Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts
Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts
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DOI：
10.1073/pnas.0235349100
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发表时间：
2003-02-04
影响因子：
11.1
通讯作者：
Sible, JC
中科院分区：
文献类型：
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作者：
Sha, W;Moore, J;Sible, JC
在细胞周期中进展的细胞必须不可逆地进行有丝分裂，而不会在正确分离染色体之前滑回间期。青蛙无细胞卵提取物中细胞周期进展的数学模型预测，进入和退出有丝分裂的不可逆转变是由分子控制系统中的滞后驱动的。迟滞是指动态系统中类似切换的开关行为。在数学模型中，切换开关是由控制 Cdc2 活性的磷酸化反应中的正反馈产生的，Cdc2 是一种与其调节亚基细胞周期蛋白 B 结合的蛋白激酶。为了确定无细胞卵提取物进入和退出有丝分裂的滞后现象是否是其基础，我们测试了 Novak-Tyson 模型的三个预测。 (i)驱动间期提取物进入有丝分裂所需的细胞周期蛋白B的最低浓度明显高于将有丝分裂提取物保持在有丝分裂中所需的最低浓度，这是滞后的证据。 (ii) 未复制的 DNA 提高了 Cdc2 激活的细胞周期蛋白阈值，表明检查点通过扩大滞后环来发挥作用。 (M) 当细胞周期蛋白 B 的浓度略高于激活阈值时，检测到 Cdc2 激活速率急剧“减慢”。所有三个预测均得到验证。这些观察结果证实滞后现象是细胞周期进入和退出有丝分裂的驱动力。
Cells progressing through the cell cycle must commit irreversibly to mitosis without slipping back to interphase before properly segregating their chromosomes. A mathematical model of cell-cycle progression in cell-free egg extracts from frog predicts that irreversible transitions into and out of mitosis are driven by hysteresis in the molecular control system. Hysteresis refers to toggle-like switching behavior in a dynamical system. In the mathematical model, the toggle switch is created by positive feedback in the phosphorylation reactions controlling the activity of Cdc2, a protein kinase bound to its regulatory subunit, cyclin B. To determine whether hysteresis underlies entry into and exit from mitosis in cell-free egg extracts, we tested three predictions of the Novak-Tyson model. (i) The minimal concentration of cyclin B necessary to drive an interphase extract into mitosis is distinctly higher than the minimal concentration necessary to hold a mitotic extract in mitosis, evidence for hysteresis. (ii) Unreplicated DNA elevates the cyclin threshold for Cdc2 activation, indication that checkpoints operate by enlarging the hysteresis loop. (M) A dramatic "slowing down" in the rate of Cdc2 activation is detected at concentrations of cyclin B marginally above the activation threshold. All three predictions were validated. These observations confirm hysteresis as the driving force for cell-cycle transitions into and out of mitosis.