Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells: role of Akt.
Insulin-like growth factor I (IGF-I) is involved in the proliferation and differentiation of adult neural progenitor cells; however, the underlying mechanism is not clear. We analysed the involvement of the phosphatidylinositol 3-kinase/Akt and MEK/extracellular signal-regulated kinase (ERK) pathways in the IGF-I-mediated proliferation of rat neural progenitor cells. Stimulation of neural progenitor cells with IGF-I enhanced the phosphorylation of Akt but not ERK. Cell proliferation assay demonstrated that 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (phosphoinositide 3-kinase inhibitor) but not 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene (U0126) (ERK inhibitor) inhibited the IGF-I-induced survival of cells, whereas fibroblast growth factor 2 (FGF-2) enhanced the IGF-I-mediated survival of cells. Consistent with the cell proliferation assay, 5'bromo-2-deoxy-uridine incorporation studies established a negative role for IGF-I in proliferation. However, FGF-2 (ERK activator) in the presence of IGF-I (Akt activator) increased the proliferation of cells. Accordingly, stimulation of the ERK pathway by FGF-2 induced the expression of cyclin D1, which is essential for the entry of cells into cell cycle, and IGF-I in the presence of FGF-2 up-regulated the expression of cyclin D1. IGF-I in the absence or presence of FGF-2 increased the phosphorylation of glycogen synthase kinase, thus supporting its role in the survival of neural progenitor cells. To further confirm the role of ERK activation in the proliferation, we cultured cells in FGF-2 + IGF-I-containing medium in the presence and absence of U0126 (ERK inhibitor), and showed the inhibition of nestin expression in U0126-treated cells. The decrease in the cyclin D1 content in conjunction with the inhibition of nestin expression by ERK inhibitor confirms the role of ERK in the proliferation of cells.
Kalluri
Haviryaji S G
HS
Department of Neurological Surgery, University of Wisconsin, Madison, WI 53792, USA.
Vemuganti
Raghu
R
Dempsey
Robert J
RJ
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008954:Models, Biological; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013234:Stem Cells / Q000502:physiology*
D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D001973:Bromodeoxyuridine