Cited by 66Amino Acid Enzymes and MetabolismPI3K/AKT/mTOR signaling in cancerSulfur Compounds in Biology

Phosphoinositide 3-Kinases Upregulate System x c − via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4 – A Pathway Active in Glioblastomas and Epilepsy

Open access
Lewerenz, Jan, Baxter, Paul, Kassubek, Rebecca, Albrecht, Philipp, Van Liefferinge, Joeri, Westhoff, Mike-Andrew, Halatsch, Marc-Eric, Karpel-Massler, Georg +10 more·2014·Antioxidants & Redox Signaling

Abstract

Aims: Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system x c − imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system x c − and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy. Results: PI3Ks induce system x c − through glycogen synthase kinase 3β (GSK-3β) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2α phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4. This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts. Moreover, the pathway is active in human glioblastoma cells. In addition, it is induced in primary cortical neurons in response to robust neuronal activity and in hippocampi from patients with temporal lobe epilepsy. Innovation: Our findings further extend the concepts of how growth factors and PI3Ks induce neuroprotection and cell growth by adding a new branch to the signaling network downstream of GSK-3β, which, ultimately, leads to the induction of the cystine/glutamate antiporter system x c − . Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy. Conclusion: PI3K-regulated system x c − activity is not only involved in the stress resistance of neuronal cells and in cell growth by increasing the cysteine supply and glutathione synthesis, but also plays a role in the pathophysiology of tumor- and non-tumor-associated epilepsy by up-regulating extracellular cerebral glutamate. Antioxid. Redox Signal. 20: 2907–2922.

Integrity signals

Registry

Crossref · 10.1089/ars.2013.5455

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Maternal infection in mice is sufficient to induce long-term PPI and social behavioural changes in the offspring, changes that are attributable to inflammation.

    “Epidemiological evidence points to maternal infection being a risk factor in schizophrenia 1 and maternal infection in mice is sufficient to induce long-term PPI and social behavioural changes in the offspring, changes that are attributable to inflammation 89 .”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Lewerenz, J., Baxter, P., Kassubek, R., Albrecht, P., Van Liefferinge, J., Westhoff, M.-A., Halatsch, M.-E., Karpel-Massler, G., Meakin, P. J., Hayes, J. D., Aronica, E., Smolders, I., Ludolph, A. C., Methner, A., Conrad, M., Massie, A., Hardingham, G. E., & Maher, P.
Affiliations
  • Universität Ulm (DE)
  • University of Edinburgh (GB)
  • Heinrich Heine University Düsseldorf (DE)
  • Vrije Universiteit Brussel
  • Ulm University
  • University of Dundee (GB)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Vrije Universiteit Brussel (BE)
  • University Medical Center of the Johannes Gutenberg University Mainz (DE)
  • Helmholtz Munich (DE)
  • Salk Institute for Biological Studies (US)
Corresponding author
  • Lewerenz, Jan
  • Maher, Pamela
Venue
Antioxidants & Redox Signaling
Published
2014-06
Volume
20
Issue
18
Pages
2907-2922
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
OpenAlex
W1161381116
Cited by
66
References
76
Citations by year
2025: 4 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 3 · 2015: 11 · 2014: 6
FWCI
3.12
Type
journal article
Language
en
Open access
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Site cant be reached (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Keywords
phosphatidylinositol 3-kinase, system xc-, SLC7A11, ATF4, glycogen synthase kinase-3β, glutathione synthesis, extracellular glutamate, oxidative stress resistance, neuroprotection, glioblastoma, epilepsy, temporal lobe epilepsy, neuronal activity, hippocampus
MeSH terms
Glycogen Synthase Kinase 3 beta, Cell Line, Epilepsy, Glioblastoma, Hippocampus, Humans, Neurons, Phosphorylation, Neoplastic Stem Cells, Signal Transduction, Eukaryotic Initiation Factor-2, Up-Regulation, Neuroprotective Agents, Phosphatidylinositol 3-Kinases, Amino Acid Transport System y+, Glycogen Synthase Kinase 3, Activating Transcription Factor 4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review