Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation.
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 G(1). 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.
Wirth
Karin G
KG
Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria.
Ricci
Romeo
R
Giménez-Abián
Juan F
JF
Taghybeeglu
Shahryar
S
Kudo
Nobuaki R
NR
Jochum
Wolfram
W
Vasseur-Cognet
Mireille
M
Nasmyth
Kim
K
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome; D017173:Caenorhabditis elegans / Q000166:cytology; D029742:Caenorhabditis elegans Proteins; D002455:Cell Division / Q000235:genetics*; D004331:Drosophila melanogaster / Q000166:cytology; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012441:Saccharomyces cerevisiae / Q000166:cytology; D029701:Saccharomyces cerevisiae Proteins; D012568:Schizosaccharomyces / Q000166:cytology; D043743:Ubiquitin-Protein Ligase Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D029701:Saccharomyces cerevisiae Proteins; D043743:Ubiquitin-Protein Ligase Complexes; C577343:APC-2 protein, C elegans; C577346:APC2 protein, S cerevisiae; C577341:Anapc2 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome