Involvement of phosphatidylinosiol 3-kinase/Akt on basic fibroblast growth factor-induced glial cell line-derived neurotrophic factor release from rat glioma cells.
Involvement of phosphatidylinosiol 3-kinase/Akt on basic fibroblast growth factor-induced glial cell line-derived neurotrophic factor release from rat glioma cells.
复制标题
磷脂酰肌醇 3-激酶/Akt 参与碱性成纤维细胞生长因子诱导的大鼠神经胶质瘤细胞释放神经胶质细胞系源性神经营养因子。
DOI：
10.1016/j.brainres.2012.04.057
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Tanabe K
中科院分区：
文献类型：
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作者：
溝田敏幸;辻川洋;正田丈裕;福田和彦;Takeda J.;Tanabe K
碱性成纤维细胞生长因子-2具有神经保护作用。星形胶质细胞通过释放神经营养因子来支持神经元，包括胶质细胞系衍生神经营养因子(GDNF)。成纤维细胞生长因子-2刺激星形胶质细胞GDNF的合成和释放。已有研究表明，成纤维细胞生长因子-2可诱导C6胶质瘤细胞p44/p42丝裂原活化蛋白(MAP)、应激激活蛋白激酶/c-Jun氨基末端激酶(SAPK/JNK)和p38 MAP激活，并通过P44/P42 MAP或SAPK/JNK刺激GDNF释放，但不能激活P38 MAP。在本研究中，我们探讨了成纤维细胞生长因子-2诱导C6细胞释放GDNF的确切机制。成纤维细胞生长因子2诱导AKT及其底物糖原合成酶3β(GSK3β)的磷酸化，并诱导3种MAP激酶。WORTMANNIN(磷脂酰肌醇3(PI3)-激酶抑制剂)或LY294002(另一种PI3-激酶抑制剂)可抑制成纤维细胞生长因子-2(FGF2)刺激的GDNF的释放。与对照siRNA转染组相比，PI3K下调的C6细胞由FGF2诱导的GDNF释放减少。PD98059(MEK 1/2的抑制剂)或SP600125(SAPK/JNK的抑制剂)分别抑制成纤维细胞生长因子-2诱导的p44/p42 MAP和SAPK/JNK的磷酸化，但不影响成纤维细胞生长因子-2诱导的Akt的磷酸化。Wortmannin或LY294002可减弱成纤维细胞生长因子-2诱导的Akt和Gsk3β的磷酸化，但对成纤维细胞生长因子-2诱导的p44/p42MAPK或SAPK/JNK的磷酸化无影响。这些结果有力地表明，PI3-K/Akt通路在成纤维细胞生长因子-2刺激C6胶质瘤细胞释放GDNF中起着积极的作用，而不依赖于p44/p42的MAPK或SAPK/JNK。
Basic fibroblast growth factor (FGF-2) has a neuroprotective effect. Astrocytes support neurons by releasing neurotrophic factors including glial cell line-derived neurotrophic factor (GDNF). FGF-2 stimulates GDNF synthesis in astrocytes and the release. It has been reported that FGF-2 induces the activation of p44/p42 mitogen-activated protein (MAP) kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAP kinase in C6 glioma cells, and that FGF-2 stimulates GDNF release through p44/p42 MAP kinase or SAPK/JNK, but not p38 MAP kinase. In the present study, we investigated the exact mechanism of FGF-2-induced GDNF release from C6 cells. FGF-2 induced the phosphorylation of Akt and its substrate, glycogen synthase kinase 3β (GSK3β) in addition to three MAP kinases in these cells. FGF-2-stimulated release of GDNF was suppressed by wortmannin (a phosphatidylinositol 3 (PI3)-kinase inhibitor) or LY294002 (another PI3-kinase inhibitor). The FGF-2-induced GDNF release from PI3-kinase-downregulated C6 cells was decreased compared with that in control siRNA-transfected cells. PD98059 (an inhibitor of MEK 1/2) or SP600125 (an inhibitor of SAPK/JNK), which suppressed FGF-2-induced phosphorylation of p44/p42 MAP kinase or SAPK/JNK respectively, did not affect FGF-2-induced Akt phosphorylation. Wortmannin or LY294002, which attenuated FGF-2-induced phosphorylation of Akt and GSK3β, had no effect on FGF-2-induced phosphorylation of p44/p42 MAP kinase or SAPK/JNK. These results strongly suggest that the PI3-kinase/Akt pathway plays a positive role in FGF-2-stimulated GDNF release independently of p44/p42 MAP kinase or SAPK/JNK in C6 glioma cells.