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.
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.
Park
J A
JA
National Creative Research Initiative Center for the Study of CNS Zinc and Department of Neurology, University of Ulsan College of Medicine, Seoul, Korea.
Koh
J Y
JY
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000502:physiology; D017874:Immediate-Early Proteins; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015032:Zinc / Q000494:pharmacology*
D016375:Antisense Elements (Genetics); D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017874:Immediate-Early Proteins; D007476:Ionophores; D009498:Neurotoxins; D014157:Transcription Factors; D015759:Ionomycin; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015032:Zinc