Irreversible APCCdh1 Inactivation Underlies the Point of No Return for Cell-Cycle Entry

被引:169
作者
Cappell, Steven D. [1 ]
Chung, Mingyu [1 ]
Jaimovich, Ariel [1 ]
Spencer, Sabrina L. [1 ,2 ]
Meyer, Tobias [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA
[2] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA
关键词
ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; RESTRICTION POINT; PHASE; PROLIFERATION; DEGRADATION; QUIESCENCE; DYNAMICS; DECISION; SPINDLE; KINASE;
D O I
10.1016/j.cell.2016.05.077
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:167 / 180
页数:14
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