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Zn(2+) induces stimulation of the c-Jun N-terminal kinase signaling pathway through phosphoinositide 3-Kinase

Authors
Eom, SJ; Kim, EY; Lee, JE; Kang, HJ; Shim, J; Kim, SU; Gwag, BJ; Choi, EJ
Citation
Molecular pharmacology, 59(5):981-986, 2001
Journal Title
Molecular pharmacology
ISSN
0026-895X1521-0111
Abstract
Zn(2+), 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, Zn(2+) 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 Zn(2+) 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 Zn(2+) resulted in the stimulation of JNK and its upstream kinases including stress-activated protein kinase kinase and mitogen-activated protein kinase kinase kinase. Zn(2+) also induced stimulation of phosphoinositide 3-kinase (PI3K) The Zn(2+)-induced JNK stimulation was blocked by LY294002, a PI3K inhibitor, or by a dominant-negative mutant of PI3Kgamma. Furthermore, overexpression of Rac1N17, a dominant negative mutant of Rac1, suppressed the Zn(2+)- and PI3Kgamma-induced JNK stimulation. The stimulatory effect of Zn(2+) on both PI3K and JNK was repressed by the free-radical scavenging agent N-acetylcysteine. Taken together, our data suggest that Zn(2+) induces stimulation of the JNK signaling pathway through PI3K-Rac1 signals and that the free-radical generation may be an important step in the Zn(2+) induction of the JNK stimulation.
MeSH terms
Acetylcysteine/pharmacologyAnimalsDrug InteractionsEnzyme ActivationFree Radical Scavengers/pharmacologyGenes, ReporterJNK Mitogen-Activated Protein KinasesLuciferasesMAP Kinase Kinase 4*MAP Kinase Kinase Kinase 1*MiceMitogen-Activated Protein Kinase Kinases/metabolismMitogen-Activated Protein Kinases/drug effectsMitogen-Activated Protein Kinases/metabolism*Phosphatidylinositol 3-Kinases/metabolism*Protein-Serine-Threonine Kinases/metabolismReactive Oxygen Species/metabolismSignal TransductionTumor Cells, CulturedZinc/pharmacology*
PMID
11306679
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
김, 승업곽, 병주
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