Publication Abstract Display
Type: Published Manuscript
Title: Fibroblast Growth Factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway:implications for neuroprotection.
Authors: Hashimoto M, Sagara Y, Langford D, Everall IP, Mallory M, Everson A, Digicaylioglu M, Masliah E
Contact: Department of Neurosciences, University of California San Diego, La Jolla, California 92093-0624, USA.
Year: 2002
Publication: The Journal of Biological Chemistry
Volume: 277 Issue: 36 Pages: 32985-91
Abstract:We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependentinactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.
Funding: NIA:AG AG01029, NIDA:DA DA12065, NIMH:MH MH45294, NIMH:MH MH58164, NIMH:MH MH59745, NIMH:MH MH62963
Keywords: 1-Phosphatidylinositol 3-Kinase, Adenoviridae, Animals, Blotting, Western, Ca(2+)-Calmodulin Dependent Protein Kinase, Cell Death, Cell Line, Cell Survival, Cells, Cultured, Cytoskeletal Proteins, DNA Fragmentation, Fibroblast Growth Factor 1, Genetic Vectors, Glutamic Acid, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Heparin Lyase, Humans, Immunohistochemistry, Microscopy, Confocal, Microscopy, Fluorescence, Models, Biological, Neurons, Neuroprotective Agents, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Rats, Recombinant Proteins, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Serine, Signal Transduction, Time Factors, Trans-Activators, beta Catenin

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