Involvement of MEK5/ERK5 signaling pathway in manganese-induced cell injury in dopaminergic MN9D cells.
Involvement of MEK5/ERK5 signaling pathway in manganese-induced cell injury in dopaminergic MN9D cells.
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MEK5/ERK5信号通路参与锰诱导的多巴胺能MN9D细胞损伤
DOI：
10.1016/j.jtemb.2020.126546
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发表时间：
2020-05-11
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Ding H;Wang F;Su L;Zhao L;Hu B;Zheng W;Yao S;Li Y
过度暴露于锰（Mn）会导致不可逆的运动障碍，其体征和症状与特发性帕金森病（IPD）相似，但不完全相同。最近的数据表明，锰毒性发生在多巴胺（DA）神经元，虽然机制仍然难以捉摸。本研究旨在探讨锰是否干扰DA神经元凋亡信号转导级联。将小鼠中脑多巴胺能MN 9D细胞暴露于浓度范围为0、400、800或1200 μM的Mn，分别指定为对照、低、中和高暴露组。流式细胞仪Annexin V/PI双染及免疫组化检测细胞凋亡。数据表明，与对照相比，Mn暴露引起典型的凋亡的形态学改变，使凋亡细胞增加2-8倍，并产生1.5-2.2倍的反应性氧化物质（ROS）（p < 0.05）。通过qPCR和Western印迹的研究显示，Mn暴露显著增加细胞外信号调节激酶5（ERK 5）和促分裂原活化的ERK激酶5（MEK 5）的蛋白表达（p < 0.05）。MER/ERK的特异性抑制剂BIX 02189的存在引起更大的细胞毒性，即，更高的细胞死亡，更多的ROS产生，和恶化的细胞凋亡，比单独用Mn处理。在Mn暴露后，与对照相比，下游效应子Bel- 2的表达降低48%，而Bax和Caspase-3的表达分别增加266.7%和90.1%（p < 0.05）。总之，这些数据提供了初步的证据，由MEK 5/ERK 5介导的信号转导级联是负责锰诱导的细胞毒性;锰暴露，通过抑制抗凋亡功能，同时促进促凋亡活性，改变神经元细胞的存活和功能抑制DA生产MN 9D细胞。
Over-exposure to manganese (Mn) causes irreversible movement disorders with signs and symptoms similar, but not identical, to idiopathic Parkinson’s disease (IPD). Recent data suggest that Mn toxicity occurs in dopaminergic (DA) neurons, although the mechanism remains elusive. This study was designed to investigate whether Mn interfered the apoptotic signaling transduction cascade in DA neurons. Mouse midbrain dopaminergic MN9D cells were exposed to Mn in a concentration range of 0, 400, 800, or 1200 μM as designated as control, low, medium, and high exposure groups, respectively. The flow cytometry with Annexin V/PI double staining and immunohistochemistry were used to assess the apoptosis. Data indicated that Mn exposure caused morphological alterations typical of apoptosis, increased apoptotic cells by 2–8 fold, and produced reactive oxidative species (ROS) by 1.5–2.2 fold as compared to controls (p < 0.05). Studies by qPCR and Western blot revealed that Mn exposure significantly increased the protein expression of extracellular signal-regulated kinase-5 (ERK5) and mitogen-activated ERK kinase-5 (MEK5) (p < 0.05). The presence of BIX02189, a specific inhibitor of MER/ERK, caused a much greater cytotoxicity, i.e., higher cell death, more ROS production, and worsened apoptosis, than did the treatment with Mn alone. Following Mn exposure, the expression of a downstream effector Bel- 2 was reduced by 48 % while those of Bax and Caspase-3 were increased by 266.7 % and 90.1 %, respectively, as compared to controls (p < 0.05). Taken together, these data provide the initial evidence that the signaling transduction cascade mediated by MEK5/ERK5 is responsible to Mn-induced cytotoxicity; Mn exposure, by suppressing anti-apoptotic function while facilitating pro-apoptotic activities, alters neuronal cell’s survival and functionally inhibits DA production by MN9D cells.
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影响因子：
3.7
作者：
Bouabid S;Delaville C;De Deurwaerdère P;Lakhdar-Ghazal N;Benazzouz A
通讯作者：
Benazzouz A
影响因子：
3.8
作者：
Chen, JY;Tsao, GC;Zheng, W
通讯作者：
Zheng, W
通过细胞外信号调节的蛋白激酶5来调节神经元存活。
影响因子：
12.4
作者：
Finegan, K. G.;Wang, X.;Lee, E-J;Robinson, A. C.;Tournier, C.
通讯作者：
Tournier, C.
DOI：
10.1016/j.bbrc.2008.09.087
发表时间：
2008-12-05
影响因子：
3.1
作者：
Tatake, Revati J.;O'Neill, Margaret M.;Snow, Roger J.
通讯作者：
Snow, Roger J.
影响因子：
4.8
作者：
Guilarte TR
通讯作者：
Guilarte TR