Abstract
Growth factor-dependent survival of a variety of mammalian cells is dependent on the activation of phosphatidylinositol (PI) 3-kinase and its downstream effector, the protein kinase Akt. Glycogen synthase kinase-3 (GSK-3) has been previously identified as a physiological target of Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell survival. Overexpression of catalytically active GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dominant-negative GSK-3 prevented apoptosis following inhibition of PI 3-kinase. GSK-3 thus plays a critical role in regulation of apoptosis and represents a key downstream target of the PI 3-kinase/Akt survival signaling pathway.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cell Survival / physiology*
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Chromones / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Gene Expression Regulation / physiology
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Microscopy, Fluorescence
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Morpholines / pharmacology
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Nerve Growth Factors / pharmacology
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Oligopeptides / pharmacology
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PC12 Cells
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / physiology
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Rats
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Transfection / genetics
Substances
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Chromones
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Cysteine Proteinase Inhibitors
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Morpholines
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Nerve Growth Factors
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Oligopeptides
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Phosphoinositide-3 Kinase Inhibitors
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aspartyl-glutamyl-valyl-aspartal
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Glycogen Synthase Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3