Abstract
The serine-threonine kinase Akt exerts its anti-apoptotic effects through several downstream targets, including the pro-apoptotic Bc1-2 family member Bad, Forkhead transcription factors, and the cyclic AMP response element-binding protein (CREB). In this report we demonstrate that Akt inhibits a conformational change in the pro-apoptotic Bax protein and its translocation to mitochondria, thus preventing the disruption of the mitochondrial inner membrane potential (DeltaPsi(m)), caspase-3 activation, and apoptosis in pre-B hematopoietic cells FL5.12 following interleukin-3 (IL-3) withdrawal. Inhibition of PI-3 kinase, but not MAPK kinase, promotes this conformational change in Bax. Moreover, overexpression of Akt suppresses the relocalization of GFP-Bax to mitochondria and apoptosis in Hela cells induced by the DNA-damaging agent methyl methanesulphonate. However, Akt does not abolish the ability of a conformationally changed Bax mutant, GFP-Bax (DeltaS184), to translocate to mitochondria and to induce apoptosis. These findings indicate that Akt exerts its anti-apoptotic effects in cells at a premitochondrial stage, at least in part, by inhibiting Bax conformational change and its redistribution to the mitochondrial membranes.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Adaptor Proteins, Signal Transducing*
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Apoptosis*
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / metabolism
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Line
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Cell Survival
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Enzyme Activation
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HeLa Cells
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Humans
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Interleukin-3 / deficiency
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Interleukin-3 / metabolism
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Membrane Potentials
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Mitochondria / enzymology
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Binding
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Protein Conformation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2*
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bcl-2-Associated X Protein
Substances
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Adaptor Proteins, Signal Transducing
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Carrier Proteins
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Caspase Inhibitors
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Interleukin-3
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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SH3GLB1 protein, human
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bcl-2-Associated X Protein
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3-Phosphoinositide-Dependent Protein Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase Kinases
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CASP3 protein, human
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Caspase 3
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Caspases