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SKI proteinSKI protein
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BackgroundBackground
The SKI protein was first identified as an oncoprotein. An oncoprotein is one that has the potential to cause abnormal cellular proliferation if mutated or if expressed in quantitative amounts. Although, for a time the method by which the SKI protein acquired such capabilities was unknown, it was recently discovered that SKI interacts with smad after stimulation by TGF-beta. TGF-beta are proteins directly associated with proliferation and cellular differentiation, while smads are transcription factors that transduce transforming growth factor-betar(TGF-beta) members to activate transcription. SKI blocks the activation of transcription witht eh smad complexes which makes the cells resistant to the inhibitory reactions of normal growth induced by TGF-beta. Note that the stimulation of TGF-beta may cause the rapid degradation of SKI. However, after a relatively brief amount of time its expression is strongly induced. [1].
StructureStructure
This protein is made up of 728 amino acids[2]. The SKI protein maintains several domains that include the amino-terminus, a proline rich area, helix-loop-helix motifs, a cysteine/histidine-rich area, a region of basic amino acids and finally a leucine zipper-like domain[3]. SKI has been currently assigned to chromosome 1p36, a common region of alteration in human cancers including melanomas.
FunctionFunction
SKI, as mentioned before is an oncoprotein that represses TGF-beta and nuclear receptor signaling from telling the cell to slow down and stop dividing. It is also involved in the regulation of cellular transformation and differentiation[4]. The SKI protein has been associated with tumors at large levels of cellular concentrations and it has been shown to interfere with normal cellular functioning. It was recently discovered that SKI plays a role not only inside the nucleus but also outside of the nucleus in the cytoplasm. Scientists have previously shown that Ski disrupts normal cell functioning by directly disrupting the expression of genes inside the cell’s nucleus[4]
Clinical ApplicationsClinical Applications
SKI has been linked to various types of cancer such as melanoma, esophageal cell carcinoma, cervical cancer and the process of tumor progresssion. The SKI oncoprotein has been demonstrated to assist tyrosine kinases to cause leukemia, recently it has been demonstrated that the protein also plays a regulatory role in several signal transduction pathways that are frequent targets for mutagenesis in human tumors. Much research performed on the SKI protein is based on the role it plays in the proliferation of cells in human melanoma[5].
ReferencesReferences
- ↑ Reed JA, Lin Q, Chen D, Mian IS, Medrano EE. SKI Pathways Inducing Progression of Human Melanoma. June 2005. http://www.ncbi.nlm.nih.gov/pubmed/15986136
- ↑ Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hedge RS. May 2004. "Crystal Struture of the Dachshund homology domain of human SKI" Structure 12 (5):785-92. http://www.ncbi.nlm.nih.gov/pubmed/15130471
- ↑ Zheng G, Teumer J, Colmenares C, Richmond C and Stavnezer E. 1997. Oncogene. http://www.nature.com/onc/journal/v22/n20/full/1206452a.html
- ↑ 4.0 4.1 Medrano E. 2003. Repression of TGF-B signaling by the oncogenic protein SKI in human melanomas: Consequences for proliferation, survival, and metastasis. http://www.nature.com/onc/journal/v22/n20/full/1206452a.html Cite error: Invalid
<ref>tag; name "function" defined multiple times with different content - ↑ Marcelain K, Hayman MJ. Fall 2005. The Ski oncoprotein is upregulated by localized centrosomes and mitotic spindle during metosis. http://www.nature.com/onc/journal/v24/n27/full/1208631a.html