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

Su Ryeon Seo, Seon Ah Chong, Syng Ill Lee, Jee Young Sung, Young Soo Ahn, Kwang Chul Chung, Jeong Taeg Seo

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 μM), a Zn2+ ionophore, and Zn2+ (10 μM) 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.

Original languageEnglish
Pages (from-to)600-610
Number of pages11
JournalJournal of Neurochemistry
Volume78
Issue number3
DOIs
Publication statusPublished - 2001 Aug 20

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Zn<sup>2+</sup>-induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells'. Together they form a unique fingerprint.

  • Cite this