Disease relevance of SKIL

• Depletion, by small interfering RNA, of SnoN and/or p53 in hepatoma cells disrupted repression of AFP transcription [1].
• All glioma cell lines expressed the SnoN protein and its expression was unaltered by treatment with TGFbeta1 [2].
• SNO is a probable target for gene amplification at 3q26 in squamous-cell carcinomas of the esophagus [3].
• Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung [4].
• Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity, and extracellular matrix production as well as a reduction in adherens junction proteins [4].

High impact information on SKIL

• By 2 hours, TGF-beta induces a marked increase in SnoN expression, resulting in termination of Smad-mediated transactivation [5].
• In addition to the D box, efficient ubiquitination and degradation of SnoN also requires the Smad3 binding site in SnoN as well as key lysine residues necessary for ubiquitin attachment [6].
• Degradation of SnoN is thought to play an important role in the transactivation of TGF-beta responsive genes [7].

Chemical compound and disease context of SKIL

• Cytotoxicity of fumonisin B1, diethylnitrosamine, and catechol on the SNO esophageal cancer cell line [8].
• In preeclampsia, a pregnancy-specific disorder associated with endothelial dysfunction, we previously found significant elevations in plasma SNO-Alb concentrations and decreased plasma ascorbate (Asc) levels [9].

Biological context of SKIL

• Upon morphological differentiation or cell-cycle arrest, SnoN translocates into the nucleus [10].
• Here, we determined the effect of genetic knock-down of SnoN by RNA interference on TGF-beta responses in mammalian cells [11].
• Our study also shows that SnoN couples the TGF-beta signal to gene expression in a cell-specific manner [11].
• Furthermore, upregulation of three candidate genes (NFIL3, SKIL, and JMJD3) was shown to be dosage and time dependent with TPA treatment and was found to be directly regulated by TPA through PKC-dependent signaling [12].
• These findings define Cdh1-APC and SnoN as components of a cell-intrinsic pathway that orchestrates axonal morphogenesis in a transcription-dependent manner in the mammalian brain [13].

Anatomical context of SKIL

• It has been described as a nuclear protein, based on studies of ectopically expressed SnoN and endogenous SnoN in cancer cell lines [10].
• Here, we show that, whereas SnoN is localized exclusively in the nucleus in cancer tissues or cells, in normal tissues and nontumorigenic or primary epithelial cells, SnoN is predominantly cytoplasmic [10].
• Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells [14].
• SnoN, snoA, and ski mRNAs accumulate in many human tissues including skeletal muscle; the snoI alternative mRNA accumulates more specifically in skeletal muscle [15].
• In addition, SnoN knockdown in vivo suggests an essential function for SnoN in the development of granule neuron parallel fibers in the cerebellar cortex [13].

Associations of SKIL with chemical compounds

• TAK1 MAPK Kinase Kinase Mediates Transforming Growth Factor-beta Signaling by Targeting SnoN Oncoprotein for Degradation [16].
• Downregulation of Ski and SnoN co-repressors by anisomycin [17].
• The three molecules are in general agreement but display subtle differences, including both cis and trans conformers for Cys 69 SNO in molecule C, and greater disorder in the Cys 62-Cys 69 helix in molecule B [18].
• In the present study we therefore investigated the cytotoxic effects of FB1, diethylnitrosamine (DEN), and CAT on a human esophageal epithelial cell line (SNO) using the methylthiazol tetrazolium assay [8].
• In the promoter region of human SnoN gene, two cAMP response elements were located in close proximity to Sp1 sites [19].

Physical interactions of SKIL

• Moreover, when expressed in chicken embryo fibroblasts, mutant Ski or SnoN defective in binding to the Smad proteins failed to induce oncogenic transformation [20].
• Here, we show that c-Ski and SnoN bind to the "SE" sequence in the C-terminal MH2 domain of Smad3, which is exposed on the N-terminal upper side of the toroidal structure of the MH2 oligomer [21].
• SnoN co-repressor binds and represses smad7 gene promoter [22].

Enzymatic interactions of SKIL

• However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN [23].
• TAK1 interacted with and phosphorylated SnoN, and this phosphorylation regulated the stability of SnoN [16].

Regulatory relationships of SKIL

• Thus, SnoN maintains the repressed state of TGF-beta-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling [5].
• The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins [20].
• Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN [6].
• Ski and SnoN overexpression inhibits smad7 reporter expression induced through TGF-beta signaling [22].
• SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-beta signaling [24].

Other interactions of SKIL

• Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein [5].
• This allows Smurf2 HECT domain to target SnoN for ubiquitin-mediated degradation by the proteasome [25].
• Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN [21].
• Thus, SnoN also seems to regulate negatively the TGF-beta-responsive smad7 gene by binding and repressing its promoter in a similar way to Ski [22].
• The proteasomal degradation of these two proteins links TGF-beta signaling to multiple signaling pathways involving SnoN and HEF1 [26].

Analytical, diagnostic and therapeutic context of SKIL

• Whereas SnoN protein was markedly diminished, its mRNA levels remained relatively constant in the obstructed kidney after ureteral ligation [27].
• Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC [28].
• The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting [28].
• Thereafter, a semi-quantitative RT-PCR, Western blot analysis and immunohistochemistry test were performed for determining Smurf2, Smad2 and SnoN at week 1, 2, 4 and 8 of establishing the liver fibrosis model [29].
• Reduced expression of SnoN significantly correlated with longer distant disease-free survival in estrogen receptor-positive patients (P = 0.0027, relative risk = 3.27; 95% confidence interval = 1.44-7.41) [30].

References