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Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34

Oncogene volume 23, pages 5643–5653 (2004)Cite this article

Abstract

It is known that excess amounts of Ski, or any member of its proto-oncoprotein family, causes disruption of the transforming growth factor beta signal transduction pathway, thus causing oncogenic transformation of cells. Previous studies indicate that Ski is a relatively unstable protein whose expression levels can be regulated by ubiquitin-mediated proteolysis. Here, we investigate the mechanism by which the stability of Ski is regulated. We show that the steady-state levels of Ski protein are controlled post-translationally by cell cycle-dependent proteolysis, wherein Ski is degraded during the interphase of the cell cycle but is relatively stable during mitosis. Furthermore, we demonstrate that the ubiquitin-conjugating enzyme Cdc34 mediates cell cycle-dependent Ski degradation both in vitro and in vivo. Overexpression of dominant-negative Cdc34 stabilizes Ski and enhances its ability to antagonize TGF-β signaling. Our data suggest that regulated proteolysis of Ski is one of the key mechanisms that control the threshold levels of this proto-oncoprotein, and thus prevents epithelial cells from becoming TGF-β resistant.

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Acknowledgements

We thank Dr Plon for the generous supply of the Cdc34 cDNA clones and Drs Kirschner, Pagano, Ruderman and Weissman for Ubc5 and Ubc10 expression clones. We also thank Dr Natalie Ahn and Dr Katheryn Resing and members of their laboratories for stimulating discussions. We also thank Drs Ahn and Goodrich for critically reading the manuscript. This work is supported by Grant CA95527-01 from the National Institutes of Health to XL.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Colorado-Boulder, Boulder, 80309, CO, USA

    Mara Macdonald, Wei Wang, Elisabeth Roberts, Tom Hiu Cheung, Richard Erickson, Matthew T Knuesel & Xuedong Liu

  2. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, 15261, PA, USA

    Yong Wan

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  1. Mara Macdonald
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  2. Yong Wan
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Correspondence to Xuedong Liu.

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Macdonald, M., Wan, Y., Wang, W. et al. Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34. Oncogene 23, 5643–5653 (2004). https://doi.org/10.1038/sj.onc.1207733

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