Linear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation.
Linear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation.
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DOI：
10.1016/j.cels.2017.10.019
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发表时间：
2017-12-27
期刊：
影响因子：
9.3
通讯作者：
Albeck JG
中科院分区：
文献类型：
--
作者：
Gillies TE;Pargett M;Minguet M;Davies AE;Albeck JG
ERK信号调节靶基因的表达，但目前还不清楚ERK活性动力学如何解释。在这里，我们调查这个问题，同时，活的，单细胞成像的两个ERK活性报告和表达的Fra-1，一个靶基因控制上皮细胞的身份。我们发现Fra-1的表达与ERK活性的幅度和持续时间成比例。在以前的“持久性检测器”和“选择性过滤器”模型中，Fra-1的表达只发生在ERK活性持续超过阈值持续时间，我们的观察表明，调节Fra-1表达的网络集成总ERK活性和响应它线性。然而，对Fra-1相干前馈回路的广义数学模型的探索表明，它可以执行线性积分或持续检测，这取决于基础mRNA产生速率和蛋白质产生延迟。我们的数据表明，显着的基础表达和短暂的延迟导致Fra-1的线性响应集成ERK活性。使用活细胞ERK活性报告基因和数学分析的组合，吉利斯等人确定立即早期基因Fra-1的产生与总ERK活性呈线性关系。这表明该网络作为ERK活性模式的线性积分器而不是选择性过滤器发挥作用。
ERK signaling regulates the expression of target genes, but it is unclear how ERK activity dynamics are interpreted. Here, we investigate this question using simultaneous, live, single-cell imaging of two ERK activity reporters and expression of Fra-1, a target gene controlling epithelial cell identity. We find that Fra-1 is expressed in proportion to the amplitude and duration of ERK activity. In contrast to previous “persistence detector” and “selective filter” models in which Fra-1 expression only occurs when ERK activity persists beyond a threshold duration, our observations demonstrate that the network regulating Fra-1 expression integrates total ERK activity and responds to it linearly. However, exploration of a generalized mathematical model of the Fra-1 coherent feedfoward loop demonstrates that it can perform either linear integration or persistence detection, depending on the basal mRNA production rate and protein production delays. Our data indicate that significant basal expression and short delays cause Fra-1 to respond linearly to integrated ERK activity. Using a combination of live-cell ERK activity reporters and mathematical analysis, Gillies et al. determine that the immediate early gene, Fra-1, is produced in linear relation to total ERK activity. This demonstrates that the network functions as a linear integrator, not a selective filter, of ERK activity patterns.
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