Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response
Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response
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DOI：
10.1128/mcb.24.3.1365-1377.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Wek, RC
中科院分区：
文献类型：
--
作者：
Jiang, HY;Wek, SA;Wek, RC
为了应对环境压力，细胞诱导基因表达程序，旨在补救细胞损伤或诱导细胞凋亡。在这份报告中，我们探讨了一个家庭的蛋白激酶磷酸化真核起始因子2（eIF 2）在协调应激基因反应的作用。我们发现，转录激活因子3（ATF 3），碱性区亮氨酸拉链（bZIP）蛋白的ATF/CREB亚家族成员的表达，诱导内质网（ER）应激或氨基酸饥饿的机制，需要eIF 2激酶PEK（Perk或EIF 2AK 3）和GCN 2（EIF 2AK 4），分别。ATF 3蛋白的表达增加发生在应激反应的早期，其机制需要相关的bZIP转录调节因子ATF 4。ATF 3有助于诱导CHOP转录因子响应氨基酸饥饿，ATF 3功能的丧失显著降低应激诱导的GADD 34表达，GADD 34是一种参与eIF 2激酶应激反应反馈控制的eIF 2蛋白磷酸酶调节亚基。小鼠胚胎成纤维细胞中ATF 3的过表达部分地绕过了PEK诱导GADD 34响应ER应激的需要，进一步支持ATF 3直接或间接地作为eIF 2激酶应激途径靶向的基因的转录激活因子的观点。这些结果表明，ATF 3在eIF 2激酶诱导的协调基因表达中具有不可或缺的作用。鉴于ATF 3是由大量的环境损伤诱导的，本研究支持eIF 2激酶参与协调基因表达，以应对比以前提出的更多样化的应激条件。
In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.