ArticleAntioxidants & redox signaling2014
Phosphoinositide 3-kinases upregulate system xc(-) via eukaryotic initiation factor 2α and activating transcription factor 4 - A pathway active in glioblastomas and epilepsy.
Article in Antioxidants & redox signaling, 2014. 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, 66 citations in OpenAlex.
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- Long-term plasticity of astrocytic phenotypes and their control by neurons in health and disease.Essays in biochemistry · 2023Review
- Multiple Roles of the Stress Sensor GCN2 in Immune Cells.International journal of molecular sciences · 2023Review
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- A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response.Frontiers in molecular neuroscience · 2023Review
- Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin.Antioxidants (Basel, Switzerland) · 2022Article
- The Role of SLC7A11 in Cancer: Friend or Foe?Cancers · 2022Review
- A Genetic Model of Epilepsy with a Partial Alzheimer's Disease-Like Phenotype and Central Insulin Resistance.Molecular neurobiology · 2022Article
- Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma.Frontiers in molecular neuroscience · 2022Review
- Saturated fatty acids entrap PDX1 in stress granules and impede islet beta cell function.Diabetologia · 2021Article
- Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation.Cell death & disease · 2021Article
- Validation of a System xFrontiers in cellular neuroscience · 2021Article
- Dysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspective.Frontiers in neurology · 2021Review
- The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases.Cell chemical biology · 2020Review
Corrections and comments
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Authors and funding
18 authors at 10 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsPhosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc(-) 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 xc(-) and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy.
resultsPI3Ks induce system xc(-) 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 xc(-). Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy.
conclusionPI3K-regulated system xc(-) 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.
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