Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria.
Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway promote cell survival. The mechanism by which the serine/threonine kinase Akt prevents cell death remains unclear. We have previously shown that Akt inhibits the activity of DEVD-targeted caspases without changing the steady-state levels of Bcl-2 and Bcl-x(L). Here we show that Akt inhibits apoptosis and the processing of procaspases to their active forms by delaying mitochondrial changes in a caspase-independent manner. Akt activation is sufficient to inhibit the release of cytochrome c from mitochondria and the alterations in the inner mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members. Taken together, our results show that Akt promotes cell survival by intervening in the apoptosis cascade before cytochrome c release and caspase activation via a mechanism that is distinct from Bad phosphorylation.
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
S G
SG
Kennedy
E S
ES
Kandel
T K
TK
Cross
N
N
Hay
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000502:physiology; D003574:Cytochrome c Group / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000528:radiation effects; D007425:Intracellular Membranes / Q000648:ultrastructure; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008845:Microinjections; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008954:Models, Biological; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014466:Ultraviolet Rays; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C494821:Bad protein, rat; C494774:Bak1 protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D011505:Protein-Tyrosine Kinases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases