Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
IET Syst Biol. 2011 Sep;5(5):293-307. doi: 10.1049/iet-syb.2010.0080.
Experiments have recently shown that p53 expression can display oscillations in response to certain stress signals. In this work, mathematical modelling and bifurcation analysis are combined to investigate under which conditions the oscillation of p53 could propagate to its direct downstream transcription targets. The authors' analysis suggests that oscillations of p53 will propagate only to proteins with medium-fast mRNA and protein turnover rates. The authors retrieved data concerning the half-life of mRNA and protein for a number of p53-promoted genes and found that, according to their model, most of them are not able to inherit the oscillation of p53 because of their slow turnover rates. However, their analysis indicates that p53 oscillation may actually fine-tune the expression pattern of a protein when it is integrated with a second oscillatory signal. The authors also consider the case of additional regulatory loops affecting p53 oscillations and involving proteins transcriptionally induced by p53. Their results for 14-3-3σ, a protein that targets the p53 inhibitor MDM2 for degradation, suggest that the addition of feedback-loop regulation may modulate basic properties of p53 oscillation and induce quick cessation of them under certain physiological conditions. Moreover, the interplay between DNA damage and 14-3-3σ may induce bistability in the oscillation of p53.
最近的实验表明，p53 的表达可以对某些应激信号做出振荡响应。在这项工作中，作者将数学建模和分岔分析相结合，研究了 p53 的振荡在何种条件下可以传播到其直接下游的转录靶标。作者的分析表明，p53 的振荡只会传播到 mRNA 和蛋白质周转率中等偏快的蛋白质上。作者检索了与许多 p53 促进的基因的 mRNA 和蛋白质半衰期有关的数据，并根据他们的模型发现，由于它们的周转率较慢，其中大多数基因无法继承 p53 的振荡。然而，他们的分析表明，当 p53 与第二个振荡信号结合时，p53 振荡实际上可以微调蛋白质的表达模式。作者还考虑了影响 p53 振荡的其他调节环的情况，这些调节环涉及 p53 转录诱导的蛋白质。他们对 14-3-3σ 的研究结果表明，14-3-3σ 是一种将 p53 抑制剂 MDM2 靶向降解的蛋白质，添加反馈环调节可能会调节 p53 振荡的基本特性，并在某些生理条件下迅速终止它们。此外，DNA 损伤和 14-3-3σ 之间的相互作用可能会诱导 p53 振荡的双稳性。
