Zn(2+) induces stimulation of the c-Jun N-terminal kinase signaling pathway through phosphoinositide 3-Kinase.
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.
Eom
S J
SJ
National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul, Korea.
Kim
E Y
EY
Lee
J E
JE
Kang
H J
HJ
Shim
J
J
Kim
S U
SU
Gwag
B J
BJ
Choi
E J
EJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D017930:Genes, Reporter; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology*
D000111:Acetylcysteine; D016166:Free Radical Scavengers; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D015032:Zinc; C482578:Map3k1 protein, mouse; C482562:Map2k4 protein, mouse