Zn2+-induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells

被引:113
作者
Seo, SR
Chong, SA
Lee, SI
Sung, JY
Ahn, YS
Chung, KC
Seo, JT
机构
[1] Yonsei Univ, Coll Dent, Dept Oral Biol, Seoul 120752, South Korea
[2] Yonsei Univ, Coll Dent, Oral Sci Res Ctr, Seoul 120752, South Korea
[3] Yonsei Univ, Project Med Sci BK21, Seoul 120752, South Korea
[4] Yonsei Univ, Coll Med, Dept Pharmacol, Seoul 120752, South Korea
关键词
c-Jun N-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinases; reactive oxygen species; Zn2+;
D O I
10.1046/j.1471-4159.2001.00438.x
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
Recent studies have provided evidence that Zn2+ plays a crucial role in ischemia- and seizure-induced neuronal death. However, the intracellular signaling pathways involved in Zn2+-induced cell death are largely unknown. In the present study, we investigated the roles of mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK), and of reactive oxygen species (ROS) in Zn2+-induced cell death using differentiated PC12 cells. Intracellular accumulation of Zn2+ induced by the combined application of pyrithione (5 muM), a Zn2+ ionophore, and Zn2+ (10 muM) caused cell death and activated JNK and ERK, but not p38 MAPK. Preventing JNK activation by the expression of dominant negative SEK1 (SEKAL) did not attenuate Zn2+-induced cell death, whereas the inhibition of ERK with PD98059 and the expression of dominant negative Ras mutant (RasN17) significantly prevented cell death. Inhibition of protein kinase C (PKC) and phosphatidylinositol-3 kinase had little effect on Zn2+-induced ERK activation. Intracellular Zn2+ accumulation resulted in the generation of ROS, and antioxidants prevented both the ERK activation and the cell death induced by Zn2+. Therefore, we conclude that although Zn2+ activates JNK and ERK, only ERK contributes to Zn2+-induced cell death, and that ERK activation is mediated by ROS via the Ras/Raf/MEK/ERK signaling pathway.
引用
收藏
页码:600 / 610
页数:11
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