Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153.
Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153.
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DOI：
10.1186/1471-2121-14-4
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发表时间：
2013-01-22
期刊：
影响因子：
--
通讯作者：
Kim YY
中科院分区：
文献类型：
--
作者：
Kim S;Cheon HS;Kim SY;Juhnn YS;Kim YY
镉（Cd）是一种具有强烈有害作用的重金属，是一种高度应激诱导的物质，在内质网（ER）内稳态被破坏（所谓的ER应激）后被强烈表达。镉诱导神经母细胞瘤细胞死亡的机制复杂，涉及细胞信号通路尚未完全确定，但部分涉及活性氧（ROS）的产生。一些研究已经将GADD 153表达与细胞死亡相关联，但是GADD 153和细胞凋亡之间的机制联系从未被证实。镉处理SH-SY 5 Y细胞后，细胞内活性氧水平升高。ROS的产生与细胞内[Ca 2 +]不一致。神经母细胞瘤细胞暴露于镉导致细胞内GADD 153和巴克水平增加，呈剂量和时间依赖性。这些基因的诱导镉减弱NAC。与正常细胞相比，GADD 153敲低细胞中Cd诱导的凋亡减少。ChIP法分析GADD 153对C/EBP与巴克启动子结合的影响。在SH-SY 5 Y细胞中观察到基础组成型GADD 153募集到巴克启动子的-3，398/-3，380区域。SH-SY 5 Y细胞暴露于Cd后，细胞内ROS水平呈剂量和时间依赖性增加。ROS的产生导致GADD 153的诱导是镉诱导细胞凋亡的原因。GADD 153通过与启动子区域（-3，398和-3，380之间）结合来调节巴克的表达。因此，我们得出结论，GADD 153敏感细胞ROS的机制，涉及上调巴克和增强氧化损伤。
Cadmium(Cd), a heavy metal, which has a potent harmful effects, is a highly stress-inducible material that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). The mechanism Cd induced cell death of neuroblastoma cells complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). Several studies have correlated GADD153 expression with cell death, but a mechanistic link between GADD153 and apoptosis has never been demonstrated. SH-SY5Y cells were treated Cd led to increase in intracellular ROS levels. ROS generation is not consistent with intracellular [Ca2+]. The exposure of neuroblastoma cells to Cd led to increase in intracellular GADD153 and Bak levels in a doses and time dependent manner. The induction of these genes by Cd was attenuated by NAC. Cd-induced apoptosis is decreased in GADD153 knockdown cells compared with normal cells. The effect of GADD153 on the binding of C/EBP to the Bak promoters were analyzed ChIP assay. Basal constitutive GADD153 recruitment to the –3,398/–3,380 region of the Bak promoter is observed in SH-SY5Y cells. The exposure of SH-SY5Y cells to Cd led to increase in intracellular ROS levels in a doses and time dependent manner. The generation of ROS result in the induction of GADD153 is causative of cadmium-induced apoptosis. GADD153 regulates Bak expression by its binding to promoter region (between −3,398 and −3,380). Therefore, we conclude that GADD153 sensitizes cells to ROS through mechanisms that involve up-regulation of BAK and enhanced oxidant injury.
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