Akt phosphorylation and NFkappaB activation are counterregulated under conditions of oxidative stress.
This study was designed to elucidate the mechanisms involved in elevated cell death arising from an altered endogenous oxidant state. Increased levels of cell death were detected in cells lacking Gpx1 following the addition of exogenous H2O2. This increased apoptosis correlated with a down-regulation in the activation of the PI(3)K-Akt survival pathway. The importance of this pathway in protecting against H2O2-induced cell death was highlighted by the increased susceptibility of wild-type cells to apoptosis when treated with the PI(3)K inhibitor, LY294002. Activation of the oxidative stress sensitive transcription factor, NFkappaB, was elevated in the Gpx1-/- cells. Significantly, NFkappaB activation could be increased in wild-type cells through the addition of dominant-negative Akt. Therefore, our results suggest that the increased susceptibility of Gpx1-/- cells to H2O2-induced apoptosis can be attributed in part to diminished activation of Akt despite an up-regulation in the activation of the prosurvival NFkappaB. Thus, the PI(3)K-Akt and NFkappaB pathways can act independently of each other in an endogenous model of oxidative stress.
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Melbourne, Victoria, Australia.
Juliet M
JM
Taylor
Peter J
PJ
Crack
Jodee A
JA
Gould
Uğur
U
Ali
Paul J
PJ
Hertzog
Rocco C
RC
Iannello
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology
D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D016328:NF-kappa B; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt