Recurrent initiation: A mechanism for triggering p53 pulses in response to DNA damage
Recurrent initiation: A mechanism for triggering p53 pulses in response to DNA damage
复制标题
DOI：
10.1016/j.molcel.2008.03.016
复制
发表时间：
2008-05-09
期刊：
影响因子：
16
通讯作者：
Lahav, Galit
中科院分区：
文献类型：
--
作者：
Batchelor, Eric;Mock, Caroline S.;Lahav, Galit
DNA损伤引发一系列p53脉冲。虽然对p53周围的相互作用了解很多，但对哪些相互作用有助于p53的动力学行为知之甚少。最简单的解释是，这些脉冲是p53/Mdm 2负反馈回路固有的振荡。在这里，我们提出的证据表明，这种简单的机制是不足以解释p53脉冲，我们表明，p53脉冲是外部驱动的上游信号激酶，ATM和Chk 2的脉冲，并通过Wip 1的p53和ATM之间的负反馈，是必不可少的，为保持p53脉冲的均匀形状。我们认为p53脉冲是由ATM重复启动引起的，ATM被持续的DNA损伤重新激活。我们的研究强调了在高时间分辨率下收集定量动态信息对于理解信号通路调控的重要性，并开辟了操纵p53脉冲的新方法，以询问有关其响应DNA损伤的功能的问题。
DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.