Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2
Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2
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DOI：
10.1038/ncb954
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发表时间：
2003-04-01
影响因子：
21.3
通讯作者：
Ferrell, JE
中科院分区：
文献类型：
--
作者：
Pomerening, JR;Sontag, ED;Ferrell, JE
在早期胚胎细胞周期中，Cdc 2-细胞周期蛋白B的功能就像一个自主振荡器，即使DNA复制或有丝分裂被阻断，其强大的生物化学节律也会继续（1）。振荡器的核心是一个负反馈回路;细胞周期蛋白积累并产生活性有丝分裂Cdc 2-细胞周期蛋白B-2、B-3; Cdc 2激活后期促进复合物（APC）; APC然后促进细胞周期蛋白降解并将Cdc 2重置为其非活性的间期状态。Cdc 2调节还涉及正反馈4，活性Cdc 2-细胞周期蛋白B刺激其激活剂Cdc 25（参考文献5-7）并使其抑制剂Wee 1和Myt 1失活（参考文献8-11）。在正确的情况下，这些正反馈回路可以用作MitoSiS的触发器（12，13），并且具有触发器的振荡器可能与生物学应用（例如细胞周期调节）特别相关（14-17）。因此，我们研究了Cdc 2激活是否是可预测的。我们证实，Cdc 2的响应不可降解的细胞周期蛋白B是短暂的突然和开关样，如果Cdc 2激活是可预期的。我们还表明，Cdc 2激活表现出滞后，一个属性的生物化学振荡器与特别相关的生物化学系统。这些发现有助于建立有丝分裂振荡器的基本系统级逻辑。
In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, whose robust biochemical rhythm continues even when DNA replication or mitosis is blocked(1). At the core of the oscillator is a negative feedback loop; cyclins accumulate and produce active mitotic Cdc2-cyclin B-2,B-3; Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback 4, with active Cdc2-cyclin B stimulating its activator Cdc25 (refs 5-7) and inactivating its inhibitors Wee1 and Myt1 (refs 8-11). Under the correct circumstances, these positive feedback loops could function as a bistable trigger for MitoSiS(12,13), and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation(14-17). Therefore, we examined whether Cdc2 activation is bistable. We confirm that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switch-like, as would be expected if Cdc2 activation were bistable. We also show that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator.