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Cell. 2016 Jun 30;166(1):167-80. doi: 10.1016/j.cell.2016.05.077.

Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.

Author information

1
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: scappell@stanford.edu.
2
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: tobias1@stanford.edu.

Abstract

Proliferating cells must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of retinoblastoma (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclosome (APC(Cdh1)) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APC(Cdh1) inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APC(Cdh1) inactivation, but not after APC(Cdh1) inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APC(Cdh1) inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle.

PMID:
27368103
DOI:
10.1016/j.cell.2016.05.077
[Indexed for MEDLINE]
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