title: Involvement of phosphatidylinositol 3-kinase/Akt on basic fibroblast growth factor-induced glial cell line-derived neurotrophic factor release from rat glioma cells.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. kumiko-t@m2.gyao.ne.jp
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tanabe
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Miki
authors.initials: M
authors.lastname: Iida
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iida
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000819:agonists / Q000378:metabolism*; D005910:Glioma / Q000201:enzymology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002867:Chromones; D016222:Fibroblast Growth Factor 2; D051100:Glial Cell Line-Derived Neurotrophic Factor; D048670:MAP Kinase Kinase 4; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D051057:Proto-Oncogene Proteins c-akt; C495041:Gdnf protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C101691:MMK4 protein, Medicago sativa