Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death

J Neurochem. 1999 Aug;73(2):450-6. doi: 10.1046/j.1471-4159.1999.0730450.x.

Abstract

Egr-1 is one of the immediate early transcription factors that are induced after brain insults. However, the mechanism and the role of Egr-1 induction are not yet determined. In the present study, using mouse cortical cultures, we examined the ionic mechanism of Egr-1 induction and its role in neuronal death. Although zinc, NMDA, or ionomycin induced comparable neuronal death in cortical culture, only zinc increased Egr-1 expression, which was attenuated by blocking zinc influx. It is intriguing that brief exposure to zinc induced sustained extracellular signal-regulated kinase (Erk) activation. PD098059, an inhibitor of the Erk 1/2 upstream kinase mitogen-activated protein kinase kinase 1 (MEK1), blocked Erk 1/2 activation, Egr-1 induction, and neuronal death by zinc. The present study has demonstrated that zinc, rather than calcium, induces lasting Egr-1 expression in cortical culture by activating Erk 1/2, which is part of a cascade that may play an active role in zinc neurotoxicity. We propose that translocation of endogenous zinc may be the key mechanism of Egr-1 induction and neuronal death in brain ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antisense Elements (Genetics) / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Death / drug effects*
  • Cell Death / physiology
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • DNA-Binding Proteins / genetics*
  • Dizocilpine Maleate / pharmacology
  • Early Growth Response Protein 1
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Space / enzymology
  • Gene Expression / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Genes, Immediate-Early / physiology
  • Immediate-Early Proteins*
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • N-Methylaspartate / pharmacology
  • Neurons / cytology*
  • Neurons / physiology
  • Neurotoxins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics*
  • Zinc / pharmacology*

Substances

  • Antisense Elements (Genetics)
  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Immediate-Early Proteins
  • Ionophores
  • Neurotoxins
  • Transcription Factors
  • Ionomycin
  • N-Methylaspartate
  • Dizocilpine Maleate
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Zinc