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A splice variant of Skp2 is retained in the cytoplasm and fails to direct cyclin D1 ubiquitination in the uterine cancer cell line SK-UT

Oncogene volume 20, pages 3641–3650 (2001)Cite this article

Abstract

Cyclin D1 is an important regulator of the transition from G1 into S phase of the cell cycle. The level to which cyclin D1 accumulates is tightly regulated. One mechanism contributing to the control of cyclin D1 levels is the regulation of its ubiquitination. SK-UT-1B cells are deficient in the degradation of D-type cyclins. We show here that p27, a substrate of the SCFSkp2 ubiquitin ligase complex, is coordinately stabilized in SK-UT-1B cells. Further, we show that expression of Skp2 in SK-UT-1B cells rescues the cyclin D1 and p27 degradation defect observed in this cell line. These results therefore indicate that the SCFSkp2 ubiquitin ligase complex affects the ubiquitination of cyclin D1. In addition, we show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCFSkp2 complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line. Finally, our data indicates that differential splicing of F-box proteins may represent an additional level of regulation of the F-box mediated ubiquitination pathway.

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Acknowledgements

We would like to thank Drs Matthew O'Connell, Patrick Humbert and Grant McArthur for critical reading of this manuscript and also Matthew Beasley for help with genomic structure analysis of Skp2. This work was supported by NHMRC grant no. 981080 and a Susan G Komen grant to D Germain.

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Authors and Affiliations

  1. Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, St-Andrew's Place, East Melbourne, Melbourne, 3002, Victoria, Australia

    Soula Ganiatsas, Renee Dow, Anne Thompson & Doris Germain

  2. Biochemistry and Molecular Biology department, Melbourne University, Parkville, 3052, Victoria, Australia

    Soula Ganiatsas, Renee Dow, Anne Thompson & Doris Germain

  3. Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, 10021, NY, USA

    Brenda Schulman

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  1. Soula Ganiatsas
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  2. Renee Dow
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  5. Doris Germain
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Correspondence to Doris Germain.

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Ganiatsas, S., Dow, R., Thompson, A. et al. A splice variant of Skp2 is retained in the cytoplasm and fails to direct cyclin D1 ubiquitination in the uterine cancer cell line SK-UT. Oncogene 20, 3641–3650 (2001). https://doi.org/10.1038/sj.onc.1204501

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