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¹ Burke Medical Research Institute, White Plains, NY 10605
² Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021
³ Discovery Translational Medicine, Wyeth Research, Collegeville, PA 19426
⁴ Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595
⁵ Department of Human Genetics, ⁶ Program in Neurogenetics, Department of Neurology, and ⁷ Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
⁸ Department of Biochemistry and Molecular Genetics, School of Medicine and School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294
⁹ Department of Anesthesiology and Intensive Care Medicine, University of Bonn, 53127 Bonn, Germany

CORRESPONDENCE Philipp S. Lange: phl2006{at}med.cornell.edu OR Rajiv R. Ratan: rratan{at}burke.org

Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress–inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress–induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4^–/– neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4^–/– mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.

Abbreviations used: ATF4, activating transcription factor 4; BHA, butylated hydroxyanisol; BSO, buthionine sulfoximine; DCF, 2',7'-dichlorofluorescin; -GCS, -glutamylcysteine synthetase; HCA, homocysteate; MAP2, microtubule-associated protein 2; MCAo, middle cerebral artery occlusion; MOI, multiplicity of infection; ROS, reactive oxygen species; TRB3, tribbles homologue 3.

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This article has been cited by other articles:

• Lange, P. S., Chavez, J. C., Pinto, J. T., Coppola, G., Sun, C.-W., Townes, T. M., Geschwind, D. H., Ratan, R. R. (2008). ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J. Cell Biol. 181: i13-i13 [Full Text]  

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