ArticleCell death and differentiation2012
Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression.
Article in Cell death and differentiation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 62 citations in OpenAlex.
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- An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.Current drug targets · 2025Review
- Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11/xCT.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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- Melatonin Alleviates Retinal Ischemia-Reperfusion Injury by Inhibiting p53-Mediated Ferroptosis.Antioxidants (Basel, Switzerland) · 2023Article
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- The impact of SBF2 on taxane-induced peripheral neuropathy.PLoS genetics · 2022Article
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- Activating transcription factor-4 promotes neuronal death induced by Parkinson's disease neurotoxins and α-synuclein aggregates.Cell death and differentiation · 2021Article
- Functional analysis of CD44 variants and xCT in canine tumours.Veterinary medicine and science · 2021Article
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Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system x(c)(-), which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13 bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2α, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid β-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance.
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