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Zn 2+ ‐induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells
Author(s) -
Seo Su Ryeon,
Chong Seon Ah,
Lee SyngIll,
Sung Jee Young,
Ahn Young Soo,
Chung Kwang Chul,
Seo Jeong Taeg
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00438.x
Subject(s) - mapk/erk pathway , microbiology and biotechnology , kinase , programmed cell death , intracellular , p38 mitogen activated protein kinases , protein kinase a , mitogen activated protein kinase , signal transduction , reactive oxygen species , extracellular , chemistry , biology , biochemistry , apoptosis
Recent studies have provided evidence that Zn 2+ plays a crucial role in ischemia‐ and seizure‐induced neuronal death. However, the intracellular signaling pathways involved in Zn 2+ ‐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 Zn 2+ ‐induced cell death using differentiated PC12 cells. Intracellular accumulation of Zn 2+ induced by the combined application of pyrithione (5 µ m ), a Zn 2+ ionophore, and Zn 2+ (10 µ m ) caused cell death and activated JNK and ERK, but not p38 MAPK. Preventing JNK activation by the expression of dominant negative SEK1 (SEK AL ) did not attenuate Zn 2+ ‐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 Zn 2+ ‐induced ERK activation. Intracellular Zn 2+ accumulation resulted in the generation of ROS, and antioxidants prevented both the ERK activation and the cell death induced by Zn 2+ . Therefore, we conclude that although Zn 2+ activates JNK and ERK, only ERK contributes to Zn 2+ ‐induced cell death, and that ERK activation is mediated by ROS via the Ras/Raf/MEK/ERK signaling pathway.