|, SKI proto-oncogene, SGS, SKV|
|RNA expression pattern|
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The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
SKI negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads and repressing the transcription of TGF-beta responsive genes. This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis, specification, and developmental fate.
The name SKI comes from the Sloan-Kettering Institute where the protein was initially discovered.
The SKI protein has a 728 amino acid sequence, with multiple domains and is expressed both inside and outside of the nucleus. It is in the same family as the SnoN protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix motif, a cysteine and histidine rich area which gives rise to the zinc finger motif, a basic amino acid region, and leucine zipper. All these domains, including a proline rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins. The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine and phenylalanine amino acid regions. Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.
The SKI oncogene is present in all cells, and is commonly active during development. Specifically, avian fibroblasts depend on the SKI protein as a transcription co-regulator inducing transformation. The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization. Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TGF- β) signaling. TGF- β is a protein which regulates cell growth. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells. It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β. The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3 and CReB-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4 complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell’s ability to stop growth and division, creating cancerous cells.
SKI has been linked to various cancers including human melanomas, esophageal squamous cell carcinoma, cervical cancer and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein’s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.
Other research has identified proteins similar to Ski. The SnoN protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.
SKI protein has been shown to interact with:
- Mothers against decapentaplegic homolog 1 and
- Mothers against decapentaplegic homolog 2,
- Mothers against decapentaplegic homolog 3,
- Promyelocytic leukemia protein,
- SKIL, and
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
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- Cohen SB, Zheng G, Heyman HC, Stavnezer E (February 1999). "Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents". Nucleic Acids Res. 27 (4): 1006–14. doi:10.1093/nar/27.4.1006. PMC . PMID 9927733.
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- Tarapore P, Richmond C, Zheng G, Cohen SB, Kelder B, Kopchick J, Kruse U, Sippel AE, Colmenares C, Stavnezer E (1997). "DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI.". Nucleic Acids Res. 25 (19): 3895–903. doi:10.1093/nar/25.19.3895. PMC . PMID 9380514.
- Dahl R, Wani B, Hayman MJ (1998). "The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42.". Oncogene. 16 (12): 1579–86. doi:10.1038/sj.onc.1201687. PMID 9569025.
- Cohen SB, Zheng G, Heyman HC, Stavnezer E (1999). "Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents.". Nucleic Acids Res. 27 (4): 1006–14. doi:10.1093/nar/27.4.1006. PMC . PMID 9927733.
- Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q (1999). "The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.". Genes Dev. 13 (17): 2196–206. doi:10.1101/gad.13.17.2196. PMC . PMID 10485843.
- Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, Weinberg RA (1999). "Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling.". Mol. Cell. 4 (4): 499–509. doi:10.1016/S1097-2765(00)80201-4. PMID 10549282.
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- Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S (2001). "Role of PML and PML-RARalpha in Mad-mediated transcriptional repression.". Mol. Cell. 7 (6): 1233–43. doi:10.1016/S1097-2765(01)00257-X. PMID 11430826.
- Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S (2001). "The Ski protein family is required for MeCP2-mediated transcriptional repression.". J. Biol. Chem. 276 (36): 34115–21. doi:10.1074/jbc.M105747200. PMID 11441023.
- Prathapam T, Kühne C, Hayman M, Banks L (2001). "Ski interacts with the evolutionarily conserved SNW domain of Skip.". Nucleic Acids Res. 29 (17): 3469–76. doi:10.1093/nar/29.17.3469. PMC . PMID 11522815.
- Reed JA, Bales E, Xu W, Okan NA, Bandyopadhyay D, Medrano EE (2001). "Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling.". Cancer Res. 61 (22): 8074–8. PMID 11719430.
- Pessah M, Marais J, Prunier C, Ferrand N, Lallemand F, Mauviel A, Atfi A (2002). "c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity.". J. Biol. Chem. 277 (32): 29094–100. doi:10.1074/jbc.M202831200. PMID 12034730.
- Wu JW, Krawitz AR, Chai J, Li W, Zhang F, Luo K, Shi Y (2002). "Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling.". Cell. 111 (3): 357–67. doi:10.1016/S0092-8674(02)01006-1. PMID 12419246.
- Dai P, Shinagawa T, Nomura T, Harada J, Kaul SC, Wadhwa R, Khan MM, Akimaru H, Sasaki H, Colmenares C, Ishii S (2002). "Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3.". Genes Dev. 16 (22): 2843–8. doi:10.1101/gad.1017302. PMC . PMID 12435627.
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