ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.
ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.
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ATF4是在体外和体内神经元中转录因子的氧化应激诱导的。
DOI：
10.1084/jem.20071460
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发表时间：
2008-05-12
影响因子：
15.3
通讯作者：
Ratan, Rajiv R.
中科院分区：
文献类型：
--
作者：
Lange, Philipp S.;Chavez, Juan C.;Pinto, John T.;Coppola, Giovanni;Sun, Chiao-Wang;Townes, Tim M.;Geschwind, Daniel H.;Ratan, Rajiv R.
氧化应激在神经系统疾病中是致病的，包括中风。氧化应激诱导的转录因子的身份及其在传播死亡级联中的作用还不清楚。在体外氧化应激模型中，谷胱甘肽耗竭诱导bZip转录因子激活转录因子4（ATF 4）的表达，并定位于神经元中假定死亡基因的启动子。ATF 4的种系缺失导致氧化应激诱导的基因表达和对氧化死亡的抵抗力显著降低。在神经元中，ATF 4调节死亡途径中的早期上游事件，因为ATF 4缺失对氧化死亡的抵抗与抗氧化剂谷胱甘肽的消耗减少有关。ATF 4的强制表达足以促进细胞死亡和谷胱甘肽的损失。在ATF 4 −/−神经元中，ATF 4蛋白表达的恢复恢复了对氧化死亡的敏感性。此外，与在啮齿动物缺血性中风模型中经历相同血流量减少的野生型小鼠相比，ATF 4 −/−小鼠经历了显著更小的梗死和改善的行为恢复。总的来说，这些发现确立了ATF 4作为神经系统中的氧化还原调节的促死亡转录激活因子，其在体外传播对氧化应激的死亡反应和在体内传播对中风的死亡反应。
Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress–inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress–induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4−/− neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4−/− mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
12.3
作者：
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通讯作者：
Zhang J