Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells.
Insulin-like growth factor I (IGF-I) is mitogenic for several types of neuronal progenitors including cerebellar granule neuron progenitors. The present study confirms that IGF-I can function as a mitogen in purified cultures of cerebellar granule cells and identifies intracellular signal transduction molecules that mediate this mitogenesis. In cultured granule cells, IGF-I inhibits GSK-3 activity and leads to phosphorylation of serine9 an inhibitory site on GSK-3beta. Phosphoinositide 3-kinase (PI3-K) activation by IGF-I can lead to phosphorylation and inactivation of GSK-3. A PI3-K inhibitor, LY294002, completely inhibited IGF-I-induced proliferation with half-maximal inhibition occurring at a concentration (1.5 micrograms) close to its reported IC50 value for inhibition of PI3-K. Lithium chloride (LiCl), a direct inhibitor of GSK-3beta, can alone stimulate granule cell proliferation and enhance proliferation induced by IGF-I. LiCl can reverse the inhibitory effect of LY294002 on granule cell proliferation suggesting that GSK-3 inhibition may be downstream of PI3-K activation in IGF-I's mitogenic pathway. Experiments further show that the expression of a dominant active form of GSK-3beta antagonizes IGF-I-induced mitogenesis. These studies support a role for inhibition of GSK-3beta activity in the signal transduction pathway by which IGF-I regulates granule neuron progenitor proliferation.
Cui
H
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Department of Pharmacology, University of Maryland School of Medicine, 655 W. Baltimore St. Rm 4-018, Baltimore, MD 21201, USA.
Meng
Y
Y
Bulleit
R F
RF
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D013936:Thymidine / Q000494:pharmacology; D014316:Tritium
D018692:Antimanic Agents; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007334:Insulin-Like Growth Factor I; D018021:Lithium Chloride; D008934:Mitogens; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013936:Thymidine; D014316:Tritium; C079103:L 690330; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one