SKI protein

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V-ski sarcoma viral oncogene homolog (avian)
Protein SKI PDB 1mr1.png
PDB rendering based on 1mr1.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SKI ; SGS; SKV
External IDs OMIM164780 MGI98310 HomoloGene31124 GeneCards: SKI Gene
RNA expression pattern
PBB GE SKI 204270 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6497 20481
Ensembl ENSG00000157933 ENSMUSG00000029050
UniProt P12755 B1AUF1
RefSeq (mRNA) NM_003036 NM_011385
RefSeq (protein) NP_003027 NP_035515
Location (UCSC) Chr 1:
2.16 – 2.24 Mb
Chr 4:
155.15 – 155.22 Mb
PubMed search [1] [2]

The Ski protein is a nuclear protooncoprotein that is associated with tumors at high cellular concentrations.[1] 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.[2]

Ski negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads and repressing the transcription of TGF-beta responsive genes.[3] 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.[4]

The name Ski comes from the Sloan-Kettering Institute where the protein was initially discovered.

Structure[edit]

Gene[edit]

The SKI proto-oncogene is located at a region close to the p73 tumor suppressor gene at the locus 1p36.3 locus of a gene, suggesting a similar function to the p73 gene.[5]

Protein[edit]

Crystal structure of the Dachshund-homology domain of human SKI.[6]

The SKI protein has a 728 amino acid sequence, with multiple domains and is expressed both inside and outside of the nucleus.[5] 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.[5] The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine and phenylalanine amino acid regions.[7] 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.[3]

Function[edit]

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.[5] The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization.[3] Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TFG- β) signaling. TFG- 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.[7] 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.[5] 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.[7]

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.[5]

Related research[edit]

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.[8]

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.[9]

Interactions[edit]

SKI protein has been shown to interact with SKIL,[10] NFIX,[11] SNW1,[12][13][14] MECP2,[15] HIPK2,[16] Promyelocytic leukemia protein,[17] Mothers against decapentaplegic homolog 3,[16][18] Mothers against decapentaplegic homolog 1[16] and Mothers against decapentaplegic homolog 2.[16][19]

References[edit]

  1. ^ Vignais ML (February 2000). "[Ski and SnoN: antagonistic proteins of TGFbeta signaling]". Bull Cancer (in French) 87 (2): 135–7. PMID 10705283. 
  2. ^ Cell 2002;111:1-20.
  3. ^ a b c Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hegde RS (May 2004). "Crystal structure of the dachshund homology domain of human SKI". Structure 12 (5): 785–92. doi:10.1016/j.str.2004.02.035. PMID 15130471. 
  4. ^ Whitman M (August 1998). "Smads and early developmental signaling by the TGFbeta superfamily". Genes Dev. 12 (16): 2445–62. doi:10.1101/gad.12.16.2445. PMID 9716398. 
  5. ^ a b c d e f Reed JA, Lin Q, Chen D, Mian IS, Medrano EE (June 2005). "SKI pathways inducing progression of human melanoma". Cancer Metastasis Rev. 24 (2): 265–72. doi:10.1007/s10555-005-1576-x. PMID 15986136. 
  6. ^ PDB 1SBX; Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hegde RS (May 2004). "Crystal structure of the dachshund homology domain of human SKI". Structure 12 (5): 785–92. doi:10.1016/j.str.2004.02.035. PMID 15130471. 
  7. ^ a b c Chen W, Lam SS, Srinath H, Schiffer CA, Royer WE, Lin K (April 2007). "Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling". J. Biol. Chem. 282 (15): 11365–76. doi:10.1074/jbc.M700186200. PMID 17283070. 
  8. ^ Ramel MC, Emery CM, Emery CS, et al. (April 2007). "Drosophila SnoN modulates growth and patterning by antagonizing TGF-beta signalling". Mech. Dev. 124 (4): 304–17. doi:10.1016/j.mod.2006.12.006. PMID 17289352. 
  9. ^ Arndt S, Poser I, Moser M, Bosserhoff AK (April 2007). "Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling". Mol. Cell. Neurosci. 34 (4): 603–11. doi:10.1016/j.mcn.2007.01.002. PMID 17292623. 
  10. ^ Cohen, S B; Zheng G, Heyman H C, Stavnezer E (February 1999). "Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents". Nucleic Acids Res. (ENGLAND) 27 (4): 1006–14. doi:10.1093/nar/27.4.1006. ISSN 0305-1048. PMC 148280. PMID 9927733. 
  11. ^ Tarapore, P; Richmond C, Zheng G, Cohen S B, Kelder B, Kopchick J, Kruse U, Sippel A E, Colmenares C, Stavnezer E (October 1997). "DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI". Nucleic Acids Res. (ENGLAND) 25 (19): 3895–903. doi:10.1093/nar/25.19.3895. ISSN 0305-1048. PMC 146989. PMID 9380514. 
  12. ^ Prathapam, T; Kühne C, Hayman M, Banks L (September 2001). "Ski interacts with the evolutionarily conserved SNW domain of Skip". Nucleic Acids Res. (England) 29 (17): 3469–76. doi:10.1093/nar/29.17.3469. PMC 55893. PMID 11522815. 
  13. ^ Dahl, R; Wani B, Hayman M J (March 1998). "The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42". Oncogene (ENGLAND) 16 (12): 1579–86. doi:10.1038/sj.onc.1201687. ISSN 0950-9232. PMID 9569025. 
  14. ^ Leong, G M; Subramaniam N, Figueroa J, Flanagan J L, Hayman M J, Eisman J A, Kouzmenko A P (May 2001). "Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription". J. Biol. Chem. (United States) 276 (21): 18243–8. doi:10.1074/jbc.M010815200. ISSN 0021-9258. PMID 11278756. 
  15. ^ Kokura, K; Kaul S C, Wadhwa R, Nomura T, Khan M M, Shinagawa T, Yasukawa T, Colmenares C, Ishii S (September 2001). "The Ski protein family is required for MeCP2-mediated transcriptional repression". J. Biol. Chem. (United States) 276 (36): 34115–21. doi:10.1074/jbc.M105747200. ISSN 0021-9258. PMID 11441023. 
  16. ^ a b c d Harada, Jun; Kokura Kenji, Kanei-Ishii Chie, Nomura Teruaki, Khan Md Matiullah, Kim Yongsok, Ishii Shunsuke (October 2003). "Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation". J. Biol. Chem. (United States) 278 (40): 38998–9005. doi:10.1074/jbc.M307112200. ISSN 0021-9258. PMID 12874272. 
  17. ^ Khan, M M; Nomura T, Kim H, Kaul S C, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi P P, Ishii S (June 2001). "Role of PML and PML-RARalpha in Mad-mediated transcriptional repression". Mol. Cell (United States) 7 (6): 1233–43. doi:10.1016/S1097-2765(01)00257-X. ISSN 1097-2765. PMID 11430826. 
  18. ^ Ueki, Nobuhide; Hayman Michael J (August 2003). "Direct interaction of Ski with either Smad3 or Smad4 is necessary and sufficient for Ski-mediated repression of transforming growth factor-beta signaling". J. Biol. Chem. (United States) 278 (35): 32489–92. doi:10.1074/jbc.C300276200. ISSN 0021-9258. PMID 12857746. 
  19. ^ Luo, K; Stroschein S L, Wang W, Chen D, Martens E, Zhou S, Zhou Q (September 1999). "The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling". Genes Dev. (UNITED STATES) 13 (17): 2196–206. doi:10.1101/gad.13.17.2196. ISSN 0890-9369. PMC 316985. PMID 10485843. 

Further reading[edit]