Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex
Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex
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DOI：
10.1038/nature02381
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发表时间：
2004-03-11
期刊：
影响因子：
64.8
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Wei, W;Ayad, NG;Kaelin, WG
细胞周期转变是由关键细胞周期调节因子的泛素依赖性降解波驱动的。SCF （Skp1/Cullin/F-box蛋白）复合物和后期促进复合物（APC）是两类主要的泛素连接酶，其活性被认为分别主要调节G1/S和中期/后期细胞周期转变（1,2）。Skp1/Cul1/Skp2 （SCFSKP2）复合物的主要靶点被认为是S期的Cdk抑制剂p27，而APC的主要靶点被认为与染色单体分离（securin）和有丝分裂退出（cyclin B）有关。尽管APC在有丝分裂中的作用相对清楚，但越来越多的证据表明，含有Cdh1的APC（APC(Cdh1)）也在细胞周期的G1期发挥作用（2,3）。在这里，我们发现F-box蛋白Skp2被APC（CDH1）多泛素化，因此被指定用于破坏。因此，SCFSKP2的积累需要APC（CDH1）事先失活。这些发现为细胞周期进程中SCF和APC活动的协调以及APC在G1中的参与提供了深入的见解。
Cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key cell-cycle regulators. SCF (Skp1/Cullin/F-box protein) complexes and anaphase-promoting complexes (APC) represent two major classes of ubiquitin ligases whose activities are thought to regulate primarily the G1/S and metaphase/anaphase cell-cycle transitions, respectively(1,2). The major target of the Skp1/Cul1/Skp2 (SCFSKP2) complex is thought to be the Cdk inhibitor p27 during S phase, whereas the principal targets for the APC are thought to be involved in chromatid separation (securin) and exit from mitosis (cyclin B). Although the role of the APC in mitosis is relatively clear, there is mounting evidence that APCs containing Cdh1 (APC(CDH1)) also have a function in the G1 phase of the cell cycle(2,3). Here, we show that the F-box protein Skp2 is polyubiquitinated, and hence earmarked for destruction, by APC(CDH1). As a result, accumulation of SCFSKP2 requires prior inactivation of APC(CDH1). These findings provide an insight into the orchestration of SCF and APC activities during cell-cycle progression, and into the involvement of the APC in G1.