Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway

被引:199
作者
Chen, Long [1 ]
Liu, Lei [1 ]
Yin, Jun [2 ]
Luo, Yan [1 ]
Huang, Shile [1 ,3 ]
机构
[1] Louisiana State Univ, Dept Biochem & Mol Biol, Hlth Sci Ctr, Shreveport, LA 71130 USA
[2] Louisiana State Univ, Dept Microbiol & Immunol, Hlth Sci Ctr, Shreveport, LA 71130 USA
[3] Louisiana State Univ, Feist Weiller Canc Ctr, Hlth Sci Ctr, Shreveport, LA 71130 USA
关键词
Hydrogen peroxide; Protein phosphatase 2A; Protein phosphatase 5; c-Jun N-terminal kinase; Extracellular signal-regulated kinase 1/2; SH-SY5Y NEUROBLASTOMA-CELLS; OXIDATIVE STRESS; GROWTH-FACTOR; IN-VITRO; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; DEATH MECHANISMS; H2O2; INJURY; P38; MAPK; C-JUN;
D O I
10.1016/j.biocel.2008.10.029
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Oxidative stress-induced neuronal apoptosis is a prominent feature found in neurodegenerative disorders. However, how oxidative stress induces neuronal apoptosis is not well understood. To address this question, undifferentiated and differentiated neuronal cell lines (PC12 and SH-SY5Y) were exposed to hydrogen peroxide (H2O2), a major oxidant generated when oxidative stress occurs. We observed that H2O2 induced generation of reactive oxygen species (ROS), leading to apoptosis of the cells in a concentration- and time-dependent manner. H2O2 rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2,JNK or p38 with kinase inhibitors (U0126, SP600125 or PD169316, respectively), downregulation of Erk1/2 or p38 using RNA interference, or expression of dominant negative c-Jun partially prevented H2O2-induced apoptosis. Pretreatment with N-acetyl-L-Cysteine (NAC) scavenged H2O2-induced ROS, blocking activation of MAPKs and cell death. Furthermore, we found that H2O2-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented H2O2-activation of Erk/12, JNK and p38, as well as cell death. Similar results were observed in primary murine neurons as well. The results suggest that H2O2-induction of ROS inhibit PP2A and PP5, leading to activation of Erk1/2, JNK and p38 pathways thereby resulting in neuronal apoptosis. Our findings suggest that inhibitors of MAPKs UNK, Erk1/2 and p38), activators of phosphatases (PP2A and PP5) or antioxidants may have potentials to prevent and treat oxidative stress-induced neurodegenerative diseases. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1284 / 1295
页数:12
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