Phosphoinositide 3-Kinases Upregulate System xc- via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4-A Pathway Active in Glioblastomas and Epilepsy
Phosphoinositide 3-Kinases Upregulate System xc- via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4-A Pathway Active in Glioblastomas and Epilepsy
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DOI：
10.1089/ars.2013.5455
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发表时间：
2014-06-01
影响因子：
6.6
通讯作者：
Maher, Pamela
中科院分区：
文献类型：
--
作者：
Lewerenz, Jan;Baxter, Paul;Maher, Pamela
目的：磷酸肌醇 3-激酶 (PI3K) 传递生长因子信号并介导细胞保护和细胞生长。胱氨酸/谷氨酸逆向转运系统x(c)(-)输入胱氨酸，同时输出谷氨酸，从而促进谷胱甘肽合成，同时增加细胞外脑谷氨酸。本研究的目的是分析生长因子和 PI3K 信号传导诱导胱氨酸/谷氨酸逆向转运蛋白系统 x(c)(-) 的途径，并证明其对神经保护、细胞生长和癫痫的生物学意义。结果：PI3Ks 通过糖原合酶激酶 3 beta (GSK-3 beta) 抑制诱导系统 x(c)(-)，全面控制非去阻遏物 2 介导的真核起始因子 2 α 磷酸化，以及随后激活转录因子 4 的翻译上调。该途径对于 PI3Ks 调节神经细胞的氧化应激抵抗和抗氧化应激至关重要。 胰岛素诱导的成纤维细胞生长。此外，该途径在人胶质母细胞瘤细胞中很活跃。此外，它在初级皮质神经元中被诱导，以响应强大的神经元活动，并在颞叶癫痫患者的海马中被诱导。创新：我们的研究结果进一步扩展了生长因子和 PI3K 如何通过向 GSK-3 beta 下游的信号网络下游添加新分支来诱导神经保护和细胞生长的概念，最终导致胱氨酸/谷氨酸逆向转运蛋白系统 x(c)(-) 的诱导。重要的是，神经元活动和癫痫海马体对这一途径的诱导表明其在癫痫中具有潜在作用。结论：PI3K调节系统x(c)(-)活性不仅通过增加半胱氨酸供应和谷胱甘肽合成参与神经细胞的应激抵抗和细胞生长，而且通过上调细胞外脑谷氨酸在肿瘤和非肿瘤相关癫痫的病理生理学中发挥作用。
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 3 beta (GSK-3 beta) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2 alpha 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-3 beta, 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.