Disease relevance of Ski

• Identification of gene targets for the fiber-specific action of the c-ski gene product provides a molecular model that could be used for the further dissection of Ski-induced hypertrophy, both in tissue culture and in vivo [1].
• In agreement with these findings, Ski-/- mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass [2].
• Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury [3].
• Quail embryo cells (QECs) are primary cultures of fibroblastoid cells that become myogenic after infection with avian retroviruses expressing the ski oncogene (SKVs). ski also stimulates proliferation of QECs and induces morphological transformation and anchorage-independent growth [4].

High impact information on Ski

• Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice [2].
• Transgenic mice embryos expressing long ds-RNA for the transcriptional corepressor Ski from this vector exhibited phenotypes that were remarkably similar to those of Ski-deficient embryos, including defects of neural tube closure and eye formation [5].
• Furthermore, a Ski mutation enhanced the digit abnormalities caused by the Gli3 gene mutation [6].
• These results show that Ski is a component of the HDAC complex and that Ski is required for the transcriptional repression mediated by this complex [7].
• The myelination-regulating transcription factor Oct6 is involved in a complex modulatory relationship with Ski [8].

Biological context of Ski

• Activation of a muscle-specific enhancer by the Ski proto-oncogene [1].
• Activation of the MLC enhancer by Ski also occurred in vivo, since bigenic progeny generated by mating MLC-CAT and MSV-skitransgenic mice displayed higher CAT activity in their muscles than did the MLC-CAT parental line [1].
• The protooncogene Ski controls Schwann cell proliferation and myelination [8].
• Conversely, overexpression of Ski in Schwann cells causes an upregulation of myelin-related genes [8].
• Functional Ski overexpression inhibits TGF-beta-mediated proliferation and prevents growth-arrested Schwann cells from reentering the cell cycle [8].

Anatomical context of Ski

• The expression from the MLC enhancer was reduced when the c-ski oncogene was cotransfected with MyoD into NIH3T3 fibroblasts [1].
• In transgenic mice, muscle-specific expression of the c-ski oncogene induces hypertrophy exclusively in a subset of fast muscle fibers [1].
• Consistent with these findings, myelinating Schwann cells upregulate Ski during development and remyelination after injury [8].
• Myelination is blocked in myelin-competent cultures derived from Ski-deficient animals, and genes encoding myelin components are downregulated in Ski-deficient nerves [8].
• This ability to antagonize BMP signaling results in neuralization by Ski in the Xenopus embryo and blocking of osteoblast differentiation of murine W-20-17 cells [9].

Associations of Ski with chemical compounds

• An association between Ski and C184M involving the leucine-rich region of C184M and the C-terminal coiled-coil motif of Ski was confirmed by glutathione S-transferase pull-down and immunoprecipitation assays [10].
• The predictive value of these profiles was verified by demonstrating that NTDs of Ski-/- mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation [11].
• Defects in Ski(-)(/)(-)() mice closely resemble those described in animals lacking several of the retinoic acid receptor genes, or in animals exposed to excess retinoic acid during gestation [12].
• The mice were divide into 3 subgroups, - one without protectans, - one protected by the sun protection lotion Sea and Ski, factor 5, - and one by Piz Buin, Factor 6 [13].

Physical interactions of Ski

• By electophoretic mobility shift assays we find that Ski is a component of one or more NFI complexes but we fail to detect Ski in Olf-1/EBF complexes [14].

Other interactions of Ski

• c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity [15].
• The involvement of c-Ski in the HDAC complex indicates that the function of the HDAC complex is important for oncogenesis [7].
• Further more, Ski and Sno negatively regulate transforming growth factor-beta (TGF-beta) signaling by recruiting this complex to Smads [16].
• Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1beta and Ski [17].
• We have shown that Ski is an important negative regulator of the Smad proteins [18].

Analytical, diagnostic and therapeutic context of Ski

• In contrast to Ski and Sno, which are ubiquitously expressed in human tissues, in situ hybridization, RT-PCR, Western blot and immunohistochemistry revealed a highly specific expression pattern for Fussel-18 in neuronal tissues, especially in the cerebellum, the spinal cord and dorsal root ganglia, during both embryogenesis and adult stage [19].

References