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Gene Review

SKIL  -  SKI-like proto-oncogene

Homo sapiens

Synonyms: SNO, Ski-like protein, Ski-related oncogene, Ski-related protein, SnoA, ...
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Disease relevance of SKIL


High impact information on SKIL


Chemical compound and disease context of SKIL


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


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


  1. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Wilkinson, D.S., Ogden, S.K., Stratton, S.A., Piechan, J.L., Nguyen, T.T., Smulian, G.A., Barton, M.C. Mol. Cell. Biol. (2005) [Pubmed]
  2. Participation of an abnormality in the transforming growth factor-beta signaling pathway in resistance of malignant glioma cells to growth inhibition induced by that factor. Zhang, L., Sato, E., Amagasaki, K., Nakao, A., Naganuma, H. J. Neurosurg. (2006) [Pubmed]
  3. SNO is a probable target for gene amplification at 3q26 in squamous-cell carcinomas of the esophagus. Imoto, I., Pimkhaokham, A., Fukuda, Y., Yang, Z.Q., Shimada, Y., Nomura, N., Hirai, H., Imamura, M., Inazawa, J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  4. Dual role of SnoN in mammalian tumorigenesis. Zhu, Q., Krakowski, A.R., Dunham, E.E., Wang, L., Bandyopadhyay, A., Berdeaux, R., Martin, G.S., Sun, L., Luo, K. Mol. Cell. Biol. (2007) [Pubmed]
  5. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Stroschein, S.L., Wang, W., Zhou, S., Zhou, Q., Luo, K. Science (1999) [Pubmed]
  6. Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Stroschein, S.L., Bonni, S., Wrana, J.L., Luo, K. Genes Dev. (2001) [Pubmed]
  7. The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Wan, Y., Liu, X., Kirschner, M.W. Mol. Cell (2001) [Pubmed]
  8. Cytotoxicity of fumonisin B1, diethylnitrosamine, and catechol on the SNO esophageal cancer cell line. Myburg, R.B., Dutton, M.F., Chuturgoon, A.A. Environ. Health Perspect. (2002) [Pubmed]
  9. S-nitrosoalbumin-mediated relaxation is enhanced by ascorbate and copper: effects in pregnancy and preeclampsia plasma. Gandley, R.E., Tyurin, V.A., Huang, W., Arroyo, A., Daftary, A., Harger, G., Jiang, J., Pitt, B., Taylor, R.N., Hubel, C.A., Kagan, V.E. Hypertension (2005) [Pubmed]
  10. Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-beta signaling by sequestration of the Smad proteins. Krakowski, A.R., Laboureau, J., Mauviel, A., Bissell, M.J., Luo, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. SnoN is a cell type-specific mediator of transforming growth factor-beta responses. Sarker, K.P., Wilson, S.M., Bonni, S. J. Biol. Chem. (2005) [Pubmed]
  12. An efficient strategy to identify early TPA-responsive genes during differentiation of HL-60 cells. Hu, L.Y., Tepper, C.G., Lo, S.H., Lin, W.C. Gene Expr. (2006) [Pubmed]
  13. Cell-Intrinsic Regulation of Axonal Morphogenesis by the Cdh1-APC Target SnoN. Stegmüller, J., Konishi, Y., Huynh, M.A., Yuan, Z., Dibacco, S., Bonni, A. Neuron (2006) [Pubmed]
  14. Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells. Zhu, Q., Pearson-White, S., Luo, K. Mol. Cell. Biol. (2005) [Pubmed]
  15. SnoI, a novel alternatively spliced isoform of the ski protooncogene homolog, sno. Pearson-White, S. Nucleic Acids Res. (1993) [Pubmed]
  16. TAK1 MAPK Kinase Kinase Mediates Transforming Growth Factor-beta Signaling by Targeting SnoN Oncoprotein for Degradation. Kajino, T., Omori, E., Ishii, S., Matsumoto, K., Ninomiya-Tsuji, J. J. Biol. Chem. (2007) [Pubmed]
  17. Downregulation of Ski and SnoN co-repressors by anisomycin. Vázquez-Macías, A., Ruíz-Mendoza, A.B., Fonseca-Sánchez, M.A., Briones-Orta, M.A., Macías-Silva, M. FEBS Lett. (2005) [Pubmed]
  18. Buried s-nitrosocysteine revealed in crystal structures of human thioredoxin(,). Weichsel, A., Brailey, J.L., Montfort, W.R. Biochemistry (2007) [Pubmed]
  19. Molecular basis for the cell type specific induction of SnoN expression by hepatocyte growth factor. Tan, R., Zhang, X., Yang, J., Li, Y., Liu, Y. J. Am. Soc. Nephrol. (2007) [Pubmed]
  20. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. He, J., Tegen, S.B., Krawitz, A.R., Martin, G.S., Luo, K. J. Biol. Chem. (2003) [Pubmed]
  21. Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN. Mizuide, M., Hara, T., Furuya, T., Takeda, M., Kusanagi, K., Inada, Y., Mori, M., Imamura, T., Miyazawa, K., Miyazono, K. J. Biol. Chem. (2003) [Pubmed]
  22. SnoN co-repressor binds and represses smad7 gene promoter. Briones-Orta, M.A., Sosa-Garrocho, M., Moreno-Alvarez, P., Fonseca-Sánchez, M.A., Macías-Silva, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Komuro, A., Imamura, T., Saitoh, M., Yoshida, Y., Yamori, T., Miyazono, K., Miyazawa, K. Oncogene (2004) [Pubmed]
  24. Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation. Wrighton, K.H., Liang, M., Bryan, B., Luo, K., Liu, M., Feng, X.H., Lin, X. J. Biol. Chem. (2007) [Pubmed]
  25. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Bonni, S., Wang, H.R., Causing, C.G., Kavsak, P., Stroschein, S.L., Luo, K., Wrana, J.L. Nat. Cell Biol. (2001) [Pubmed]
  26. The 26S proteasome system in the signaling pathways of TGF-beta superfamily. Wang, T. Front. Biosci. (2003) [Pubmed]
  27. Downregulation of SnoN Expression in Obstructive Nephropathy Is Mediated by an Enhanced Ubiquitin-Dependent Degradation. Tan, R., Zhang, J., Tan, X., Zhang, X., Yang, J., Liu, Y. J. Am. Soc. Nephrol. (2006) [Pubmed]
  28. 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) [Pubmed]
  29. Abnormal expression of Smurf2 during the process of rat liver fibrosis. Cai, Y., Shen, X.Z., Zhou, C.H., Wang, J.Y. Chinese journal of digestive diseases. (2006) [Pubmed]
  30. Ski-related novel protein N (SnoN), a negative controller of transforming growth factor-beta signaling, is a prognostic marker in estrogen receptor-positive breast carcinomas. Zhang, F., Lundin, M., Ristimäki, A., Heikkilä, P., Lundin, J., Isola, J., Joensuu, H., Laiho, M. Cancer Res. (2003) [Pubmed]
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