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The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis

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Abstract

Ski is an oncoprotein that represses transforming growth factor-β and nuclear receptor signaling. Despite evidence that relates increased Ski protein levels directly with tumor progression in human cells, the signaling pathways that regulate Ski expression are mostly unidentified. Here we show that the Ski protein levels vary throughout the cell cycle, being lowest at G0/G1. This reduction in Ski protein levels results from proteosomal degradation as suggested by in vivo ubiquitination of Ski and the effects of proteosomal inhibitors. In contrast, an upregulation of the Ski protein was observed in cells going through mitosis. At this stage, we also found that Ski is phosphorylated. In vitro and in vivo data suggest that the phosphorylation of Ski in mitosis is carried out by the main kinase controlling the progression of mitosis, namely cdc2/cyclinB. Interestingly, immunofluorescence experiments, supported by biochemical data, show not only an increase in the Ski protein levels, but also a dramatic redistribution of Ski to the centrosomes and mitotic spindle throughout mitosis. Studies to date on Ski have focused on its role as a transcriptional regulator. However, Ski's increased level and specific relocalization during mitosis suggest that Ski might play a distinct role during this particular phase of the cell cycle.

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Abbreviations

TGF-β:

transforming growth factor-β

cdk:

cyclin-dependent kinase

DAPI:

4,6-diamidino-2-phenylindole

SB:

sample buffer.

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Acknowledgements

We would like to thank Drs Nobuhide Ueki and Ricardo Armisén for help with the discussion of the manuscript and technical advice. We are grateful to Drs Gail Mandel and Patrick Hearing for allowing us to use their laboratory facilities and Dr Clemencia Colmenares for providing us with ski−/− MEFs. This work was supported by U.S. Public Health Service Grant CA42573 from the National Cancer Institute.

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  1. Department of Molecular Genetics and Microbiology, SUNY at Stony Brook, Stony Brook, NY, 11794-5222, USA

    Katherine Marcelain & Michael J Hayman

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  1. Katherine Marcelain
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  2. Michael J Hayman
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Marcelain, K., Hayman, M. The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis. Oncogene 24, 4321–4329 (2005). https://doi.org/10.1038/sj.onc.1208631

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