Regulated translation initiation controls stress-induced gene expression in mammalian cells
Regulated translation initiation controls stress-induced gene expression in mammalian cells
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DOI：
10.1016/s1097-2765(00)00108-8
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发表时间：
2000-11-01
期刊：
影响因子：
16
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Harding, HP;Novoa, I;Ron, D
磷酸化真核起始因子2（eIF2 α）α亚基的蛋白激酶在应激细胞中被激活，并负调节蛋白质合成。鼠细胞中靶向突变的表型分析揭示了eIF2 α激酶在未折叠蛋白反应（UPR）和氨基酸饥饿细胞中调节基因表达的新作用。当被其同源上游应激信号激活时，哺乳动物eIF2激酶PERK和GCN 2抑制大多数mRNA的翻译，但选择性地增加激活转录因子4（ATF 4）的翻译，导致下游基因CHOP（GADD 153）的诱导。这是第一个哺乳动物信号传导途径的例子同源的充分研究酵母一般控制反应，其中eIF2 α磷酸化激活参与氨基酸生物合成的基因。因此，哺乳动物细胞利用一种古老的途径来调节基因表达，以响应不同的应激信号。
Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2 alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2 alpha kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2 alpha phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.