The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change.
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.
Yamaguchi
H
H
Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Wang
H G
HG
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007377:Interleukin-3 / Q000172:deficiency / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D007377:Interleukin-3; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C494814:BID protein, human; C429293:SH3GLB1 protein, human; C505407:CASP3 protein, human