Phosphoinositide 3-Kinases Upregulate System x c − via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4 – A Pathway Active in Glioblastomas and Epilepsy
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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.
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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 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [89]
Cites
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
Schafer, F. Q., & Buettner, G. R. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00480-4 · Cited by 4,587 · see citing works
An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., Calfon, M. A., Sadri, N., Yun, C., Popko, B., Paules, R. S., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00105-9 · Cited by 3,336 · see citing works
Regulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells
Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R. C., Schapira, M., & Ron, D. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00108-8 · Cited by 3,281 · see citing works
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316 · see citing works
A molecular mechanism for the effect of lithium on development.
Klein, P. S., & Melton, D. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8455 · Cited by 2,305 · see citing works
The multifaceted roles of glycogen synthase kinase 3β in cellular signaling
Grimes, C. A., & Jope, R. S. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(01)00011-9 · Cited by 1,429 · see citing works
Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
Scheuner, D. L., Song, B., McEwen, E. L., Liu, C., Laybutt, D. R., Gillespie, P. J., Saunders, T. L., Bonner‐Weir, S., & Kaufman, R. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00265-9 · Cited by 1,355 · see citing works
Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L., & COYLE, J. T. (1989) · Neuron · doi:10.1016/0896-6273(89)90043-3 · Cited by 1,033 · see citing works
Glutathione : chemical, biochemical, and medical aspects
Dolphin, D., Avramović, O., & Poulson, R. (1989) · Medical Entomology and Zoology · Cited by 760 · see citing works
Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., & Cuadrado, A. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01204-10 · Cited by 759 · see citing works
Self-citationSun, P., Enslen, H., Myung, P. S., & Maurer, R. A. (1994) · Genes & Development · doi:10.1101/gad.8.21.2527 · Cited by 736 · see citing works
ER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Bi, M., Naczki, C., Koritzinsky, M., Fels, D. R., Blais, J. D., Hu, N., Harding, H. P., Novoa, I., Varia, M. A., Raleigh, J. A., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600777 · Cited by 732 · see citing works
Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., & Hayes, J. D. (2013) · Oncogene · doi:10.1038/onc.2012.388 · Cited by 657 · see citing works
Self-citationATF4-dependent transcription mediates signaling of amino acid limitation
Kilberg, M. S., Shan, J., & Su, N. Y. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.05.008 · Cited by 595 · see citing works
PI 3-kinase p110β: a new target for antithrombotic therapy
Jackson, S. P., Schoenwaelder, S. M., Goncalves, I., Nesbitt, W. S., Yap, C. L., Wright, C. E., Kenche, V. B., Anderson, K. E., Dopheide, S. M., Yuan, Y., et al. (2005) · Nature Medicine · doi:10.1038/nm1232 · Cited by 582 · see citing works
Glutamate release by primary brain tumors induces epileptic activity
Buckingham, S. C., Campbell, S. L., Haas, B. R., Montana, V., Robel, S., Ogunrinu, T., & Sontheimer, H. (2011) · Nature Medicine · doi:10.1038/nm.2453 · Cited by 578 · see citing works
Targeting phosphoinositide 3-kinase—Moving towards therapy
Marone, R., Cmiljanović, V., Giese, B., & Wymann, M. P. (2007) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2007.10.003 · Cited by 548 · see citing works
Sasaki, H., Sato, H., Kuriyama-Matsumura, K., Sato, K., Maebara, K., Wang, H., Tamba, M., Itoh, K., Yamamoto, M. P., & Bannai, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208704200 · Cited by 544 · see citing works
Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity
Hardingham, G. E., Arnold, F. J. L., & Bading, H. (2001) · Nature Neuroscience · doi:10.1038/85109 · Cited by 537 · see citing works
Self-citationSynaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Papadia, S., Soriano, F. X., Léveillé, F., Martel, M.-A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2071 · Cited by 498 · see citing works
Self-citationIdentification of Activating Transcription Factor 4 (ATF4) as an Nrf2-interacting Protein
He, C. H., Gong, P., Hu, B., Stewart, D., Choi, M. E., Choi, A. M. K., & Alam, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101198200 · Cited by 473 · see citing works
Eukaryotic Initiation Factor 2 Phosphorylation and Translational Control in Metabolism
Baird, T. D., & Wek, R. C. (2012) · Advances in Nutrition · doi:10.3945/an.112.002113 · Cited by 470 · see citing works
Exploring the specificity of the PI3K family inhibitor LY294002
Gharbi, S., Zvelebil, M., Shuttleworth, S. J., Hancox, T. C., Saghir, N., Timms, J. F., & Waterfield, M. D. (2007) · Biochemical Journal · doi:10.1042/bj20061489 · Cited by 463 · see citing works
McMahon, M. J., Lamont, D. J., Beattie, K. A., & Hayes, J. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007387107 · Cited by 445 · see citing works
Self-citationKaufman, R. J., Davies, M. V., Pathak, V. K., & Hershey, J. W. B. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.3.946-958.1989 · Cited by 395 · see citing works
eIF2 and the control of cell physiology
Proud, C. G. (2004) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2004.11.004 · Cited by 378 · see citing works
Blume‐Jensen, P., Janknecht, R., & Hunter, T. R. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70302-1 · Cited by 360 · see citing works
Protein kinase C activation inhibits glutamate-induced cytotoxicity in a neuronal cell line
Davis, J. B., & Maher, P. A. (1994) · Brain Research · doi:10.1016/0006-8993(94)90334-4 · Cited by 358 · see citing works
Self-citationAutocrine Glutamate Signaling Promotes Glioma Cell Invasion
Lyons, S. A., Chung, W. J., Weaver, A. K., Ogunrinu, T., & Sontheimer, H. W. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2034 · Cited by 342 · see citing works
The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death
Banjac, A., Perisic, T., Sato, H., Seiler, A., Bannai, S., Weiss, N., Kölle, P., Tschoep, K., Issels, R. D., Daniel, P. T., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210796 · Cited by 324 · see citing works
Self-citationInhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
Chung, W. J., Lyons, S. A., Nelson, G. M., Hamza, H., Gladson, C. L., Gillespie, G. Y., & Sontheimer, H. W. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.5258-04.2005 · Cited by 316 · see citing works
Oncogenic Mutations of PIK3CA in Human Cancers
Samuels, Y., & Waldman, T. (2010) · Current Topics in Microbiology and Immunology · doi:10.1007/82_2010_68 · Cited by 291 · see citing works
Romano, P. R., Garcia-Barrio, M. T., Zhang, X., Wang, Q., Taylor, D. R., Zhang, F., Herring, C., Mathews, M. B., Qin, J., & Hinnebusch, A. G. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.4.2282 · Cited by 272 · see citing works
Regulation of protein synthesis by insulin
Proud, C. G. (2006) · Biochemical Society Transactions · doi:10.1042/bst20060213 · Cited by 270 · see citing works
Knobbe-Thomsen, C. B., & Reifenberger, G. (2003) · Brain Pathology · doi:10.1111/j.1750-3639.2003.tb00481.x · Cited by 236 · see citing works
Lee, J., Hanson, J. M., Chu, W. A., & Johnson, J. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100734200 · Cited by 227 · see citing works
Nuclear Translocation of fibroblast growth factor (FGF) receptors in response to FGF-2.
Maher, P. A. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.134.2.529 · Cited by 224 · see citing works
Self-citationBundel, D. D., Schallier, A., Loyens, E., Fernando, R. N., Miyashita, H., Liefferinge, J. V., Vermoesen, K., Bannai, S., Sato, H., Michotte, Y. M., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5465-10.2011 · Cited by 193 · see citing works
Self-citationSavaskan, N. E., Heckel, A., Hahnen, E., Engelhorn, T., Doerfler, A., Ganslandt, O., Nimsky, C., Buchfelder, M., & Eyüpoglu, I. Y. (2008) · Nature Medicine · doi:10.1038/nm1772 · Cited by 192 · see citing works
Rutkowski, D. T., & Kaufman, R. J. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00100-x · Cited by 192 · see citing works
Quesada, A., Lee, B. Y., & Micevych, P. E. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20609 · Cited by 187 · see citing works
Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation
Sato, H., Nomura, S., Maebara, K., Sato, K., Tamba, M., & Bannai, S. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.10.009 · Cited by 176 · see citing works
Lewerenz, J., Albrecht, P., Tien, M. T., Henke, N., Karumbayaram, S., Kornblum, H. I., Wiedau‐Pazos, M., Schubert, D., Maher, P. A., & Methner, A. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06347.x · Cited by 174 · see citing works
Self-citationLewerenz, J., & Maher, P. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807325200 · Cited by 173 · see citing works
Self-citationGlutamate is associated with a higher risk of seizures in patients with gliomas
Yuen, T., Morokoff, A. P., Bjorksten, A. R., D’Abaco, G. M., Paradiso, L., Finch, S. J., Wong, D., Reid, C. A., Powell, K. L., Drummond, K. J., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e318266fa89 · Cited by 173 · see citing works
GCN2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation
Jiang, H.-Y., & Wek, R. C. (2005) · Biochemical Journal · doi:10.1042/bj20041164 · Cited by 169 · see citing works
Adams, C. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610510200 · Cited by 165 · see citing works
Lewerenz, J., Klein, M., & Methner, A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03921.x · Cited by 164 · see citing works
Self-citationJohnson, D. A., Andrews, G. K., Xu, W., & Johnson, J. A. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00913.x · Cited by 156 · see citing works
Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review)
Libra, M. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1312 · Cited by 140 · see citing works
Lü, B., Jiang, Y. J., Zhou, Y., Xu, F. Y., Hatch, G. M., & Choy, P. C. (2005) · Biochemical Journal · doi:10.1042/bj20041348 · Cited by 127 · see citing works
Early Events in M-CSF Receptor Signaling
Bourette, R. P., & Rohrschneider, L. R. (2000) · Growth Factors · doi:10.3109/08977190009001065 · Cited by 125 · see citing works
Shen, J., Wu, Y., Xu, J., Zhang, J., Sinclair, S. H., Yanoff, M., Xu, G., Li, W., & Xu, G. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3544 · Cited by 123 · see citing works
Liang, H., Pei, D., Zhang, Q., Guan, Q., & Zhang, G. (2005) · Brain Research · doi:10.1016/j.brainres.2005.05.043 · Cited by 118 · see citing works
Increased xCT Expression Correlates With Tumor Invasion and Outcome in Patients With Glioblastomas
Takeuchi, S., Wada, K., Toyooka, T., Shinomiya, N., Shimazaki, H., Nakanishi, K., Nagatani, K., Otani, N., Osada, H., Uozumi, Y., et al. (2012) · Neurosurgery · doi:10.1227/neu.0b013e318276b2de · Cited by 102 · see citing works
Activating transcription factor 4 regulates osteoclast differentiation in mice
Cao, H., Yu, S., Yao, Z., Galson, D. L., Jiang, Y., Zhang, X., Fan, J., Lu, B., Guan, Y., Luo, M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42106 · Cited by 97 · see citing works
Hypoxia Increases the Dependence of Glioma Cells on Glutathione
Ogunrinu, T., & Sontheimer, H. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.161190 · Cited by 96 · see citing works
Li, L., Xu, B., Zhu, Y., Chen, L., Sokabe, M., & Chen, L. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.02.009 · Cited by 95 · see citing works
Gupta, K., Patani, R., Baxter, P. S., Serio, A., Story, D., Tsujita, T., Hayes, J. D., Pedersen, R. A., Hardingham, G. E., & Chandran, S. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.154 · Cited by 86 · see citing works
Self-citationMubarak, B. R. A., Soriano, F. X., & Hardingham, G. E. (2009) · Channels · doi:10.4161/chan.3.4.9381 · Cited by 82 · see citing works
Self-citationLewerenz, J., Sato, H., Albrecht, P., Henke, N., Noack, R., Methner, A., & Maher, P. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.165 · Cited by 74 · see citing works
Self-citationBerger, R. S., Jennewein, C., Marschall, V., Karl, S., Cristofanon, S., Wagner, L., Vellanki, S. H., Hehlgans, S., Rödel, F., Debatin, K., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0218 · Cited by 71 · see citing works
Self-citationSweeney, G., Garg, R. R., Ceddia, R. B., Li, D., Ishiki, M., Somwar, R., Foster, L. J., Neilsen, P. O., Prestwich, G. D., Rudich, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402897200 · Cited by 66 · see citing works
Sun, X., Yao, H., Douglas, R. M., Gu, X. Q., Wang, J., & Haddad, G. G. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06450.x · Cited by 54 · see citing works
Time-dependent changes in striatal xCT protein expression in hemi-Parkinson rats
Massie, A., Schallier, A., Mertens, B., Vermoesen, K., Bannai, S., Sato, H., Smolders, I. J., & Michotte, Y. M. (2008) · Neuroreport · doi:10.1097/wnr.0b013e328312181c · Cited by 51 · see citing works
Self-citationLewerenz, J., Letz, J., & Methner, A. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02019.x · Cited by 46 · see citing works
Self-citationA novel approach to enhancing cellular glutathione levels
Maher, P. A., Lewerenz, J., Lozano, C., & Torres, J. L. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05620.x · Cited by 44 · see citing works
Self-citationDissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas
Savaskan, N. E., Seufert, S., Hauke, J., Tränkle, C., Eyüpoglu, I. Y., & Hahnen, E. (2010) · Oncogene · doi:10.1038/onc.2010.391 · Cited by 40 · see citing works
Insulin Signaling and the General Amino Acid Control Response
Malmberg, S. E., & Adams, C. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801331200 · Cited by 40 · see citing works
Gorter, J. A., Zurolo, E., Iyer, A. M., Fluiter, K., van Vliet, E. A., Baayen, J. C., & Aronica, E. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02678.x · Cited by 34 · see citing works
Self-citationEffect of insulin on the activity of amino acid transport systems in cultured human fibroblasts
Longo, N., Franchi‐Gazzola, R., Bussolati, O., Dall’Asta, V., Foà, P. P., Guidotti, G., & Gazzola, G. C. (1985) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(85)90093-x · Cited by 27 · see citing works
Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity
Sims, B., Clarke, M., Njah, W., Hopkins, E. S., & Sontheimer, H. W. (2010) · Brain Research · doi:10.1016/j.brainres.2010.01.040 · Cited by 25 · see citing works
Inageda, K. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.040 · Cited by 21 · see citing works
Functional upregulation of system xc− by fibroblast growth factor-2
Liu, X., Resch, J. M., Rush, T., & Lobner, D. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.09.019 · Cited by 19 · see citing works
Pauly, K., Fritz, K., Furey, A., & Lobner, D. (2011) · Journal of Endodontics · doi:10.1016/j.joen.2011.03.031 · Cited by 10 · see citing works
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Weiland, A., Wang, Y., Wu, W., Lan, X., Han, X., Li, Q., & Wang, J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1403-3 · Cited by 469 · see citing works
Sato, M., Kusumi, R., Hamashima, S., Kobayashi, S., Sasaki, S., Komiyama, Y., Izumikawa, T., Conrad, M., Bannai, S., & Sato, H. (2018) · Scientific Reports · doi:10.1038/s41598-018-19213-4 · Cited by 409 · see citing works
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Self-citationMeng-Shian, C., Wang, S., Hsu, C., Yin, P., Yeh, T.-S., Lee, H., & Tseng, L. (2017) · Oncotarget · doi:10.18632/oncotarget.23055 · Cited by 299 · see citing works
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Castilho, B. A., Shanmugam, R., da Silva, R. C., Ramesh, R., Himme, B. M., & Sattlegger, E. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.04.006 · Cited by 303 · see citing works
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Li, S., Lu, Z., Sun, R., Guo, S., Gao, F., Cao, B., & Aa, J. (2022) · Cancers · doi:10.3390/cancers14133059 · Cited by 85 · see citing works
Identification of GSK-3 as a potential therapeutic entry point for epilepsy.
Aourz, N., Serruys, A.-S. K., Chabwine, J. N., Balegamire, P. B., Afrikanova, T., Edrada-Ebel, R., Grey, A. I., Kamuhabwa, A. R., Walrave, L., Esguerra, C. V., et al. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00281 · Cited by 49 · see citing works
Self-citationDysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspective
Alcoreza, O. B., Patel, D. C., Tewari, B. P., & Sontheimer, H. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.652159 · Cited by 44 · see citing works
Comparative analysis of antibodies to xCT (Slc7a11): Forewarned is forearmed
Liefferinge, J. V., Bentea, E., Demuyser, T., Albertini, G., Follin-Arbelet, V. V., Holmseth, S., Merckx, E., Sato, H., Aerts, J. L., Smolders, I. J., et al. (2015) · The Journal of Comparative Neurology · doi:10.1002/cne.23889 · Cited by 44 · see citing works
Self-citationControl of neuronal excitability by GSK-3beta: epilepsy and beyond.
Jaworski, T. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118745 · Cited by 43 · see citing works
D’Angelo, B., Ek, C. J., Sun, Y., Zhu, C., Sandberg, M., & Mallard, C. E. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.09.017 · Cited by 41 · see citing works
Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma
Hills, K., Kostarelos, K., & Wykes, R. C. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.903115 · Cited by 42 · see citing works
Multiple Roles of the Stress Sensor GCN2 in Immune Cells
Zhao, C.-X., Guo, H., Hou, Y.-X., Lei, T., Wei, D., & Zhao, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054285 · Cited by 38 · see citing works
Non-canonical Keap1-independent activation of Nrf2 in astrocytes by mild oxidative stress
Al-Mubarak, B. R., Bell, K. F. S., Chowdhry, S., Meakin, P. J., Baxter, P. S., McKay, S., Dando, O., Ashford, M. L. J., Gazaryan, I. G., Hayes, J. D., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102158 · Cited by 39 · see citing works
Self-citationEffects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice
Fang, F., Chen, D., Yu, P., Qian, W., Zhou, J., Liu, J., Gao, R., Wang, J., & Xiao, H. (2015) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2015.01.017 · Cited by 37 · see citing works
Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models
Leclercq, K., Liefferinge, J. V., Albertini, G., Neveux, M., Dardenne, S., Mairet‐Coello, G., Vandenplas, C., Deprez, T., Chong, S., Foerch, P., et al. (2019) · Epilepsia · doi:10.1111/epi.16055 · Cited by 35 · see citing works
Self-citationSaturated fatty acids entrap PDX1 in stress granules and impede islet beta cell function
Zhang, M., Yang, C., Zhu, M., Li, Q., Luo, Y., Cheng, H., Geng, R., Xu, X., Cheng, Q., & Liu, Y. (2021) · Diabetologia · doi:10.1007/s00125-021-05389-4 · Cited by 34 · see citing works
Merckx, E., Albertini, G., Paterka, M., Jensen, C., Albrecht, P., Dietrich, M., Liefferinge, J. V., Bentea, E., Verbruggen, L., Demuyser, T., et al. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0787-0 · Cited by 33 · see citing works
Self-citationNrf2 target genes can be controlled by neuronal activity in the absence of Nrf2 and astrocytes
Deighton, R. F., Márkus, N. M., Al-Mubarak, B., Bell, K. F. S., Papadia, S., Meakin, P. J., Chowdhry, S., Hayes, J. D., & Hardingham, G. E. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402097111 · Cited by 30 · see citing works
Self-citationTargeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation
Baxter, P. S., Márkus, N. M., Dando, O., He, X., Al-Mubarak, B. R., Qiu, J., & Hardingham, G. E. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03507-z · Cited by 29 · see citing works
Self-citationWang, X., Li, Y., Wang, H., Zhu, M., Guo, D., Wang, G., Gao, Y., Yang, Z. R., Tang, L., Yang, C., et al. (2017) · Toxicology in Vitro · doi:10.1016/j.tiv.2017.06.026 · Cited by 28 · see citing works
Wang, H., Lei, X., Zhang, Z., Ommati, M. M., Tang, Z., & Yuan, J. (2022) · Toxicology · doi:10.1016/j.tox.2022.153192 · Cited by 27 · see citing works
Moreira‐Filho, C. A., Bando, S. Y., Bertonha, F. B., Iamashita, P., Silva, F. N., Costa, L. D. F., da Silva, A. V., Castro, L. H. M., & Tzu, W. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0128174 · Cited by 25 · see citing works
Shan, J., Donelan, W., Hayner, J. N., Zhang, F., Dudenhausen, E. E., & Kilberg, M. S. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.12.013 · Cited by 25 · see citing works
Shi, J., He, Y., Hewett, S. J., & Hewett, J. A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.697821 · Cited by 23 · see citing works
Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures
Lin, R., Jones, N. C., & Kwan, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103676 · Cited by 23 · see citing works
Burnside, S. W., & Hardingham, G. E. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170013 · Cited by 21 · see citing works
Self-citationSulfasalazine decreases mouse cortical hyperexcitability
Alcoreza, O. B., Tewari, B. P., Bouslog, A., Savoia, A., Sontheimer, H. W., & Campbell, S. L. (2019) · Epilepsia · doi:10.1111/epi.16073 · Cited by 21 · see citing works
Castro-Torres, R. D., Ureña‐Guerrero, M. E., Chacón, L. M. M., Pedré, L. L., Estupiñán-Díaz, B., Rocha, L., Orozco-Suárez, S. A., Rivera-Cervantes, M. C., Alonso‐Vanegas, M., & Beas‐Zárate, C. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01519-6 · Cited by 20 · see citing works
Fang, F., Gao, Y., Wang, T., Chen, D., Liu, J., Qian, W., Cheng, J., Gao, R., Wang, J., & Xiao, H. (2016) · Toxicology Letters · doi:10.1016/j.toxlet.2016.01.007 · Cited by 19 · see citing works
Carr, M. J., González, G., Martinelli, A., Wastika, C. E., Ito, K., Orba, Y., Sasaki, M., Hall, W. W., & Sawa, H. (2019) · Virus Genes · doi:10.1007/s11262-019-01683-x · Cited by 19 · see citing works
Change of cystine/glutamate antiporter expression in ethanol-dependent rats
Peana, A. T., Muggironi, G., & Bennardini, F. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00311 · Cited by 18 · see citing works
Liefferinge, J. V., Jensen, C., Albertini, G., Bentea, E., Demuyser, T., Merckx, E., Aronica, E., Smolders, I. J., & Massie, A. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.01.080 · Cited by 18 · see citing works
Self-citationNeuronal Activity and Its Role in Controlling Antioxidant Genes
Qiu, J., Dando, O., Febery, J. A., Fowler, J. H., Chandran, S., & Hardingham, G. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21061933 · Cited by 17 · see citing works
Self-citationSears, S. M. S., Hewett, J. A., & Hewett, S. J. (2019) · Epilepsia Open · doi:10.1002/epi4.12307 · Cited by 15 · see citing works
Loewen, J. L., Albertini, G., Dahle, E. J., Sato, H., Smolders, I. J., Massie, A., & Wilcox, K. S. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.04.010 · Cited by 16 · see citing works
Self-citationAlves, S. S., da Silva-Júnior, R. M. P., Delfino-Pereira, P., Pereira, M. G. A. G., Vasconcelos, I. C., Schwaemmle, H., Mazzei, R. F., Carlos, M. L., Espreáfico, E. M., Tedesco, A. C., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02810-w · Cited by 14 · see citing works
Liang, Z., & Maher, P. A. (2022) · Antioxidants · doi:10.3390/antiox11112197 · Cited by 14 · see citing works
Self-citationKim, J.-E., Park, H., Lee, J., Kim, T.-H., & Kang, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165643 · Cited by 14 · see citing works
Synaptic Activity Regulates Mitochondrial Iron Metabolism to Enhance Neuronal Bioenergetics
Tena‐Morraja, P., Riqué‐Pujol, G., Müller‐Sánchez, C., Reina, M., Martínez-Estrada, O. M., & Soriano, F. X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24020922 · Cited by 11 · see citing works
Osuch, B., Misztal, T., Pałatyńska, K., & Tomaszewska-Zaremba, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094845 · Cited by 10 · see citing works
Emerging roles of system antiporter and its inhibition in CNS disorders
Patel, D., Kharkar, P. S., & Nandave, M. (2015) · Molecular Membrane Biology · doi:10.3109/09687688.2015.1096972 · Cited by 10 · see citing works
Rawat, K., Gautam, V., Sandhu, A., Bhatia, A., & Saha, L. (2023) · Neuroscience · doi:10.1016/j.neuroscience.2023.10.019 · Cited by 7 · see citing works
The System xc- Cystine/Glutamate Antiporter: An Exciting Target for Antiepileptogenic Therapy?
Gallagher, M. J. (2020) · Epiliepsy currents/Epilepsy currents · doi:10.1177/1535759719891983 · Cited by 7 · see citing works
Mir, M. Y., Seh, B. A., Zahra, S., & Légrádi, Á. (2025) · Brain Sciences · doi:10.3390/brainsci15080809 · Cited by 6 · see citing works
Validation of a System xc– Functional Assay in Cultured Astrocytes and Nervous Tissue Samples
Beckers, P., Lara, O., do Nascimento, I. B., Desmet, N., Massie, A., & Hermans, E. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.815771 · Cited by 6 · see citing works
Self-citationFerroptosis in Diabetic Cardiomyopathy and Atherosclerosis: Mechanisms and Clinical Prospects
Huang, W., Han, X., Meng, Z., Chen, X., Lü, A., & Cheung, K. C.-P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262110661 · Cited by 5 · see citing works
Long-term plasticity of astrocytic phenotypes and their control by neurons in health and disease
Wardlaw, K. S., & Hardingham, G. E. (2023) · Essays in Biochemistry · doi:10.1042/ebc20220090 · Cited by 4 · see citing works
Self-citationAourz, N., LEUVEN, F. V., Allaoui, W., Eeckhaut, A. V., Bundel, D. D., & Smolders, I. J. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00782 · Cited by 2 · see citing works
Self-citationInhibitors of Oxytosis/Ferroptosis: A New Class of Therapeutics for Alzheimer’s Disease
Maher, P. A. (2023) · Springer eBooks · doi:10.1007/978-3-031-39171-2_22 · Cited by 2 · see citing works
Self-citationDando, O., McQueen, J., Burr, K., Kind, P. C., Chandran, S., Hardingham, G. E., & Qiu, J. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1392408 · Cited by 1 · see citing works
Self-citationDesai, M., Singh, S. D., Nagamani, S., Malik, S., Singh, A., Kukreti, R., Kukreti, S., & Grewal, G. K. (2025) · Scientific Reports · doi:10.1038/s41598-025-02884-1 · Cited by 1 · see citing works
INTERACTOME REWIRING THROUGH CANCER-ASSOCIATED MUTATION IN GROWTH FACTOR SIGNALING PATHWAYS
Wong, C.-J. (2017) · TSpace (University of Toronto)
Intact corticostriatal function in aged system xc- - deficient mice
Pauw, L. D., Villers, A., Moore, C., Lara, O., Vanonckelen, O., Verbruggen, L., Sato, H., Bentea, E., Arckens, L., Ris, L., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03686-9
Self-citationCAPSAZEPINE ATTENUATES CANCER-INDUCED BONE PAIN BY INHIBITING GLUTAMATE RELEASE
Balenko, M. D. (2014) · MacSphere (McMaster University) · doi:10.71548/18108
- 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
- ORCID
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2014-06
- Volume
- 20
- Issue
- 18
- Pages
- 2907-2922
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- PMC
- PMC4038988
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
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