Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest.
Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest.
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DOI：
10.1016/j.molcel.2018.06.031
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发表时间：
2018-08-16
期刊：
影响因子：
16
通讯作者：
Lahav G
中科院分区：
文献类型：
--
作者：
Reyes J;Chen JY;Stewart-Ornstein J;Karhohs KW;Mock CS;Lahav G
生物信号需要是鲁棒的，并过滤小的波动，但保持对信号的灵敏度在很宽的幅度范围内。在这里，我们研究了DNA损伤信号的波动如何与长期细胞周期停滞的维持相关。使用活细胞成像，我们量化了照射后一周内单个人类细胞的分裂概况。我们发现了一个细胞亚群，最初建立细胞周期停滞，然后零星逃逸和分裂。使用荧光报告和数学建模，我们确定了肿瘤抑制因子p53的振荡模式的波动触发了p21和CDK2之间的急剧转换，导致从逮捕逃脱。p53稳定性的瞬时扰动模仿了单个细胞中的噪声，足以触发逃逸。我们的研究结果表明，介导细胞周期转换的自我增强电路可以将p53信号的小波动转化为大的表型变化。Reyes等人表明，单个人类细胞在DNA损伤后一周内维持细胞周期停滞的能力各不相同。他们表明，肿瘤抑制因子p53的振荡动力学波动可以触发从停滞状态到增殖状态的转换。
Biological signals need to be robust and filter small fluctuations, yet maintain sensitivity to signals across a wide range of magnitudes. Here we studied how fluctuations in DNA damage signaling relate to maintenance of long-term cell cycle arrest. Using live-cell imaging, we quantified division profiles of individual human cells in the course of one week after irradiation. We found a subset of cells that initially establish cell cycle arrest, and then sporadically escape and divide. Using fluorescent reporters and mathematical modeling, we determined that fluctuations in the oscillatory pattern of the tumor suppressor p53 trigger a sharp switch between p21 and CDK2, leading to escape from arrest. Transient perturbation of p53 stability mimicked the noise in individual cells and was sufficient to trigger escape from arrest. Our results show that the self-reinforcing circuitry that mediates cell cycle transitions can translate small fluctuations in p53 signaling into large phenotypic changes. Reyes et al. show that individual human cells vary in their ability to maintain cell cycle arrest in the course of one week after DNA damage. They show that fluctuations in the oscillatory dynamics of the tumor suppressor p53 can trigger a switch from an arrested to a proliferative state.
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