Cell fate decision mediated by p53 pulses
Cell fate decision mediated by p53 pulses
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p53 脉冲介导的细胞命运决定
DOI：
10.1073/pnas.0813088106
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发表时间：
2009-07-28
影响因子：
11.1
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Zhang, Xiao-Peng;Liu, Feng;Wang, Wei
肿瘤抑制因子p53在细胞对各种应激的反应中起着至关重要的作用。最近的实验表明，电离辐射（IR）引起DNA损伤后，p53水平出现一系列脉冲。然而，p53脉冲如何控制细胞存活和死亡仍不清楚。在这里，我们开发了一个集成的模型与四个模块的p53网络和探索机制的基础上的动态网络的细胞命运的决定。通过数值模拟，以下过程的特点。首先，DNA修复蛋白与IR诱导的双链断裂结合，形成复合物，然后通过共济失调毛细血管扩张突变（ATM）检测。激活的ATM启动p53振荡器产生脉冲。因此，p53的靶基因被选择性地诱导以控制细胞命运。我们认为p53促进轻微DNA损伤的修复，但抑制严重损伤的修复。我们证明，细胞的命运是由依赖于DNA损伤程度的p53脉冲的数量。在低损伤水平下，很少的p53脉冲通过诱导p21引起细胞周期停滞并促进细胞存活，而在高损伤水平下，持续的p53脉冲通过诱导p53AIP1触发细胞凋亡。我们发现p53可以通过调节DNA修复的效率和保真度来有效地维持基因组的完整性。我们还表明，在DNA损伤的产生和修复的随机性导致细胞命运的变化。这些发现与实验观察一致，并促进了我们对p53网络的动力学和功能的理解。
The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.