A MINIMAL CASCADE MODEL FOR THE MITOTIC OSCILLATOR INVOLVING CYCLIN AND CDC2 KINASE
A MINIMAL CASCADE MODEL FOR THE MITOTIC OSCILLATOR INVOLVING CYCLIN AND CDC2 KINASE
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DOI：
10.1073/pnas.88.20.9107
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发表时间：
1991-10-01
影响因子：
11.1
通讯作者：
GOLDBETER, A
中科院分区：
文献类型：
--
作者：
GOLDBETER, A
提出了有丝分裂振荡器的最小模型。该模型建立在最近的实验进展基础上，基于翻译后修饰级联，可在细胞周期中调节 cdc2 激酶的活性。该模型涉及早期两栖动物胚胎中遇到的情况，其中细胞周期蛋白的积累足以触发有丝分裂的开始。在双环级联模型的第一个循环中，细胞周期蛋白通过可逆的去磷酸化促进cdc2激酶的激活，在第二个循环中，细胞周期蛋白2激酶通过可逆的磷酸化激活细胞周期蛋白蛋白酶。细胞周期蛋白激活 cdc2 激酶，而激酶触发细胞周期蛋白的降解，这表明振荡可能源于这种负反馈环路 [Felix, M. A., Labbe, J. C., Doree, M., Hunt, T. & Karsenti, E. (1990) Nature (London) 346, 379-382]。这一猜想得到了模型的证实，模型表明，只要在细胞周期蛋白激活cdc2激酶和cdc2激酶激活细胞周期蛋白水解过程中存在阈值，级联中就会出现极限环型的持续振荡。分析表明，有丝分裂振荡如何很容易因与这些阈值相关的时间滞后以及 cdc2 诱导的细胞周期蛋白降解提供的延迟负反馈而产生。根据先前描述的共价修饰调节的生化系统的零级超敏感性现象，提出了阈值起源的机制。
A minimal model for the mitotic oscillator is presented. The model, built on recent experimental advances, is based on the cascade of post-translational modification that modulates the activity of cdc2 kinase during the cell cycle. The model pertains to the situation encountered in early amphibian embryos, where the accumulation of cyclin suffices to trigger the onset of mitosis. In the first cycle of the bicyclic cascade model, cyclin promotes the activation of cdc2 kinase through reversible dephosphorylation, and in the second cycle, cdc2 kinase activates a cyclin protease by reversible phosphorylation. That cyclin activates cdc2 kinase while the kinase triggers the degradation of cyclin has suggested that oscillations may originate from such a negative feedback loop [Felix, M. A., Labbe, J. C., Doree, M., Hunt, T. & Karsenti, E. (1990) Nature (London) 346, 379-382]. This conjecture is corroborated by the model, which indicates that sustained oscillations of the limit cycle type can arise in the cascade, provided that a threshold exists in the activation of cdc2 kinase by cyclin and in the activation of cyclin proteolysis by cdc2 kinase. The analysis shows how mitotic oscillations may readily arise from time lags associated with these thresholds and from the delayed negative feedback provided by cdc2-induced cyclin degradation. A mechanism for the origin of the thresholds is proposed in terms of the phenomenon of zero-order ultrasensitivity previously described for biochemical systems regulated by covalent modification.