Conservation and Divergence of p53 Oscillation Dynamics across Species.
Conservation and Divergence of p53 Oscillation Dynamics across Species.
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DOI：
10.1016/j.cels.2017.09.012
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发表时间：
2017-10-25
期刊：
影响因子：
9.3
通讯作者：
Lahav G
中科院分区：
文献类型：
--
作者：
Stewart-Ornstein J;Cheng HWJ;Lahav G
肿瘤抑制转录因子p53在蛋白水平上高度保守，在DNA损伤反应中起关键作用。p53调控的一个重要方面是其响应DNA损伤的动力学，包括振荡。在这里，我们观察到，虽然p53动力学的定性振荡性质是保守的跨细胞系来自人，猴，狗，小鼠和大鼠，振荡周期是可变的。具体而言，啮齿动物细胞表现出快速的p53振荡，而狗、猴和人类细胞表现出较慢的振荡。计算建模和实验确定了p53和MDM 2之间更强的负反馈作为啮齿动物更快振荡的驱动因素，这表明振荡的特定周期是网络级属性。总的来说，我们的研究表明，尽管高度保守的信号，p53振荡的定量特征可以在进化过程中发散。我们警告说，强氨基酸保守的蛋白质和转录网络的相似性并不一定意味着保守的时间动态。
The tumor suppressing transcription factor p53 is highly conserved at the protein level and plays a key role in the DNA damage response. One important aspect of p53 regulation is its dynamics in response to DNA damage, which include oscillations. Here, we observe that while the qualitative oscillatory nature of p53 dynamics is conserved across cell lines derived from human, monkey, dog, mouse and rat, the oscillation period is variable. Specifically, rodent cells exhibit rapid p53 oscillations, whereas dog, monkey and human cells show slower oscillations. Computational modeling and experiments identify stronger negative feedback between p53 and MDM2 as the driver of faster oscillations in rodents, suggesting that an oscillation's specific period is a network-level property. In total, our study shows that despite highly conserved signaling, the quantitative features of p53 oscillations can diverge across evolution. We caution that strong amino acid conservation of proteins and transcriptional network similarity do not necessarily imply conservation of time dynamics.
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