Sun Tingzhe, Li Xinda, Shen Pingping
School of Life Sciences, AnQing Normal University, AnQing, Anhui, 246011, China.
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210023, China.
Oncotarget. 2017 Mar 7;8(10):17105-17114. doi: 10.18632/oncotarget.15062.
During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width. Meanwhile, weakened DNA-PK mediated ATM inhibition was insufficient to reproduce such dynamic behavior. Moreover, the information flow was shifted predominantly to the first pulse under DNA-PK inhibition. Furthermore, the amplified p53 responses were relatively robust. Taken together, our model can faithfully replicate amplified p53 responses under DNA-PK inhibition and provide insights into cell fate decision by manipulating p53 dynamics.
在DNA双链断裂（DSB）修复过程中，磷脂酰肌醇3激酶（PI3K）样激酶的协同激活可激活p53信号通路。最近的研究发现了这些激酶之间的新相互作用，表明在DNA-PK抑制下首次出现p53脉冲放大。然而，尚未建立理论模型来描述这种动态变化。在当前的工作中，我们用DNA-PK抑制剂对延长的p53脉冲进行了建模。我们可以确定第一个脉冲的幅度和宽度呈剂量依赖性增加。同时，DNA-PK介导的ATM抑制减弱不足以重现这种动态行为。此外，在DNA-PK抑制下，信息流主要转移到第一个脉冲。此外，放大的p53反应相对稳健。综上所述，我们的模型可以如实地复制DNA-PK抑制下放大的p53反应，并通过操纵p53动态变化为细胞命运决定提供见解。
