Hydrogen peroxide-induced Akt phosphorylation regulates Bax activation

Abstract

Reactive oxygen species such as hydrogen peroxide (H 2 O 2 ) are involved in many cellular processes that positively and negatively regulate cell fate. H 2 O 2 , acting as an intracellular messenger, activates phosphatidylinositol-3 kinase (PI3K) and its downstream target Akt, and promotes cell survival. The aim of the current study was to understand the mechanism by which PI3K/Akt signaling promotes survival in SH-SY5Y neuroblastoma cells. We demonstrate that PI3K/Akt mediates phosphorylation of the pro-apoptotic Bcl-2 family member Bax. This phosphorylation suppresses apoptosis and promotes cell survival. Increased survival in the presence of H 2 O 2 was blocked by LY294002, an inhibitor of PI3K activation. LY294002 prevented Bax phosphorylation and resulted in Bax translocation to the mitochondria, cytochrome c release, caspase-3 activation, and cell death. Collectively, these findings reveal a mechanism by which H 2 O 2 -induced activation of PI3K/Akt influences posttranslational modification of Bax and inactivate a key component of the cell death machinery.

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

“…Thus, it would appear that mitochondrial H 2 O 2 plays a role in reinforcing signaling programs in differentiating adipocytes. Hydrogen peroxide has also been found to induce the phosphorylation and activation of Akt and the autophosphorylation of insulin receptor, both of which play a part in the induction of adipocyte differentiation ( Papaconstantinou, 2009;Sadidi et al, 2009). Thus, it is possible that mitochondrial H 2 O 2 release serves as a positive feedback signal that prolongs the induction of adipocyte differentiation cascades.…”

Annexin A11 knockdown inhibits in vitro proliferation and enhances survival of Hca-F cell via Akt2/FoxO1 pathway and MMP-9 expression

“…4 B and C). Increased Bax/Bcl-2 ratio can lead to the release of cytochrome c and contribute to high cell apoptosis rate via caspase activation in the mitochondrial pathway [27,28]. Our data clearly suggested that Anxa11 knockdown might reduce Hca-F cell apoptosis through extrinsic apoptosis pathway.…”

Oxidative Stress Induces Neuronal Apoptosis Through Suppressing Transcription Factor EB Phosphorylation at Ser467

“…The pro-survival function of Akt/protein kinase B depends on its phosphorylation of a number of downstream targets to inhibit cell death. Multiple pro-apoptosis proteins, including Bad [42], Bax [43], caspase-9 [44], glycogen synthase kinase-3-β (GSK-3β) [45], and forkhead transcription factors [46], are also phosphorylated by Akt. Akt not only phosphorylates these pro-apoptotic proteins, but also inactivates them, and retains them in the cytoplasm to inhibit the transcription of relevant pro-apoptotic genes, thereby suppressing cell apoptosis.…”