Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Institute (NKI-AVL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Biochem Soc Trans. 2010 Feb;38(Pt 1):72-7. doi: 10.1042/BST0380072.
Active cyclin B1-Cdk1 (cyclin-dependent kinase 1) keeps cells in mitosis, allowing time for spindle microtubules to capture the chromosomes and for incorrect chromosome-spindle attachments to be repaired. Meanwhile, securin, an inhibitor of separase, secures cohesion between sister chromatids, preventing anaphase onset. The spindle checkpoint is a signalling pathway emerging from improperly attached chromosomes that inhibits Cdc20, the mitotic activator of the APC/C (anaphase-promoting complex/cyclosome) ubiquitin ligase. Blocking Cdc20 stabilizes cyclin B1 and securin to delay mitotic exit and anaphase until all chromosomes reach bipolar spindle attachments. Cells entering mitosis in the absence of a functional spindle checkpoint degrade cyclin B1 and securin right after nuclear-envelope breakdown, in prometaphase. Interestingly, two APC/C substrates, cyclin A and Nek2A, are normally degraded at nuclear-envelope breakdown, even when the spindle checkpoint is active. This indicates that the APC/C is activated early in mitosis, whereas cyclin B1 and securin are protected as long as the spindle checkpoint inhibits Cdc20. Remarkably, destruction of cyclin A and Nek2A also depends on Cdc20. The paradox of Cdc20 being both active and inhibited in prometaphase could be explained if cyclin A and Nek2A are either exceptionally efficient Cdc20 substrates, or if they are equipped with 'stealth' mechanisms to effectively escape detection by the spindle checkpoint. In the present paper, we discuss recently emerging models for spindle-checkpoint-independent APC/C-Cdc20 activity, which might even have implications for cancer therapy.
有活性的细胞周期蛋白 B1-Cdk1（细胞周期蛋白依赖性激酶 1）使细胞保持在有丝分裂状态，为纺锤体微管捕获染色体和修复错误的染色体-纺锤体连接提供时间。同时，securin 作为 separase 的抑制剂，确保姐妹染色单体之间的黏合，防止后期起始。纺锤体检查点是一种从附着不当的染色体中出现的信号通路，它抑制 Cdc20，即 APC/C（有丝分裂促进复合物/细胞周期蛋白体）泛素连接酶的有丝分裂激活剂。阻断 Cdc20 稳定了 cyclin B1 和 securin，以延迟有丝分裂退出和后期，直到所有染色体都达到双极纺锤体附着。在没有功能纺锤体检查点的情况下进入有丝分裂的细胞，在前期核膜破裂后立即降解 cyclin B1 和 securin。有趣的是，两个 APC/C 底物 cyclin A 和 Nek2A 即使在纺锤体检查点活跃的情况下，也通常在核膜破裂时降解。这表明 APC/C 在有丝分裂早期被激活，而只要纺锤体检查点抑制 Cdc20，cyclin B1 和 securin 就会受到保护。值得注意的是，cyclin A 和 Nek2A 的破坏也依赖于 Cdc20。如果 cyclin A 和 Nek2A 是 Cdc20 的特别有效底物，或者它们配备了“隐形”机制来有效地逃避纺锤体检查点的检测，那么 Cdc20 在前期既活跃又受到抑制的悖论就可以得到解释。在本文中，我们讨论了最近出现的纺锤体检查点独立 APC/C-Cdc20 活性模型，这些模型甚至可能对癌症治疗具有重要意义。
