Kaern M, Hunding A
Department of Chemistry, University of Toronto, Ontario, Canada.
J Theor Biol. 1998 Jul 7;193(1):47-57. doi: 10.1006/jtbi.1998.0677.
The autonomous cell divisions during the early development of Xenopus laevis believed to comprise a universal cell cycle engine. Recent experimental data indicates that the Cdk2-cyclin E kinase is required for the rapid divisions during Xenopus embryogenesis and that the complex is crucial for the transition into mitosis. In the present paper, the activity of Cdk2-cyclin E is incorporated into an existing comprehensive model of the cell cycle engine as an activity operating in parallel with the mitosis promotion factor (MPF) on the phosphatase Cdc25. This introduces interesting regulatory and dynamic properties for the transition into mitosis that reveals new insight into the mechanisms of the cell division process. It is shown that the Cdk2-cyclin E complex can act as an effective modulator of the threshold MPF activity needed to initiate mitosis. When the Cdk2-cyclin E activity is below a critical value, the cell cycle arrests in a well-defined state of low MPF activity corresponding to G2 arrest. In agreement with experiments a single mitotic event occurs following injection of free cyclin B. Above a critical activity, the presence of Cdk2-cyclin E allows for sustained oscillations corresponding to repeated cell divisions and the Cdk2-cyclin E may be the cause for the suppressed G2 checkpoint in the early embryonic cell cycles. A detailed bifurcation analysis reveals that the transition from steady to oscillatory behavior involves a homoclinic orbit of infinite period through an omega explosion. The general properties of the omega explosion explain the bifurcation as a dynamic mechanism well-suited for the G2 checkpoint and suggest a plausible explanation for the elongation of the cell cycle as observed at the mid-blastula transition. The proposed mechanism also suggests a plausible explanation of G2 checkpoint failure following DNA damage in human cells overexpressing Cdk2 and we suggest that the onset of mitosis in the mammalian cell occurs as the result of a slow passage through a critical point.
非洲爪蟾早期发育过程中的自主细胞分裂被认为包含一个通用的细胞周期引擎。最近的实验数据表明，Cdk2 - 细胞周期蛋白E激酶在非洲爪蟾胚胎发生过程中的快速分裂中是必需的，并且该复合物对于向有丝分裂的转变至关重要。在本文中，Cdk2 - 细胞周期蛋白E的活性被纳入现有的细胞周期引擎综合模型中，作为一种与有丝分裂促进因子（MPF）并行作用于磷酸酶Cdc25的活性。这为向有丝分裂的转变引入了有趣的调节和动态特性，揭示了对细胞分裂过程机制的新见解。结果表明，Cdk2 - 细胞周期蛋白E复合物可以作为启动有丝分裂所需的阈值MPF活性的有效调节剂。当Cdk2 - 细胞周期蛋白E活性低于临界值时，细胞周期停滞在对应于G2期停滞的低MPF活性的明确状态。与实验一致，注射游离细胞周期蛋白B后会发生单个有丝分裂事件。高于临界活性时，Cdk2 - 细胞周期蛋白E的存在允许对应于重复细胞分裂的持续振荡，并且Cdk2 - 细胞周期蛋白E可能是早期胚胎细胞周期中G2检查点被抑制的原因。详细的分岔分析表明，从稳定行为到振荡行为的转变涉及通过ω爆炸的无限周期同宿轨道。ω爆炸的一般特性将这种分岔解释为一种非常适合G2检查点的动态机制，并为在囊胚中期转变时观察到的细胞周期延长提出了合理的解释。所提出的机制还为过表达Cdk2的人类细胞中DNA损伤后G2检查点失效提供了合理的解释，并且我们认为哺乳动物细胞中有丝分裂的开始是缓慢通过一个临界点的结果。
