Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.
Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.
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DOI：
10.1016/j.freeradbiomed.2010.12.032
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发表时间：
2011-03-01
影响因子：
7.4
通讯作者：
Huang, Shile
中科院分区：
文献类型：
--
作者：
Chen, Long;Xu, Baoshan;Liu, Lei;Luo, Van;Zhou, Hongyu;Chen, Wenxing;Shen, Tao;Han, Xiuzhen;Kontos, Christopher D.;Huang, Shile
关键词：
镉（Cd）是一种剧毒环境污染物，可诱发神经退行性疾病。最近我们证明，Cd 部分通过激活哺乳动物雷帕霉素靶点 (mTOR) 途径诱导神经元凋亡。然而，根本机制尚不清楚。在这里，我们发现，Cd 通过上调 PC12 和 SH-SY5Y 细胞中 NADPH 氧化酶 2 (NOX2) 及其调节蛋白 (p22phox、p67phox、p40phox、p47phox 和 Rac1) 的表达来诱导活性氧 (ROS) 的产生。 Cd 诱导 ROS 有助于激活 mTOR 信号传导，而用 ROS 清除剂 N-乙酰基-L-半胱氨酸 (NAC) 进行预处理可防止这一事件。进一步的研究表明，Cd 诱导的 ROS 增加了 I 型胰岛素样生长因子受体 β 亚基 (IGFRβ) 的磷酸化，而 NAC 消除了这种磷酸化。 Wortmannin 是一种磷酸肌醇 3'-激酶 (PI3K) 抑制剂，可部分减弱 Cd 诱导的 Akt、p70 S6 激酶 1 (S6K1) 和真核起始因子 4E (eIF4E) 结合蛋白 1 (4E-BP1) 的磷酸化，以及神经元细胞的凋亡。此外，10号染色体上缺失的野生型磷酸酶和张力蛋白同源物（PTEN）的过度表达或用氨基咪唑甲酰胺核糖核苷酸（AICAR）（一种AMP激活的蛋白激酶（AMPK）激活剂）进行预处理，部分阻止了Cd诱导的ROS和mTOR途径的激活以及细胞死亡。结果表明，Cd 诱导 ROS 激活 mTOR 信号传导，导致神经元细胞死亡，部分是通过激活正调节因子 IGFR/PI3K 和抑制负调节因子 PTEN/AMPK 来实现的。研究结果表明，PI3K 和 mTOR 抑制剂、AMPK 激活剂或抗氧化剂可用于预防 Cd 诱导的神经退行性疾病。
Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd induces neuronal apoptosis in part through activation of the mammalian target of rapamycin (mTOR) pathway. However, the underlying mechanism is unknown. Here we show that Cd induced generation of reactive oxygen species (ROS) by upregulating expression of NADPH oxidase 2 (NOX2) and its regulatory proteins (p22phox, p67phox, p40phox, p47phox and Rac1) in PC12 and SH-SY5Y cells. Cd induction of ROS contributed to activation of mTOR signaling, as pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented this event. Further studies reveal that Cd induction of ROS increased phosphorylation of type I insulin-like growth factor receptor β subunit (IGFRβ), which was abrogated by NAC. Wortmannin, a phosphoinositide 3′-kinase (PI3K) inhibitor, partially attenuated Cd-induced phosphorylation of Akt, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), as well as apoptosis of the neuronal cells. In addition, overexpression of wild-type phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or pretreatment with aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-activated protein kinase (AMPK) activator, partially prevented Cd-induced ROS and activation of mTOR pathway, as well as cell death. The results indicate that Cd induction of ROS activates mTOR signaling, leading to neuronal cell death, in part by activating the positive regulators IGFR/PI3K, and by inhibiting the negative regulators PTEN/AMPK. The findings suggest that the inhibitors of PI3K and mTOR, activators of AMPK, or antioxidants may be exploited for prevention of Cd-induced neurodegenerative diseases.
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影响因子：
6.6
作者：
Frey RS;Ushio-Fukai M;Malik AB
通讯作者：
Malik AB
影响因子：
4
作者：
Huang, S;Houghton, PJ
通讯作者：
Houghton, PJ
DOI：
10.1073/pnas.0610068104
发表时间：
2007-04-24
影响因子：
11.1
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
8
作者：
Liu, L.;Chen, L.;Huang, S.
通讯作者：
Huang, S.
影响因子：
7.4
作者：
Chen, Long;Liu, Lei;Huang, Shile
通讯作者：
Huang, Shile