Abstract
Cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key cell-cycle regulators. SCF (Skp1/Cullin/F-box protein) complexes and anaphase-promoting complexes (APC) represent two major classes of ubiquitin ligases whose activities are thought to regulate primarily the G1/S and metaphase/anaphase cell-cycle transitions, respectively1,2. The major target of the Skp1/Cul1/Skp2 (SCFSKP2) complex is thought to be the Cdk inhibitor p27 during S phase, whereas the principal targets for the APC are thought to be involved in chromatid separation (securin) and exit from mitosis (cyclin B). Although the role of the APC in mitosis is relatively clear, there is mounting evidence that APCs containing Cdh1 (APCCDH1) also have a function in the G1 phase of the cell cycle2,3. Here, we show that the F-box protein Skp2 is polyubiquitinated, and hence earmarked for destruction, by APCCDH1. As a result, accumulation of SCFSKP2 requires prior inactivation of APCCDH1. These findings provide an insight into the orchestration of SCF and APC activities during cell-cycle progression, and into the involvement of the APC in G1.
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Acknowledgements
We thank W. Harper, J. Lukas and M. Meyerson for critical reading of the manuscript; J. Lukas for reagents; M. Pagano for sharing unpublished data; and members of the Kirschner and Kaelin Laboratories for useful discussions. W.G.K. is a Howard Hughes Medical Institute Investigator. This work is supported in part by NIH grants to M.W.K. and W.G.K.
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Supplementary information
Supplementary figure 1
Binding of Cdh1 mutants to Skp2. (PDF 1105 kb)
Supplementary figure 2
Binding of Skp2 mutants to Cdh1. (PDF 787 kb)
Supplementary figure 3
Binding of Skp2 and Skp2Δdb to Cdh1 in vivo. (PDF 610 kb)
Supplementary figure 4
Immunoblot analysis of HeLa cells transfected with the indicated siRNA, synchronized by growth in nocodazole, and then released for the indicated periods of time. (PDF 473 kb)
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Wei, W., Ayad, N., Wan, Y. et al. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194–198 (2004). https://doi.org/10.1038/nature02381
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DOI: https://doi.org/10.1038/nature02381
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