Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation
- Karin G. Wirth1,
- Romeo Ricci2,
- Juan F. Giménez-Abián1,
- Shahryar Taghybeeglu1,
- Nobuaki R. Kudo1,
- Wolfram Jochum3,
- Mireille Vasseur-Cognet4, and
- Kim Nasmyth1,5
- 1 Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria
- 2 Institute of Physiology, Cardiovascular Research, University of Zürich and Department of Cardiology, University Hospital Zürich, Zürich, Switzerland
- 3 Institute of Clinical Pathology, University Hospital Zürich, CH-8091 Zürich, Switzerland
- 4 ICGM, Faculté Cochin-GDPM, 75014 Paris, France
Abstract
The anaphase-promoting complex or cyclosome (APC/C) is an ubiquitin protein ligase that together with Cdc20 and Cdh1 targets mitotic proteins for degradation by the proteosome. APC–Cdc20 activity during mitosis triggers anaphase by destroying securin and cyclins. APC–Cdh1 promotes degradation of cyclins and other proteins during G1. We show that loss of APC/C during embryogenesis is early lethal before embryonic day E6.5 (E6.5). To investigate the role of APC/C in quiescent cells, we conditionally inactivated the subunit Apc2 in mice. Deletion of Apc2 in quiescent hepatocytes caused re-entry into the cell cycle and arrest in metaphase, resulting in liver failure. Re-entry into the cell cycle either occurred without any proliferative stimulus or could be easily induced. We demonstrate that the APC has an additional function to prevent hepatocytes from unscheduled re-entry into the cell cycle.
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Footnotes
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Supplemental material is available at http://www.genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.285404.
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↵5 Corresponding author.
↵5 E-MAIL k.nasmyth{at}nt.imp.univie.ac.at; FAX 0043-1-798-9390.
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- Accepted November 10, 2003.
- Received September 15, 2003.
- Cold Spring Harbor Laboratory Press
