Floyd Suzanne, Pines Jonathon, Lindon Catherine
Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Curr Biol. 2008 Nov 11;18(21):1649-58. doi: 10.1016/j.cub.2008.09.058. Epub 2008 Oct 30.
Control of mitotic cell cycles by the anaphase-promoting complex or cyclosome (APC/C) ubiquitin ligase depends on its coactivators Cdc20 and Cdh1. APC/C(Cdc20) is active during mitosis and promotes anaphase onset by targeting mitotic cyclins and securin. APC/C(Cdh1) becomes active during mitotic exit and has essential targets in G1 phase. It is not known whether targeting of substrates by APC/C(Cdh1) plays any role in the final stages of mitosis. Here, we have investigated the role of APC/C(Cdh1) at this time in the cell cycle by using siRNA-mediated depletion of Cdh1 in human cells.
In contrast to the current view that Cdh1 takes over from Cdc20 at anaphase, we show that reduced Cdh1 levels have no effect on destruction of many APC/C substrates during mitotic exit but strongly and specifically stabilize Aurora kinases. We find that APC/C(Cdh1) is required for assembly of a robust spindle midzone at anaphase and for normal timings of spindle elongation and cytokinesis. The effect of Cdh1 siRNA on anaphase spindle dynamics requires Aurora A, and its effect can be mimicked by nondegradable Aurora kinase.
Targeting of Aurora kinases at anaphase by APC/C(Cdh1) participates in the control of mitotic exit and cytokinesis.
后期促进复合体或周期体（APC/C）泛素连接酶对有丝分裂细胞周期的调控依赖于其共激活因子Cdc20和Cdh1。APC/C（Cdc20）在有丝分裂期间活跃，通过靶向有丝分裂周期蛋白和分离酶促进后期起始。APC/C（Cdh1）在有丝分裂退出期间变得活跃，并在G1期有重要靶点。目前尚不清楚APC/C（Cdh1）对底物的靶向作用在有丝分裂的最后阶段是否发挥任何作用。在这里，我们通过在人类细胞中使用siRNA介导的Cdh1缺失来研究APC/C（Cdh1）在细胞周期这个阶段的作用。
与目前认为Cdh1在后期从Cdc20接管的观点相反，我们发现降低Cdh1水平对有丝分裂退出期间许多APC/C底物的降解没有影响，但能强烈且特异性地稳定极光激酶。我们发现APC/C（Cdh1）是后期强大的纺锤体中间区组装以及纺锤体伸长和胞质分裂正常时间所必需的。Cdh1 siRNA对后期纺锤体动力学的影响需要极光激酶A，并且其作用可以被不可降解的极光激酶模拟。
APC/C（Cdh1）在后期对极光激酶的靶向作用参与了有丝分裂退出和胞质分裂的调控。
