Center for Quantitative Systems Biology and Department of Physics, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, China.
BMC Biol. 2013 Jun 21;11:73. doi: 10.1186/1741-7007-11-73.
The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage.
We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53.
Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
p53 途径会针对不同的 DNA 损伤而呈现差异化激活，从而导致哺乳动物细胞出现不同的表型结果。最近的证据表明，p53 表达的动态变化在细胞命运的差异化调控中起着重要作用，但仍存在一些问题，即 p53 动力学及其后续的细胞反应是如何受到可变 DNA 损伤的调节的。
我们发现了一种新的、由 DNA 损伤强度调节的 p53 动力学双模态开关，这对细胞命运控制至关重要。在低 DNA 损伤后，p53 经历周期性脉冲，细胞进入细胞周期停滞。在高 DNA 损伤后，p53 经历强烈的单调增加，细胞激活凋亡。我们发现，这种损伤剂量依赖性的双模态开关是由于 Mdm2 的差异上调所致，Mdm2 主要通过调节 p53 的诱导水平和促凋亡活性来控制细胞命运的替代。
我们的发现不仅揭示了 p53 动力学和细胞命运的一种新的调控模式，还表明 p53 振荡可能作为一种抑制物发挥作用，维持低水平的 p53 诱导和促凋亡活性，从而使细胞周期停滞，以允许损伤修复。
