{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:18:53Z","timestamp":1788355133398,"version":"build-2803163510"},"reference-count":75,"publisher":"SAGE Publications","issue":"18","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine\/glutamate antiporter system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    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\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    PI3Ks induce system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    through glycogen synthase kinase 3\u03b2 (GSK-3\u03b2) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2\u03b1 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.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:<\/jats:italic>\n                    <\/jats:bold>\n                    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-3\u03b2, which, ultimately, leads to the induction of the cystine\/glutamate antiporter system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    . Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    PI3K-regulated system x\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    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.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                    20: 2907\u20132922.\n                  <\/jats:p>","DOI":"10.1089\/ars.2013.5455","type":"journal-article","created":{"date-parts":[[2013,11,12]],"date-time":"2013-11-12T13:29:24Z","timestamp":1384262964000},"page":"2907-2922","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":62,"title":["Phosphoinositide 3-Kinases Upregulate System x\n                    <sub>c<\/sub>\n                    <sup>\u2212<\/sup>\n                    <i>via<\/i>\n                    Eukaryotic Initiation Factor 2\u03b1 and Activating Transcription Factor 4\u2009\u2013\u2009A Pathway Active in Glioblastomas and Epilepsy"],"prefix":"10.1177","volume":"20","author":[{"given":"Jan","family":"Lewerenz","sequence":"first","affiliation":[{"name":"Ulm 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