Zn2+ Induces Stimulation of the c-Jun N-Terminal Kinase Signaling Pathway through Phosphoinositide 3-Kinase
- Soo-Jung Eom1,
- Eun Young Kim2,
- Ji Eun Lee1,
- Hyo Jung Kang2,
- Jaekyung Shim1,
- Seong Up Kim3,
- Byoung Joo Gwag2 and
- Eui-Ju Choi1
- 1National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul, Korea (S.-J.E., J.E.L., J.S., E.-J.C.); and 2Department of Pharmacology (E.Y.K., H.J.K., B.J.G.) and 3Brain Disease Research Center (S.U.K.), School of Medicine, Ajou University, Suwon, Kyungki-do, Korea
Abstract
Zn2+, one of the most abundant trace metal ions in mammalian cells, modulates the functions of many regulatory proteins associated with a variety of cellular activities. In the central nervous system, Zn2+ is highly localized in the cerebral cortex and hippocampus. It has been proposed to play a role in normal brain function as well as in the pathophysiology of certain neurodegenerative disorders. We here report that Zn2+induced stimulation of the c-Jun N-terminal kinase (JNK) pathway in mouse primary cortical cells and in various cell lines. Exposure of cells to Zn2+ resulted in the stimulation of JNK and its upstream kinases including stress-activated protein kinase kinase and mitogen-activated protein kinase kinase kinase. Zn2+also induced stimulation of phosphoinositide 3-kinase (PI3K) The Zn2+-induced JNK stimulation was blocked by LY294002, a PI3K inhibitor, or by a dominant-negative mutant of PI3Kγ. Furthermore, overexpression of Rac1N17, a dominant negative mutant of Rac1, suppressed the Zn2+- and PI3Kγ-induced JNK stimulation. The stimulatory effect of Zn2+ on both PI3K and JNK was repressed by the free-radical scavenging agentN-acetylcysteine. Taken together, our data suggest that Zn2+ induces stimulation of the JNK signaling pathway through PI3K-Rac1 signals and that the free-radical generation may be an important step in the Zn2+ induction of the JNK stimulation.
Footnotes
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Send reprint requests to: Eui-Ju Choi, Ph.D., Graduate School of Biotechnology, Korea University, Seoul, 136–701, South Korea. E-mail: ejchoi{at}mail.korea.ac.kr
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This work was supported by the Creative Research Initiatives Program of the Korean Ministry of Science and Technology (to E.-J.C.), and in part by a grant from the Hallym Academy of Science, Hallym University (E.-J.C.).
- Abbreviations:
- MAPK
- mitogen-activated protein kinase
- ERK
- extracellular signal-regulated kinase
- JNK
- c-Jun N-terminal kinase
- SAPK
- stress-activated protein kinase
- PI3K
- phosphoinositide 3-kinase
- AP-1
- activator protein 1
- ATF-2
- activating transcription factor 2
- NAC
- N-acetylcysteine
- ROS
- reactive oxygen species
- SEK
- stress-activated protein kinase kinase
- MEKK
- mitogen-activated protein kinase kinase kinase
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- Received July 24, 2000.
- Accepted January 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
