The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change

Oncogene. 2001 Nov 22;20(53):7779-86. doi: 10.1038/sj.onc.1204984.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Adaptor Proteins, Signal Transducing*
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line
  • Cell Survival
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Interleukin-3 / deficiency
  • Interleukin-3 / metabolism
  • Membrane Potentials
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2*
  • bcl-2-Associated X Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • BAX protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • Interleukin-3
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • SH3GLB1 protein, human
  • bcl-2-Associated X Protein
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases