Boolean network-based analysis of the apoptosis network: Irreversible apoptosis and stable surviving
Boolean network-based analysis of the apoptosis network: Irreversible apoptosis and stable surviving
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DOI：
10.1016/j.jtbi.2009.04.024
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发表时间：
2009-08-21
影响因子：
2
通讯作者：
Liu, Haiyan
中科院分区：
文献类型：
--
作者：
Mai, Zhongxing;Liu, Haiyan
为了理解与细胞凋亡的不可逆性和细胞存活的稳定性相关的分子相互作用网络的设计原理，我们构建了一个整合了内在和外在促凋亡通路与促存活信号转导通路的布尔网络。我们对细胞命运对初始状态和输入信号的依赖性进行了统计分析。这些分析再现了关键外部信号和网络成分的众所周知的促凋亡和抗凋亡作用。我们发现，外部GF信号本身并没有改变随机选择的初始状态时，没有外部TNF信号的凋亡率，但可以显着抵消TNF信号诱导的凋亡。虽然一个完整的模型产生预期的不可逆性的细胞凋亡过程中，替代模型缺少一个或多个四个选定的组件间连接表明，直接涉及胱天蛋白酶3的反馈回路是必不可少的，以维持不可逆的细胞凋亡。当涉及caspase 3的反馈环被去除时，涉及P53的反馈环表现出补偿效应。GF信号显著增加了网络生存状态的稳定性。凋亡网络似乎通过设计使用不同的模块来控制凋亡过程的不可逆性和存活状态的稳定性。这样的设计可以适应网络所需的可塑性，以适应不同的细胞环境：取决于外部促存活信号的强度，细胞凋亡可以容易地或困难地通过不同强度的促凋亡信号诱导，但以不变的不可逆性进行。(C)2009爱思唯尔有限公司保留所有权利。
To understand the design principles of the molecular interaction network associated with the irreversibility of cell apoptosis and the stability of cell surviving, we constructed a Boolean network integrating both the intrinsic and extrinsic pro-apoptotic pathways with pro-survival signal transduction pathways. We performed statistical analyses of the dependences of cell fate on initial states and on input signals. The analyses reproduced the well-known pro-and anti-apoptotic effects of key external signals and network components. We found that the external GF signal by itself did not change the apoptotic ratio from randomly chosen initial states when there is no external TNF signal, but can significantly offset apoptosis induced by the TNF signal. While a complete model produces the expected irreversibility of the apoptosis process, alternative models missing one or more of four selected inter-component connections indicate that the feedback loops directly involving the caspase 3 are essential for maintaining irreversibility of apoptosis. The feedback loops involving P53 showed compensating effects when those involving caspase 3 have been removed. The GF signal significantly increases the stability of the surviving states of the network. The apoptosis network seems to use different modules by design to control the irreversibility of the apoptosis process and the stability of the surviving states. Such a design may accommodate the needed plasticity for the network to adapt to different cellular environments: depending on the strength of external pro-surviving signals, apoptosis can be induced either easily or difficultly by pro-apoptotic signal of varying strengths, but proceed with invariable irreversibility. (C) 2009 Elsevier Ltd. All rights reserved.