Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death.
Oxidative stress induced by glutathione depletion in the mouse HT22 neuroblastoma cell line and embryonic rat immature cortical neurons causes a delayed, sustained activation of extracellular signal-regulated kinase (ERK) 1/2, which is required for cell death. This sustained activation of ERK1/2 is mediated primarily by a selective inhibition of distinct ERK1/2-directed phosphatases either by enhanced degradation (i.e., for mitogen-activated protein kinase phosphatase-1) or as shown here by reductions in enzymatic activity (i.e., for protein phosphatase type 2A). The inhibition of ERK1/2 phosphatases in HT22 cells and immature neurons subjected to glutathione depletion results from oxidative stress because phosphatase activity is restored in cells treated with the antioxidant butylated hydroxyanisole. This leads to reduced ERK1/2 activation and neuroprotection. Furthermore, an increase in free intracellular zinc that accompanies glutathione-induced oxidative stress in HT22 cells and immature neurons contributes to selective inhibition of ERK1/2 phosphatase activity and cell death. Finally, ERK1/2 also functions to maintain elevated levels of zinc. Thus, the elevation of intracellular zinc within neurons subjected to oxidative stress can trigger a robust positive feedback loop operating through activated ERK1/2 that rapidly sets into motion a zinc-dependent pathway of cell death.
Ho
Yeung
Y
Department of Neuroscience, University of Pittsburgh School of Medicine, 7041 BST 3, 3501 Fifth Ave., Pittsburgh, PA 15261, USA.
Samarasinghe
Ranmal
R
Knoch
Megan E
ME
Lewis
Marcia
M
Aizenman
Elias
E
DeFranco
Donald B
DB
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D004622:Embryo, Mammalian / Q000166:cytology; D049410:Luciferases, Renilla / Q000032:analysis / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015032:Zinc / Q000494:pharmacology*
D049410:Luciferases, Renilla; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054639:Mitogen-Activated Protein Kinase Phosphatases; D015032:Zinc