p53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions
p53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions
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DOI：
10.15252/msb.20188685
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发表时间：
2019-09-01
影响因子：
9.9
通讯作者：
Batchelor, Eric
中科院分区：
文献类型：
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作者：
Harton, Marie D.;Koh, Woo Seuk;Batchelor, Eric
p53肿瘤抑制因子调节对细胞应激的不同反应。虽然不同的压力产生不同的p53动力学，细胞解码p53动力学差异调节靶基因的机制还没有很好地理解。在这里，我们确定了在单个细胞中，典型的p53靶基因启动子如何在对p53动力学特征的响应性方面发生变化。采用化学扰动的方法，我们独立调制p53脉冲的幅度，持续时间，或频率，然后我们监测p53水平和目标启动子在单个细胞中的激活。我们确定了不同的信号处理功能阈值响应幅度调制，不应期响应持续时间调制，和动态滤波响应频率调制。然后，我们发现信号处理功能不仅影响p53靶启动子的激活，还影响p53的调节和下游细胞功能。我们的研究显示了不同的启动子如何差异解码p53动力学的特征以产生不同的反应，从而深入了解扰动p53动力学如何用于产生不同的细胞命运。
The p53 tumor suppressor regulates distinct responses to cellular stresses. Although different stresses generate different p53 dynamics, the mechanisms by which cells decode p53 dynamics to differentially regulate target genes are not well understood. Here, we determined in individual cells how canonical p53 target gene promoters vary in responsiveness to features of p53 dynamics. Employing a chemical perturbation approach, we independently modulated p53 pulse amplitude, duration, or frequency, and we then monitored p53 levels and target promoter activation in individual cells. We identified distinct signal processing features-thresholding in response to amplitude modulation, a refractory period in response to duration modulation, and dynamic filtering in response to frequency modulation. We then showed that the signal processing features not only affect p53 target promoter activation, they also affect p53 regulation and downstream cellular functions. Our study shows how different promoters can differentially decode features of p53 dynamics to generate distinct responses, providing insight into how perturbing p53 dynamics can be used to generate distinct cell fates.