Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Electrical and Computer Engineering, Department of Biomedical Engineering, Department of Mathematical Sciences, and Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA.
Mol Syst Biol. 2019 Sep;15(9):e8685. doi: 10.15252/msb.20188685.
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.
p53 肿瘤抑制因子调节细胞应激的不同反应。尽管不同的应激会产生不同的 p53 动力学，但细胞如何解码 p53 动力学以差异调节靶基因的机制尚不清楚。在这里，我们在单个细胞中确定了经典的 p53 靶基因启动子对 p53 动力学特征的反应性差异。我们采用化学干扰方法，分别调节 p53 脉冲幅度、持续时间或频率，然后在单个细胞中监测 p53 水平和靶启动子激活。我们发现了不同的信号处理特征——对幅度调制的阈值响应、对持续时间调制的不应期以及对频率调制的动态滤波。然后我们表明，信号处理特征不仅影响 p53 靶启动子的激活，还影响 p53 调节和下游细胞功能。我们的研究表明，不同的启动子如何对 p53 动力学的特征进行差异解码，从而产生不同的反应，为如何干扰 p53 动力学以产生不同的细胞命运提供了深入的了解。
