Zn2+ induces stimulation of the c-Jun N-terminal kinase signaling pathway through phosphoinositide 3-kinase

Soo Jung Eom, Eun Young Kim, Ji Eun Lee, Hyo Jung Kang, Jaekyung Shim, Seong Up Kim, Byoung Joo Gwag, Eui Ju Choi

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


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 agent N-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.

Original languageEnglish
Pages (from-to)981-986
Number of pages6
JournalMolecular Pharmacology
Issue number5
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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