p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM.
p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM.
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DOI：
10.1126/scisignal.aah6671
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发表时间：
2017-04-25
影响因子：
7.3
通讯作者：
Lahav G
中科院分区：
文献类型：
--
作者：
Stewart-Ornstein J;Lahav G
细胞系统显示出广泛的信号动力学。这些动力学中有许多是高度定型的，例如固定频率的振荡。然而，大多数关于信号动力学作用的研究都集中在一个或几个细胞系上，使得组织或细胞系之间的动力学多样性在很大程度上是一个未探索的问题。在这里，我们专注于肿瘤抑制蛋白p53的动力学，它在响应电离辐射被证明表现出振荡，在响应DNA损伤中发挥作用。我们建立了12个表达野生型p53的癌细胞系的活细胞报告基因，并定量了p53对一系列双链断裂诱导DNA损伤剂量的响应动力学。在许多测试的细胞系中，我们发现p53振荡并且振荡的周期是固定的。其他细胞系表现出不同的动态行为，包括单一的宽脉冲或连续诱导。通过结合p53信号传导动力学的单细胞测定、活细胞中的小分子筛选方法和数学建模，我们鉴定了干扰p53动力学的分子，并确定了DNA修复效率和激酶ATM活性的细胞特异性变化控制了定义p53动力学的信号传导景观。由于野生型p53的动力学在细胞系之间变化很大，我们的研究强调了使用一个细胞系作为模型系统的局限性，并强调了研究不同细胞系和遗传背景中其他关键信号通路的动力学的重要性。
Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. Here we focused on the dynamics of the tumor suppressor protein p53, which in response to ionizing radiation was shown to exhibit oscillations that play a role in the response to DNA damage. We established live cell reporters for 12 cancer cell lines expressing wild-type p53 and quantified p53 dynamics in response to a range of double strand break inducing DNA damage doses. In many of the tested cell lines, we found that p53 oscillates and the periodicity of the oscillations was fixed. Other cell lines exhibited distinct dynamic behaviors, including a single broad pulse or a continuous induction. By combining single cell assays of p53 signaling dynamics, small molecule screening approaches in live-cells, and mathematical modeling, we identified molecules that perturb p53 dynamics and determined that cell-specific variation in the efficiency of DNA repair and the activity of the kinase ATM controlled the signaling landscape defining p53 dynamics. Because the dynamics of wild-type p53 varied substantially between cell lines, our study highlights the limitation of using one line as a model system and emphasizes the importance of studying the dynamics of other critical signaling pathways across different cell lines and genetic backgrounds.
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影响因子：
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