NYMC Faculty Publications
ATF4 Is an Oxidative Stress–Inducible, Prodeath Transcription Factor in Neurons in Vitro and in Vivo
First Page
1227
Last Page
1242
Document Type
Article
Publication Date
5-12-2008
Department
Biochemistry and Molecular Biology
Abstract
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.
Recommended Citation
Lange, P. S., Chavez, J. C., Pinto, J. T., Coppola, G., Sun, C., Townes, T. M., . . . Ratan, R. R. (2008). ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo. The Journal of Experimental Medicine, 205(5), 1227-1242. doi:10.1084/jem.20071460
Publisher's Statement
Originally published in The Journal of Experimental Medicine. Licensed under CC-BY-NC-SA 4.0. https://doi.org/10.1084/jem.20071460
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Biological Factors Commons, Molecular Biology Commons
Comments
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