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c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements

Oncogene volume 23, pages 5068–5076 (2004)Cite this article

Abstract

c-Ski inhibits transforming growth factor-β (TGF-β) signaling through interaction with Smad proteins. c-Ski represses Smad-mediated transcriptional activation, probably through its action as a transcriptional co-repressor. c-Ski also inhibits TGF-β-induced downregulation of genes such as c-myc. However, mechanisms for transcriptional regulation of target genes by c-Ski have not been fully determined. In this study, we examined how c-Ski inhibits both TGF-β-induced transcriptional activation and repression. DNA-affinity precipitation analysis revealed that c-Ski enhances the binding of Smad2 and 4, and to a lesser extent Smad3, to both CAGA and TGF-β1 inhibitory element probes. A c-Ski mutant, which is unable to interact with Smad4, failed to enhance the binding of Smad complex on these probes and to inhibit the Smad-responsive promoter. These results suggest that stabilization of inactive Smad complexes on DNA is a critical event in c-Ski-mediated inhibition of TGF-β signaling.

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Acknowledgements

This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Science, Sports and Technology of Japan. We thank M Laiho and J Massagué for R-mutant Mv1Lu cells, B Blackwood and RN Eisenman for c-myc cDNA, and N Nomura and S Pearson-White for c-Ski and SnoN cDNAs. We are grateful to T Imamura, T Watabe and M Saitoh for helpful discussions.

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  1. Mitsuyasu Kato

    Present address: Institute of Basic Medical Sciences, University of Tsukuba, Ibaragi, 305-8575, Japan

Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 113-0033, Tokyo, Japan

    Hiroyuki Suzuki, Miki Kondo, Kohei Miyazono & Keiji Miyazawa

  2. Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, 170-8455, Tokyo, Japan

    Hiroyuki Suzuki, Ken Yagi, Miki Kondo, Mitsuyasu Kato & Kohei Miyazono

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  1. Hiroyuki Suzuki
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Correspondence to Kohei Miyazono.

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Suzuki, H., Yagi, K., Kondo, M. et al. c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene 23, 5068–5076 (2004). https://doi.org/10.1038/sj.onc.1207690

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