagata M, Goto K, Ehata S, Kobayashi N, Saitoh M, Miyoshi H, Imamura T, Miyazawa K, Miyazono K
Genes Cells 2006 Nov;11(11):1267-80.
PMID 17054724
 
Identification of a phosphorylation site in c-Ski as serine 515
Nagata M, Nagata S, Yuki K, Isogaya K, Saitoh M, Miyazono K, Miyazawa K
J Biochem 2010 Oct;148(4):423-7.
PMID 20624875
 
Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer
Nakao T, Kurita N, Komatsu M, Yoshikawa K, Iwata T, Utsunomiya T, Shimada M
Int J Clin Oncol 2011 Apr;16(2):145-52.
PMID 21107877
 
Induction of the c-ski proto-oncogene by phorbol ester correlates with induction of megakaryocyte differentiation
Namciu S, Lieberman MA, Stavnezer E
Oncogene 1994 May;9(5):1407-16.
PMID 8152801
 
Enhanced expression of mouse c-ski accompanies terminal skeletal muscle differentiation in vivo and in vitro
Namciu S, Lyons GE, Micales BK, Heyman HC, Colmenares C, Stavnezer E
Dev Dyn 1995 Nov;204(3):291-300.
PMID 8573720
 
Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor
Nomura T, Khan MM, Kaul SC, Dong HD, Wadhwa R, Colmenares C, Kohno I, Ishii S
Genes Dev 1999 Feb 15;13(4):412-23.
PMID 10049357
 
Differential expression of SKI oncogene protein in hemangiomas
O TM, Tan M, Tarango M, Fink L, Mihm M, Ma Y, Waner M
Otolaryngol Head Neck Surg 2009 Aug;141(2):213-8.
PMID 19643254
 
The ski/sno protooncogene family in hematopoietic development
Pearson-White S, Deacon D, Crittenden R, Brady G, Iscove N, Quesenberry PJ
Blood 1995 Sep 15;86(6):2146-55.
PMID 7662963
 
The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC
Ponath V, Frech M, Bittermann M, Al Khayer R, Neubauer A, Brendel C, Pogge von Strandmann E
Cancers (Basel) 2020 Oct 3;12(10):2857.
PMID 33023028
 
Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations
Poninska JK, Bilinska ZT, Franaszczyk M, Michalak E, Rydzanicz M, Szpakowski E, Pollak A, Milanowska B, Truszkowska G, Chmielewski P, Sioma A, Janaszek-Sitkowska H, Klisiewicz A, Michalowska I, Makowiecka-Ciesla M, Kolsut P, Stawinski P, Foss-Nieradko B, Szperl M, Grzybowski J, Hoffman P, Januszewicz A, Kusmierczyk M, Ploski R
J Transl Med 2016 May 4;14(1):115.
PMID 27146836
 
Ski regulates Hippo and TAZ signaling to suppress breast cancer progression
Rashidian J, Le Scolan E, Ji X, Zhu Q, Mulvihill MM, Nomura D, Luo K
Sci Signal 2015 Feb 10;8(363):ra14.
PMID 25670202
 
Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling
Reed JA, Bales E, Xu W, Okan NA, Bandyopadhyay D, Medrano EE
Cancer Res 2001 Nov 15;61(22):8074-8.
PMID 11719430
 
Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia
Ritter M, Kattmann D, Teichler S, Hartmann O, Samuelsson MK, Burchert A, Bach JP, Kim TD, Berwanger B, Thiede C, Jäger R, Ehninger G, Schäfer H, Ueki N, Hayman MJ, Eilers M, Neubauer A
Leukemia 2006 Mar;20(3):437-43.
PMID 16424870
 
The Ski Protein is Involved in the Transformation Pathway of Aurora Kinase A
Rivas S, Armisén R, Rojas DA, Maldonado E, Huerta H, Tapia JC, Espinoza J, Colombo A, Michea L, Hayman MJ, Marcelain K
J Cell Biochem 2016 Feb;117(2):334-43.
PMID 26138431
 
Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions
Rosenfeld JA, Crolla JA, Tomkins S, Bader P, Morrow B, Gorski J, Troxell R, Forster-Gibson C, Cilliers D, Hislop RG, Lamb A, Torchia B, Ballif BC, Shaffer LG
Am J Med Genet A 2010 Aug;152A(8):1951-9.
PMID 20635359
 
Influence of melanoma inhibitory activity on transforming growth factor-beta signaling in malignant melanoma
Rothhammer T, Bosserhoff AK
Melanoma Res 2006 Aug;16(4):309-16.
PMID 16845326
 
Shprintzen-Goldberg syndrome associated with first cervical vertebra defects
Saito T, Nakane T, Yagasaki H, Naito A, Sugita K
Pediatr Int 2017 Oct;59(10):1098-1100.
PMID 28857439
 
Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization
Sakakura C, Mori T, Sakabe T, Ariyama Y, Shinomiya T, Date K, Hagiwara A, Yamaguchi T, Takahashi T, Nakamura Y, Abe T, Inazawa J
Genes Chromosomes Cancer 1999 Apr;24(4):299-305.
PMID 10092127
 
The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome
Schepers D, Doyle AJ, Oswald G, Sparks E, Myers L, Willems PJ, Mansour S, Simpson MA, Frysira H, Maat-Kievit A, Van Minkelen R, Hoogeboom JM, Mortier GR, Titheradge H, Brueton L, Starr L, Stark Z, Ockeloen C, Lourenco CM, Blair E, Hobson E, Hurst J, Maystadt I, Destrée A, Girisha KM, Miller M, Dietz HC, Loeys B, Van Laer L
Eur J Hum Genet 2015 Feb;23(2):224-8.
PMID 24736733
 
A two-gene signature, SKI and SLAMF1, predicts time-to-treatment in previously untreated patients with chronic lymphocytic leukemia
Schweighofer CD, Coombes KR, Barron LL, Diao L, Newman RJ, Ferrajoli A, O', Brien S, Wierda WG, Luthra R, Medeiros LJ, Keating MJ, Abruzzo LV
PLoS One 2011;6(12):e28277.
PMID 22194822
 
Generation of Ski-knockdown mice by expressing a long double-strand RNA from an RNA polymerase II promoter
Shinagawa T, Ishii S
Genes Dev 2003 Jun 1;17(11):1340-5.
PMID 12782652
 
The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
Singbrant S, Wall M, Moody J, Karlsson G, Chalk AM, Liddicoat B, Russell MR, Walkley CR, Karlsson S
Haematologica 2014 Apr;99(4):647-55.
PMID 24415629
 
Possible role for the c-ski gene in the proliferation of myogenic cells in regenerating skeletal muscles of rats
Soeta C, Suzuki M, Suzuki S, Naito K, Tachi C, Tojo H
Dev Growth Differ 2001 Apr;43(2):155-64.
PMID 11284965
 
Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway
Song L, Chen X, Gao S, Zhang C, Qu C, Wang P, Liu L
Tumour Biol 2016 Oct 12.
PMID 27734340
 
Characterization of chicken c-ski oncogene products expressed by retrovirus vectors
Sutrave P, Copeland TD, Showalter SD, Hughes SH
Mol Cell Biol 1990 Jun;10(6):3137-44.
PMID 2188109
 
The induction of skeletal muscle hypertrophy by a ski transgene is promoter-dependent
Sutrave P, Leferovich JM, Kelly AM, Hughes SH
Gene 2000 Jan 4;241(1):107-16.
PMID 10607904
 
c-Ski accelerates renal cancer progression by attenuating transforming growth factor β signaling
Taguchi L, Miyakuni K, Morishita Y, Morikawa T, Fukayama M, Miyazono K, Ehata S
Cancer Sci 2019 Jun;110(6):2063-2074.
PMID 30972853
 
SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells
Takahata M, Inoue Y, Tsuda H, Imoto I, Koinuma D, Hayashi M, Ichikura T, Yamori T, Nagasaki K, Yoshida M, Matsuoka M, Morishita K, Yuki K, Hanyu A, Miyazawa K, Inazawa J, Miyazono K, Imamura T
J Biol Chem 2009 Jan 30;284(5):3334-3344.
PMID 19049980
 
Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski
Takeda M, Mizuide M, Oka M, Watabe T, Inoue H, Suzuki H, Fujita T, Imamura T, Miyazono K, Miyazawa K
Mol Biol Cell 2004 Mar;15(3):963-72.
PMID 14699069
 
DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI
Tarapore P, Richmond C, Zheng G, Cohen SB, Kelder B, Kopchick J, Kruse U, Sippel AE, Colmenares C, Stavnezer E
Nucleic Acids Res 1997 Oct 1;25(19):3895-903.
PMID 9380514
 
Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease
Tecalco-Cruz AC, Ríos-López DG, Vázquez-Victorio G, Rosales-Alvarez RE, Macías-Silva M
Signal Transduct Target Ther 2018 Jun 8;3:15.
PMID 29892481
 
Expression of the nuclear oncogene Ski in patients with acute myeloid leukemia treated with all-trans retinoic acid
Teichler S, Schlenk RF, Strauch K, Hagner NM, Ritter M, Neubauer A
Haematologica 2008 Jul;93(7):1105-7.
PMID 18508800
 
Differential effect of the expression of TGF-β pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior
Theohari I, Giannopoulou I, Magkou C, Nomikos A, Melissaris S, Nakopoulou L
APMIS 2012 Feb;120(2):92-100.
PMID 22229264
 
Signal-dependent N-CoR requirement for repression by the Ski oncoprotein
Ueki N, Hayman MJ
J Biol Chem 2003 Jul 4;278(27):24858-64.
PMID 12716897
 
Ski can negatively regulates macrophage differentiation through its interaction with PU.1
Ueki N, Zhang L, Hayman MJ
Oncogene 2008 Jan 10;27(3):300-7.
PMID 17621263
 
Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-β signaling
Verma NK, Dempsey E, Long A, Davies A, Barry SP, Fallon PG, Volkov Y, Kelleher D
J Biol Chem 2012 Aug 3;287(32):27204-16.
PMID 22707713
 
Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus
Villanacci V, Bellone G, Battaglia E, Rossi E, Carbone A, Prati A, Verna C, Niola P, Morelli A, Grassini M, Bassotti G
Hum Pathol 2008 Mar;39(3):403-9.
PMID 18261624
 
Differential role of Sloan-Kettering Institute (Ski) protein in Nodal and transforming growth factor-beta (TGF-β)-induced Smad signaling in prostate cancer cells
Vo BT, Cody B, Cao Y, Khan SA
Carcinogenesis 2012 Nov;33(11):2054-64.
PMID 22843506
 
The Role of c-SKI in Regulation of TGFβ-Induced Human Cardiac Fibroblast Proliferation and ECM Protein Expression
Wang J, Guo L, Shen D, Xu X, Wang J, Han S, He W
J Cell Biochem 2017 Jul;118(7):1911-1920.
PMID 28214335
 
The mechanism of TGF-β/miR-155/c-Ski regulates endothelial-mesenchymal transition in human coronary artery endothelial cells
Wang J, He W, Xu X, Guo L, Zhang Y, Han S, Shen D
Biosci Rep 2017 Aug 23;37(4):BSR20160603.
PMID 28607031
 
c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion
Wang L, Hou Y, Sun Y, Zhao L, Tang X, Hu P, Yang J, Zeng Z, Yang G, Cui X, Liu M
Mol Oncol 2013 Dec;7(6):1116-28.
PMID 24011664
 
Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function
Wang P, Chen Z, Meng ZQ, Fan J, Luo JM, Liang W, Lin JH, Zhou ZH, Chen H, Wang K, Shen YH, Xu ZD, Liu LM
Carcinogenesis 2009 Sep;30(9):1497-506.
PMID 19546161
 
Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells
Wang W, Mariani FV, Harland RM, Luo K
Proc Natl Acad Sci U S A 2000 Dec 19;97(26):14394-9.
PMID 11121043
 
Identification of STRA6 and SKI sequence variants in patients with anophthalmia/microphthalmia
White T, Lu T, Metlapally R, Katowitz J, Kherani F, Wang TY, Tran-Viet KN, Young TL
Mol Vis 2008;14:2458-65.
PMID 19112531
 
Crystal structure of the dachshund homology domain of human SKI
Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hegde RS
Structure 2004 May;12(5):785-92.
PMID 15130471
 
The SKI proto-oncogene restrains the resident CD103 + CD8 + T cell response in viral clearance
Wu B, Zhang G, Guo Z, Wang G, Xu X, Li JL, Whitmire JK, Zheng J, Wan YY
Cell Mol Immunol 2020 Jul 1.
PMID 32612153
 
MiR-1908 promotes scar formation post-burn wound healing by suppressing Ski-mediated inflammation and fibroblast proliferation
Xie C, Shi K, Zhang X, Zhao J, Yu J
Cell Tissue Res 2016 Nov;366(2):371-380.
PMID 27256397
 
Ski regulates Smads and TAZ signaling to suppress lung cancer progression
Xie M, Wu X, Zhang J, Zhang J, Li X
Mol Carcinog 2017 Oct;56(10):2178-2189.
PMID 28398634
 
Ski prevents TGF-β-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer
Yang H, Zhan L, Yang T, Wang L, Li C, Zhao J, Lei Z, Li X, Zhang HT
Oncol Rep 2015 Jul;34(1):87-94.
PMID 25955797
 
Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36
Zaveri HP, Beck TF, Hernández-García A, Shelly KE, Montgomery T, van Haeringen A, Anderlid BM, Patel C, Goel H, Houge G, Morrow BE, Cheung SW, Lalani SR, Scott DA
PLoS One 2014 Jan 15;9(1):e85600.
PMID 24454898
 
Chronic expression of Ski induces apoptosis and represses autophagy in cardiac myofibroblasts
Zeglinski MR, Davies JJ, Ghavami S, Rattan SG, Halayko AJ, Dixon IM
Biochim Biophys Acta 2016 Jun;1863(6 Pt A):1261-8.
PMID 27039037
 
MiR-34a/miR-93 target c-Ski to modulate the proliferaton of rat cardiac fibroblasts and extracellular matrix deposition in vivo and in vitro
Zhang C, Zhang Y, Zhu H, Hu J, Xie Z
Cell Signal 2018 Jun;46:145-153.
PMID 29551367
 
Ski regulates muscle terminal differentiation by transcriptional activation of Myog in a complex with Six1 and Eya3
Zhang H, Stavnezer E
J Biol Chem 2009 Jan 30;284(5):2867-2879.
PMID 19008232
 
Overexpression of c-Ski promotes cell proliferation, invasion and migration of gastric cancer associated fibroblasts
Zhang H, Wang JS, Chen XG, Kang L, Lin MB
Kaohsiung J Med Sci 2019 Apr;35(4):214-221.
PMID 30896889
 
A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability
Zhang L, Xu X, Sun K, Sun J, Wang Y, Liu Y, Yang N, Tao C, Cai B, Shi G, Zhang F, Shi J
Am J Med Genet A 2019 Jun;179(6):936-939.
PMID 30883014
 
Reversing SKI-SMAD4-mediated suppression is essential for T H 17 cell differentiation
Zhang S, Takaku M, Zou L, Gu AD, Chou WC, Zhang G, Wu B, Kong Q, Thomas SY, Serody JS, Chen X, Xu X, Wade PA, Cook DN, Ting JPY, Wan YY
Nature 2017 Nov 2;551(7678):105-109.
PMID 29072299
 
SKI and SMAD4 are essential for IL-21-induced Th17 differentiation
Zhang S, Zhang G, Wan YY
Mol Immunol 2019 Oct;114:260-268.
PMID 31398665
 
Identification of direct serum-response factor gene targets during Me2SO-induced P19 cardiac cell differentiation
Zhang SX, Garcia-Gras E, Wycuff DR, Marriot SJ, Kadeer N, Yu W, Olson EN, Garry DJ, Parmacek MS, Schwartz RJ
J Biol Chem 2005 May 13;280(19):19115-26.
PMID 15699019
 
Genomic expression analysis by single-cell mRNA differential display of quiescent CD8 T cells from tumour-infiltrating lymphocytes obtained from in vivo liver tumours
Zhang W, Ding J, Qu Y, Hu H, Lin M, Datta A, Larson A, Liu GE, Li B
Immunology 2009 May;127(1):83-90.
PMID 18778280
 
Knockdown of Ski decreases osteosarcoma cell proliferation and migration by suppressing the PI3K/Akt signaling pathway
Zhao X, Fang Y, Wang X, Yang Z, Li D, Tian M, Kang P
Int J Oncol 2020 Jan;56(1):206-218.
PMID 31746363
 
576 kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy
Zhu X, Zhang Y, Wang J, Yang JF, Yang YF, Tan ZP
Gene 2013 Oct 10;528(2):352-5.
PMID 23892090
 

Citation

This paper should be referenced as such :
Frech M, Neubauer A
SKI (SKI proto-oncogene);
Atlas Genet Cytogenet Oncol Haematol. in press


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(1;1)(p36;p36) PRDM16/SKI
t(1;17)(p36;q25) METRNL/SKI


External links

Nomenclature
HGNC (Hugo)SKI   10896
Cards
AtlasSKIID42303ch1p36
Entrez_Gene (NCBI)SKI    SKI proto-oncogene
AliasesSGS; SKV
GeneCards (Weizmann)SKI
Ensembl hg19 (Hinxton)ENSG00000157933 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000157933 [Gene_View]  ENSG00000157933 [Sequence]  chr1:2228319-2310213 [Contig_View]  SKI [Vega]
ICGC DataPortalENSG00000157933
TCGA cBioPortalSKI
AceView (NCBI)SKI
Genatlas (Paris)SKI
SOURCE (Princeton)SKI
Genetics Home Reference (NIH)SKI
Genomic and cartography
GoldenPath hg38 (UCSC)SKI  -     chr1:2228319-2310213 +  1p36.33-p36.32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SKI  -     1p36.33-p36.32   [Description]    (hg19-Feb_2009)
GoldenPathSKI - 1p36.33-p36.32 [CytoView hg19]  SKI - 1p36.33-p36.32 [CytoView hg38]
ImmunoBaseENSG00000157933
genome Data Viewer NCBISKI [Mapview hg19]  
OMIM164780   182212   
Gene and transcription
Genbank (Entrez)AK309515 X15218
RefSeq transcript (Entrez)NM_003036
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SKI
Alternative Splicing GalleryENSG00000157933
Gene ExpressionSKI [ NCBI-GEO ]   SKI [ EBI - ARRAY_EXPRESS ]   SKI [ SEEK ]   SKI [ MEM ]
Gene Expression Viewer (FireBrowse)SKI [ Firebrowse - Broad ]
GenevisibleExpression of SKI in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6497
GTEX Portal (Tissue expression)SKI
Human Protein AtlasENSG00000157933-SKI [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP12755   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP12755  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP12755
Splice isoforms : SwissVarP12755
PhosPhoSitePlusP12755
Domains : Interpro (EBI)c-SKI_SMAD4-bd_dom    DNA-bd_dom_put_sf    SAND-like_dom_sf    Ski    SKI/SNO/DAC    Ski_DNA-bd_sf    Tscrpt_reg_SKI_SnoN   
Domain families : Pfam (Sanger)c-SKI_SMAD_bind (PF08782)    Ski_Sno (PF02437)   
Domain families : Pfam (NCBI)pfam08782    pfam02437   
Domain families : Smart (EMBL)c-SKI_SMAD_bind (SM01046)  
Conserved Domain (NCBI)SKI
Blocks (Seattle)SKI
PDB (RSDB)1MR1    1SBX    5XOD   
PDB Europe1MR1    1SBX    5XOD   
PDB (PDBSum)1MR1    1SBX    5XOD   
PDB (IMB)1MR1    1SBX    5XOD   
Structural Biology KnowledgeBase1MR1    1SBX    5XOD   
SCOP (Structural Classification of Proteins)1MR1    1SBX    5XOD   
CATH (Classification of proteins structures)1MR1    1SBX    5XOD   
SuperfamilyP12755
Human Protein Atlas [tissue]ENSG00000157933-SKI [tissue]
Peptide AtlasP12755
HPRD01271
IPIIPI00220921   
Protein Interaction databases
DIP (DOE-UCLA)P12755
IntAct (EBI)P12755
BioGRIDSKI
STRING (EMBL)SKI
ZODIACSKI
Ontologies - Pathways
QuickGOP12755
Ontology : AmiGO"negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription repressor activity, RNA polymerase II-specific  neural tube closure  lens morphogenesis in camera-type eye  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription regulator complex  transcription regulator complex  cytoplasm  centrosome  transcription, DNA-templated  transforming growth factor beta receptor signaling pathway  zinc ion binding  negative regulation of cell population proliferation  anterior/posterior axis specification  negative regulation of Schwann cell proliferation  myotube differentiation  nuclear body  PML body  transcription repressor complex  protein kinase binding  protein domain specific binding  olfactory bulb development  myelination in peripheral nervous system  positive regulation of Wnt signaling pathway  embryonic limb morphogenesis  BMP signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  negative regulation of histone deacetylation  ubiquitin protein ligase binding  negative regulation of activin receptor signaling pathway  protein-containing complex  somatic stem cell population maintenance  identical protein binding  camera-type eye development  positive regulation of DNA binding  nose morphogenesis  negative regulation of osteoblast differentiation  positive regulation of transcription by RNA polymerase II  SMAD binding  SMAD binding  histone deacetylase inhibitor activity  negative regulation of fibroblast proliferation  camera-type eye morphogenesis  skeletal muscle fiber development  cell motility  roof of mouth development  retina development in camera-type eye  face morphogenesis  bone morphogenesis  SMAD protein signal transduction  repressing transcription factor binding"  
Ontology : EGO-EBI"negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  negative regulation of transcription by RNA polymerase II  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription repressor activity, RNA polymerase II-specific  neural tube closure  lens morphogenesis in camera-type eye  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription regulator complex  transcription regulator complex  cytoplasm  centrosome  transcription, DNA-templated  transforming growth factor beta receptor signaling pathway  zinc ion binding  negative regulation of cell population proliferation  anterior/posterior axis specification  negative regulation of Schwann cell proliferation  myotube differentiation  nuclear body  PML body  transcription repressor complex  protein kinase binding  protein domain specific binding  olfactory bulb development  myelination in peripheral nervous system  positive regulation of Wnt signaling pathway  embryonic limb morphogenesis  BMP signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  negative regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  negative regulation of BMP signaling pathway  negative regulation of histone deacetylation  ubiquitin protein ligase binding  negative regulation of activin receptor signaling pathway  protein-containing complex  somatic stem cell population maintenance  identical protein binding  camera-type eye development  positive regulation of DNA binding  nose morphogenesis  negative regulation of osteoblast differentiation  positive regulation of transcription by RNA polymerase II  SMAD binding  SMAD binding  histone deacetylase inhibitor activity  negative regulation of fibroblast proliferation  camera-type eye morphogenesis  skeletal muscle fiber development  cell motility  roof of mouth development  retina development in camera-type eye  face morphogenesis  bone morphogenesis  SMAD protein signal transduction  repressing transcription factor binding"  
REACTOMEP12755 [protein]
REACTOME PathwaysR-HSA-2173795 [pathway]   
NDEx NetworkSKI
Atlas of Cancer Signalling NetworkSKI
Wikipedia pathwaysSKI
Orthology - Evolution
OrthoDB6497
GeneTree (enSembl)ENSG00000157933
Phylogenetic Trees/Animal Genes : TreeFamSKI
HOGENOMP12755
Homologs : HomoloGeneSKI
Homology/Alignments : Family Browser (UCSC)SKI
Gene fusions - Rearrangements
Fusion : MitelmanPRDM16/SKI [1p36.32/1p36.33]  
Fusion : MitelmanSKI/CA6 [1p36.33/1p36.23]  
Fusion : MitelmanSKI/KCNT2 [1p36.33/1q31.3]  
Fusion : MitelmanSKI/PRKCZ [1p36.33/1p36.33]  
Fusion : MitelmanSKI/SSU72 [1p36.33/1p36.33]  
Fusion PortalSKI 1p36.33 CA6 1p36.23 SKCM
Fusion PortalSKI 1p36.33 KCNT2 1q31.3 BRCA
Fusion PortalSKI 1p36.33 PRKCZ 1p36.33 BRCA
Fusion PortalSKI 1p36.33 SSU72 1p36.33 GBM
Fusion : Fusion_HubABLIM1--SKI    AHNAK--SKI    AKAP8--SKI    AMPD2--SKI    ARHGEF2--SKI    ARHGEF26--SKI    ARPC5L--SKI    ARRDC2--SKI    BRD2--SKI    BRD3--SKI    BSG--SKI    C5ORF30--SKI    CCDC101--SKI    CDC42EP1--SKI    CHFR--SKI   
CNN2--SKI    COL9A3--SKI    COX20--SKI    CPSF3L--SKI    CYP4B1--SKI    ENAH--SKI    ERICH1--SKI    ESCO1--SKI    FAM129B--SKI    FAM69B--SKI    FAM76B--SKI    FKRP--SKI    GAK--SKI    GAS6--SKI    GAS8--SKI   
GLIPR1--SKI    ING1--SKI    IQSEC1--SKI    IQSEC3--SKI    KCNAB2--SKI    KIAA0319L--SKI    KIRREL3--SKI    LDB1--SKI    LFNG--SKI    LPP--SKI    MCF2L--SKI    MEF2A--SKI    MFI2--SKI    MRPS36--SKI    NAP1L4--SKI   
OSBPL5--SKI    PANK4--SKI    PLXNB2--SKI    POLR3H--SKI    PPP3CA--SKI    PRDM16--SKI    PRKCZ--SKI    PRRT2--SKI    PRSS23--SKI    PTPRG--SKI    PTPRN2--SKI    RAB40B--SKI    RCAN1--SKI    RGPD5--SKI    RNF125--SKI   
SCYL3--SKI    SDCBP--SKI    SDF4--SKI    SEPT9--SKI    SH3PXD2A--SKI    SKI--ADARB1    SKI--CA6    SKI--CAPZB    SKI--CLK3    SKI--KCNT2    SKI--LDHA    SKI--PDF    SKI--PJA2    SKI--PRDM16    SKI--PRKCZ   
SKI--RBM38    SKI--SKI    SKI--SPSB1    SKI--SSU72    SLC35A1--SKI    SLC35E2B--SKI    SMAD3--SKI    SNHG16--SKI    SNRNP70--SKI    SYNE2--SKI    TBC1D22A--SKI    TFPT--SKI    TGM4--SKI    THBS2--SKI    TMEM200B--SKI   
TMSB10--SKI    TTC28--SKI    UBAP2L--SKI    UGDH--SKI    USP1--SKI    USP5--SKI    UVSSA--SKI    VWF--SKI    ZBTB2--SKI    ZBTB46--SKI    ZEB2--SKI    ZFPM2--SKI    ZNF827--SKI   
Fusion : QuiverSKI
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSKI [hg38]
dbVarSKI
ClinVarSKI
MonarchSKI
1000_GenomesSKI 
Exome Variant ServerSKI
GNOMAD BrowserENSG00000157933
Varsome BrowserSKI
Genomic Variants (DGV)SKI [DGVbeta]
DECIPHERSKI [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSKI 
Mutations
ICGC Data PortalSKI 
TCGA Data PortalSKI 
Broad Tumor PortalSKI
OASIS PortalSKI [ Somatic mutations - Copy number]
Cancer Gene: CensusSKI 
Somatic Mutations in Cancer : COSMICSKI  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSKI
Mutations and Diseases : HGMDSKI
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SKI
DgiDB (Drug Gene Interaction Database)SKI
DoCM (Curated mutations)SKI (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SKI (select a term)
intoGenSKI
NCG6 (London) select SKI
Cancer3DSKI(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM164780    182212   
Orphanet1738    2275   
DisGeNETSKI
MedgenSKI
Genetic Testing Registry SKI
NextProtP12755 [Medical]
GENETestsSKI
Target ValidationSKI
Huge Navigator SKI [HugePedia]
ClinGenSKI (curated)
Clinical trials, drugs, therapy
MyCancerGenomeSKI
Protein Interactions : CTD
Pharm GKB GenePA35796
PharosP12755
Clinical trialSKI
Miscellaneous
canSAR (ICR)SKI (select the gene name)
HarmonizomeSKI
DataMed IndexSKI
Probes
Litterature
PubMed143 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXSKI
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Mar 25 20:09:59 CET 2021

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