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Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry

Nature volume 432, pages 588–595 (2004)Cite this article

Abstract

Oscillations in cyclin-dependent kinase (CDK) activity drive the somatic cell cycle. After entry into mitosis, CDKs activate the anaphase-promoting complex (APC), which then promotes cyclin degradation and mitotic exit. The re-accumulation of cyclin A causes the inactivation of APC and entry into S phase, but how cyclin A can accumulate in the presence of active APC has remained unclear. Here we show that, during G1, APC autonomously switches to a state permissive for cyclin A accumulation. Crucial to this transition is the APCCdh1-dependent autoubiquitination and proteasomal degradation of the ubiquitin-conjugating enzyme (E2) UbcH10. Because APC substrates inhibit the autoubiquitination of UbcH10, but not its E2 function, APC activity is maintained as long as G1 substrates are present. Thus, through UbcH10 degradation and cyclin A stabilization, APC autonomously downregulates its activity. This indicates that the core of the metazoan cell cycle could be described as a self-perpetuating but highly regulated oscillator composed of alternating CDK and APC activities.

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Figure 1: Cyclin A degradation is specifically impaired at low concentrations of UbcH10.
Figure 2: Cell-cycle regulation of E2 enzymes and cyclin A.
Figure 3: Degradation of UbcH10 in G1 is mediated by APC-dependent autoubiquitination.
Figure 4: Misregulation of UbcH10 degradation interferes with cyclin A accumulation.
Figure 5: Control of autonomous APC inactivation by Emi1.

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Acknowledgements

We are very grateful to P. Jackson for Emi1 constructs and the Emi1-antibody. We thank the members of the Kirschner laboratory for advice, especially S. Rankin, K. Kwan and N. Ayad; J. Schaletzky, O. Stemmann and M. Springer for discussions; and M. Overholczer for help with the FACS analysis. M.R. was funded by an EMBO long-term fellowship and by a fellowship of the Human Frontiers Science Organization. This work was supported by grants from the National Institutes of Health to M.W.K.

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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Michael Rape & Marc W. Kirschner

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  1. Michael Rape
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  2. Marc W. Kirschner
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Correspondence to Marc W. Kirschner.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

The data in this figure shows that extracts of synchronized somatic cells recapitulate APC-activity. It also demonstrates that cyclin A-ubiquitination is more efficient in the presence of UbcH10 compared to UbcH5. (JPG 35 kb)

Supplementary Figure 2

This figure contains the gels of the ubiquitination reaction that have been quantified for figures 3b, d, e. (JPG 38 kb)

Supplementary Figure 3

The data in this figure shows that expression of stable UbcH10 transiently decreases cyclin A levels, and that elevation of UbcH10 levels decrease the fraction of S-phase cells. (JPG 30 kb)

Supplementary Figure 4

In this figure, the mitotic phenotypes of the UbcH10 depletion are depicted. (JPG 23 kb)

Supplementary Figure Legends (DOC 27 kb)

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Rape, M., Kirschner, M. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature 432, 588–595 (2004). https://doi.org/10.1038/nature03023

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