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© The Rockefeller University Press, 0021-9525/2001//997 $5.00
The Journal of Cell Biology, Volume 152, Number 5, , 2001 997-1006

Regulation of Antioxidant Metabolism by Translation Initiation Factor 2

^a Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037
^b Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037
The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037.(858) 453-4100, ext

Oxidative stress and highly specific decreases in glutathione (GSH) are associated with nerve cell death in Parkinson's disease. Using an experimental nerve cell model for oxidative stress and an expression cloning strategy, a gene involved in oxidative stress–induced programmed cell death was identified which both mediates the cell death program and regulates GSH levels. Two stress-resistant clones were isolated which contain antisense gene fragments of the translation initiation factor (eIF)2 and express a low amount of eIF2. Sensitivity is restored when the clones are transfected with full-length eIF2; transfection of wild-type cells with the truncated eIF2 gene confers resistance. The phosphorylation of eIF2 also results in resistance to oxidative stress. In wild-type cells, oxidative stress results in rapid GSH depletion, a large increase in peroxide levels, and an influx of Ca²⁺. In contrast, the resistant clones maintain high GSH levels and show no elevation in peroxides or Ca²⁺ when stressed, and the GSH synthetic enzyme -glutamyl cysteine synthetase (GCS) is elevated. The change in GCS is regulated by a translational mechanism. Therefore, eIF2 is a critical regulatory factor in the response of nerve cells to oxidative stress and in the control of the major intracellular antioxidant, GSH, and may play a central role in the many neurodegenerative diseases associated with oxidative stress.

Key Words: oxidative stress • glutathione • eIF2 • resistance • glutamate

© 2001 The Rockefeller University Press

Abbreviations used in this paper: AD, Alzheimer's disease; DCF, dichlorofluorescein; eIF, translation initiation factor; GSH, glutathione; GCS, gamma-glutamyl cysteine synthetase; MTT, 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide; PCD, programmed cell death; PD, Parkinson's disease; ROS, reactive oxygen species.

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