Bifurcation analysis of the regulatory modules of the mammalian G1/S transition
Bifurcation analysis of the regulatory modules of the mammalian G1/S transition
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DOI：
10.1093/bioinformatics/bth110
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发表时间：
2004-07-01
期刊：
影响因子：
5.8
通讯作者：
Herzel, H
中科院分区：
文献类型：
--
作者：
Swat, M;Kel, A;Herzel, H
动机：细胞周期的数学模型有助于理解其基本机制。现代仿真工具使关键组件及其相互作用的分析变得非常有效。本文重点关注哺乳动物细胞中控制 G(1)/S 转变的基因-蛋白质网络中小模块和反馈的作用。该网络的突变可能导致细胞增殖失控。分叉分析有助于识别这个极其复杂的交互网络的关键组成部分。结果：我们识别了网络中控制 G(1)/S 转换的各种正反馈环和负反馈环。结果表明，E2F1 和双激活剂-抑制剂模块的正反馈调节可以导致双稳态。核心模块的扩展保留了双稳态等基本特征。完整的模型除了双稳态之外还表现出跨临界分岔。我们将这些分叉与细胞周期检查点和 G(1)/S 相变点联系起来。因此，核心模块可以解释复杂的G(1)/S网络的主要特征，并具有鲁棒的决策功能。
Motivation: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G(1)/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network.Results: We identify various positive and negative feedback loops in the network controlling the G(1)/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G(1)/S phase transition point. Thus, core modules can explain major features of the complex G(1)/S network and have a robust decision taking function.