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

Molecular Cancer

Research

Erwan Le Scolan¹  Kunxin Luo¹  Alain Mauviel²  Vasileia I Alexaki²  Delphine Javelaud²  Leon van Kempen³ 

[1] Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA;Institut Curie, University Center, Building 110, Orsay, France;INSERM U1021, University Center, Building 110, Orsay, France;CNRS UMR3347, University Center, Building 110, Orsay, France;Université Paris XI, Orsay, France;Radboud University Nijmegen Medical Centre, The Netherlands;

关键词: Melanoma;    Melanoma Cell;    Melanoma Cell Line;    Human Melanoma Cell Line;    Proteasome Inhibitor MG132;   

DOI  :  10.1186/1476-4598-10-2

 received in 2010-06-17, accepted in 2011-01-06,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundSKI 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.ResultsIn 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.ConclusionsDespite 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.

【 授权许可】

Unknown   
© Javelaud et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.