Control of mitotic transitions by the anaphase-promoting complex
Control of mitotic transitions by the anaphase-promoting complex
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DOI：
10.1098/rstb.1999.0502
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发表时间：
1999-09-29
期刊：
影响因子：
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通讯作者：
Kirschner, MW
中科院分区：
文献类型：
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作者：
Fang, GW;Yu, HT;Kirschner, MW
蛋白水解控制细胞周期中几个点的关键转变。在有丝分裂中，后期启动和退出有丝分裂需要激活大型泛素蛋白连接酶，即后期促进复合物（APC）。我们表明 APC 受到 CDC20、CDH1 和 MAD2 等调控因子网络的复杂控制。 CDC20和CDH1是APC的激活剂；它们直接与 APC 结合并激活其细胞周期蛋白泛素化活性。 CDC20 在后期开始时以破坏盒 (DB) 依赖性方式激活 APC，而 CDH1 从后期后期到 G1 激活 APC，对 DB 的特异性显然要宽松得多。因此，CDC20和CDH1控制APC的激活时间顺序和底物特异性，从而调节有丝分裂和G1期间的不同事件。检查点蛋白 MAD2 充当 APC 抑制剂，抵消 CDC20 的影响。当纺锤体组装检查点被激活时，MAD2与CDC20和APC形成三元复合物以阻止APC的激活，从而将细胞阻滞在中期。因此，正负调节因子的组合建立了 APC 的调节回路，确保细胞分裂过程中事件的有序进展。
Proteolysis controls key transitions at several points in the cell cycle. In mitosis, the activation of a large ubiquitin-protein ligase, the anaphase-promoting complex (APC), is required for anaphase initiation and for exit from mitosis. We show that APC is under complex control by a network of regulatory factors, CDC20, CDH1 and MAD2. CDC20 and CDH1 are activators of APC; they bind directly to APC and activate its cyclin ubiquitination activity. CDC20 activates APC at the onset of anaphase in a destruction box (DB)-dependent manner, while CDH1 activates APC from late anaphase through G1 with apparently a much relaxed specificity for the DB. Therefore, CDC20 and CDH1 control both the temporal order of activation and the substrate specificity of APC, and hence regulate different events during mitosis and G1. Counteracting the effect of CDC20, the checkpoint protein MAD2 acts as an inhibitor of APC. When the spindle-assembly checkpoint is activated, MAD2 forms a ternary complex with CDC20 and APC to prevent activation of APC, and thereby arrests cells at prometaphase. Thus, a combination of positive and negative regulators establishes a regulatory circuit of APC, ensuring an ordered progression of events through cell division.