Abstract
The F-box protein p45SKP2 is the substrate-targeting subunit of the ubiquitin–protein ligase SCFSKP2 and is frequently overexpressed in transformed cells. Here we report that expression of p45SKP2 in untransformed fibroblasts activates DNA synthesis in cells that would otherwise growth-arrest. Expression of p45SKP2 in quiescent fibroblasts promotes p27Kip1 degradation, allows the generation of cyclin-A-dependent kinase activity and induces S phase. Coexpression of a degradation-resistant p27Kip1 mutant suppresses p45SKP2-induced cyclin-A-kinase activation and S-phase entry. We propose that p45SKP2 is important in the progression from quiescence to S phase and that the ability of p45SKP2 to promote p27Kip1 degradation is a key aspect of its S-phase-inducing function. In transformed cells, p45SKP2 may contribute to deregulated initiation of DNA replication by interfering with p27Kip1 function.
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Acknowledgements
We thank members of our laboratory for helpful discussions; D. Cobrinik for MEFs; B. Amati for retroviral plasmids for p27Kip1; members of the Matus laboratory, in particular B. Ludin and S. Käch, for help in GFP analysis; and B. Amati and B. Hemmings for critical reading of the manuscript. This work was supported by a postdoctoral fellowship to H.S. from the Erwin Schrödinger Society, Austria. E.C. is supported by a grant from the Swiss National Science Foundation. A.M. and C.W. are supported by the Novartis Research Foundation. W.K. is a START Fellow and is supported by the Swiss National Science Foundation and the Novartis Research Foundation.
Correspondence and requests for material should be addressed to W.K.
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Sutterlüty, H., Chatelain, E., Marti, A. et al. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1, 207–214 (1999). https://doi.org/10.1038/12027
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DOI: https://doi.org/10.1038/12027
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