National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):8990-5. doi: 10.1073/pnas.1100600108. Epub 2011 May 16.
The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choose between these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associated the network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by both the level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partially activated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varying in a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated by further modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather high levels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-like behaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the execution of apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNA damage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavior occurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominance of distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamics and cell fate decision.
肿瘤抑制因子 p53 主要通过在 DNA 损伤反应中诱导细胞周期停滞/DNA 修复或细胞凋亡来发挥作用。然而，目前我们尚未完全了解细胞如何在这两种结果之间进行选择。我们构建了一个包含四个模块的 p53 信号网络模型，并将网络动力学与电离辐射后的细胞结果联系起来。我们发现，细胞反应受到 p53 水平和翻译后修饰的双重调控，且 p53 的激活是一个渐进的过程。首先，p53 被 Ser-15/20 等初级修饰部分激活，以诱导细胞周期停滞，其水平以一系列脉冲的形式变化。如果在经历一定数量的 p53 脉冲后，损伤仍无法修复，p53 会被进一步修饰（如 Ser-46 的磷酸化）完全激活，从而触发细胞凋亡，其浓度切换到相当高的水平。因此，在不可修复的损伤细胞中，p53 经历了两阶段反应。这种 p53 的脉冲和开关样行为的组合可能代表了一种灵活有效的控制模式，避免了过早的细胞凋亡，并促进了细胞凋亡的执行。在我们的模型中，由 DNA 损伤触发的 ATM 脉冲周期性地驱动 p53 脉冲。p53-Mdm2 和 ATM-p53-Wip1 负反馈环负责 p53 脉冲，而当 p53-PTEN-Akt-Mdm2 正反馈环占主导地位时，开关行为就会发生。我们的结果表明，不同反馈环的顺序优势可能会引发多相动力学行为。这项工作为 p53 动力学和细胞命运决定提供了新的机制。
