Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA.
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Cell Syst. 2017 Dec 27;5(6):549-563.e5. doi: 10.1016/j.cels.2017.10.019. Epub 2017 Nov 29.
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 feedforward 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.
ERK 信号转导调节靶基因的表达，但 ERK 活性动力学如何被解释尚不清楚。在这里，我们使用同时、实时、单细胞成像两种 ERK 活性报告器和 Fra-1（控制上皮细胞身份的靶基因）的表达来研究这个问题。我们发现 Fra-1 的表达与 ERK 活性的幅度和持续时间成比例。与之前的“持续检测器”和“选择性滤波器”模型不同，在这些模型中，Fra-1 的表达仅在 ERK 活性持续超过阈值持续时间时才发生，我们的观察表明，调节 Fra-1 表达的网络整合了总 ERK 活性并线性响应它。然而，对 Fra-1 相干前馈环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 产生率和蛋白质产生延迟。我们的数据表明，显著的基础表达和短延迟导致 Fra-1对整合的 ERK 活性线性响应。
