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Cited by 272Endoplasmic Reticulum Stress and DiseaseRedox biology and oxidative stressCell death mechanisms and regulation

ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo

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Lange, Philipp S., Chavez, Juan C., Pinto, John T., Coppola, Giovanni, Sun, Chiao-Wang, Townes, Tim M., Geschwind, Daniel H., Ratan, Rajiv R.·2008·The Journal of Experimental Medicine
DOI 10.1084/jem.20071460PMC PMC2373852
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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.

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  • Known ATF4 target genes Trib3 and Chac1 were induced by 2-DG.

    “We verified that known ATF4 target genes, Tribbles 3 (Trib3), a modulator of AKT, and Chac1, a cyclohydrolase that degrades glutathione,51”

    From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [51]

    The Results section (page unavailable) reports that TRB3 mRNA is induced by HCA in an ATF4-dependent manner, supporting TRB3 as an ATF4 target. The passages found do not identify Chac1 as an ATF4 target or report induction of either gene by 2-DG; the source studies HCA-induced oxidative stress instead. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GSK2606414 significantly inhibited transcription of the ATF4 target gene Trib3 in primary neurons.

    “GSK2606414 significantly inhibited 2-DG-induced eIF2α phosphorylation (Figures 6G and 6H) and transcription of the ATF4 target gene, Trib3, in primary neurons51”

    From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [51]

    The Results (page not provided) measure TRB3 mRNA in cortical neurons and examine an ATF4-binding site in its promoter, supporting the identification of Trib3/TRB3 as an ATF4 target gene. The paper does not report treatment with GSK2606414 or show that it inhibited Trib3 transcription; that experimental result is not supported by this citation. (LLM, conf=0.88)

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Authors
Lange, P. S., Chavez, J. C., Pinto, J. T., Coppola, G., Sun, C.-W., Townes, T. M., Geschwind, D. H., & Ratan, R. R.
Affiliations
  • University of Bonn (DE)
  • Cornell University (US)
  • New York Medical College (US)
  • 6Program in Neurogenetics, Department of Neurology,
  • University of Alabama at Birmingham (US)
  • University of California, Los Angeles (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2008-05-05
Volume
205
Issue
5
Pages
1227-1242
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20071460
PMC
PMC2373852
OpenAlex
W2105818495
Cited by
272
References
62
Citations by year
2026: 15 · 2025: 16 · 2024: 17 · 2023: 19 · 2022: 17 · 2021: 21 · 2020: 12 · 2019: 18 · 2018: 19 · 2017: 9 · 2016: 17 · 2015: 17 · 2014: 20 · 2013: 16 · 2012: 13
FWCI
3.79
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
  • Touro Scholar (Touro College) (submittedVersion, cc-by-nc-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • American Heart Association
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • Burke Foundation
  • Deutsche Forschungsgemeinschaft
  • Universität zu Köln
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS040591, NS40591)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
ATF4, oxidative stress, neuronal cell death, transcription factors, glutathione depletion, ischemic stroke, infarct size, redox regulation, bZIP transcription factors, neuroprotection, stroke recovery
MeSH terms
Animals, Cell Nucleus, Cell Survival, Cells, Cultured, Cerebral Cortex, Chromatin, DNA, Neurons, Plasmids, Polymerase Chain Reaction, Leucine Zippers, Cell Death, Mice, Knockout, Oxidative Stress, Mice, Activating Transcription Factor 4

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