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Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression.

Abstract : BACKGROUND: SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood. RESULTS: In this study, we found elevated SKI and SnoN protein levels in a panel of melanoma cell lines, as compared to normal melanocytes. There was no correlation between SKI protein content and the capacity of melanoma cells to invade Matrigel™, to form subcutaneous tumors, or to metastasize to bone after intracardiac inoculation into nude mice. Nor did we find a correlation between SKI expression and histopathological staging of human melanoma. TGF-β induced a rapid and dose-dependent degradation of SKI protein, associated with SMAD3/4 specific transcriptional response and induction of pro-metastatic target genes, partially prevented by pharmacologic blockade of proteasome activity. SKI knockdown in 1205Lu melanoma cells did not alter their invasive capacity or transcriptional responses to TGF-β, and did not allow p21 expression in response to TGF-β or reveal any growth inhibitory activity of TGF-β. CONCLUSIONS: Despite high expression in melanoma cells, the role of SKI in melanoma remains elusive: SKI does not efficiently interfere with the pro-oncogenic activities of TGF-β, unless stabilized by proteasome blockade. Its highly labile nature makes it an unlikely target for therapeutic intervention.
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Submitted on : Monday, October 3, 2011 - 9:12:32 PM
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Delphine Javelaud, Leon van Kempen, Vasileia Alexaki, Erwan Le Scolan, Kunxin Luo, et al.. Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression.. Molecular Cancer, BioMed Central, 2011, 10 (1), pp.2. ⟨10.1186/1476-4598-10-2⟩. ⟨inserm-00628646⟩



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