Induction of early growth response gene 1 (EGR1) by endoplasmic reticulum stress is mediated by the extracellular regulated kinase (ERK) arm of the MAPK pathways.
Induction of early growth response gene 1 (EGR1) by endoplasmic reticulum stress is mediated by the extracellular regulated kinase (ERK) arm of the MAPK pathways.
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内质网应激对早期生长反应基因 1 (EGR1) 的诱导是由 MAPK 通路的细胞外调节激酶 (ERK) 臂介导的。
DOI：
10.1016/j.bbamcr.2018.09.009
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kilberg,MichaelS
中科院分区：
文献类型：
--
作者：
Shan,Jixiu;Dudenhausen,Elizabeth;Kilberg,MichaelS
内质网应激激活了三条主要的信号通路，统称为未折叠蛋白反应，导致翻译和转录控制机制，决定细胞的反应是适应性的还是凋亡性的。本研究表明，在HepG2人肝癌细胞中，ER应激触发的信号通路超越了三个主要通路，包括丝裂原活化蛋白激酶(MAPK)信号通路，导致早期生长反应1(Egr1)基因转录的激活。分析为SRC-RAS-RAF-MEK-ERK级联机制提供了证据，导致转录因子ELK1的磷酸化增强。ELK1和血清反应因子(SRF)结构性地与EGR1启动子结合，并被核定位的ERK磷酸化。内质网应激增加了磷酸化SRF和phopsho-ELK1启动子的丰度，但SRF的磷酸化是短暂的。ELK1基因敲除对Egr1mRNA的基础含量影响不大，但可完全阻断内质网应激引起的Egr1mRNA含量的增加。相反，基因敲除SRF可抑制Egr1mRNA的基础含量，但对内质网应激诱导的Egr1mRNA含量影响不大。这项研究强调了MAPK信号在内质网应激反应中的重要性，并确定ELK1是转录调节因子，EGR1基因是靶标。
Endoplasmic reticulum (ER) stress activates three principal signaling pathways, collectively known as the unfolded protein response, leading to translational and transcriptional control mechanisms that dictate the cell's response as adaptive or apoptotic. The present study illustrates that for HepG2 human hepatocellular carcinoma cells the signaling pathways triggered by ER stress extend beyond the three principal pathways to include mitogen-activated protein kinase (MAPK) signaling, leading to activation of transcription from the early growth response 1 (EGR1) gene. Analysis provided evidence for a SRC-RAS-RAF-MEK-ERK cascade mechanism that leads to enhanced phosphorylation of the transcription factor ELK1. ELK1 and serum response factor (SRF) are constitutively bound to theEGR1promoter and are phosphorylated by nuclear localized ERK. The promoter abundance of both phospho-SRF and phopsho-ELK1 was increased by ER stress, but the SRF phosphorylation was transient. Knockdown of ELK1 had little effect on the basal EGR1 mRNA content, but completely blocked the increase in response to ER stress. Conversely, knockdown of SRF suppressed basal EGR1 mRNA content, but had only a small effect on the induction by ER stress. This research highlights the importance of MAPK signaling in response to ER stress and identifies ELK1 as a transcriptional mediator and theEGR1gene as a target.
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