Hydrogen peroxide controls Akt activity via ubiquitination/degradation pathways
TLDR
It is demonstrated that hydrogen peroxide-induced oxidative stress regulates the activity of the anti-apoptotic protein Akt via the ubiquitin-proteasome degradation system and that H2O2-induced cytotoxicity was mediated by active Akt degradation.Abstract:
Akt is a well-established protein that regulates cell growth, survival and anti-apoptotic mechanisms. In this study, we demonstrated that hydrogen peroxide (H2O2)-induced oxidative stress regulates the activity of the anti-apoptotic protein Akt via the ubiquitin-proteasome degradation system. H2O2 induced cytotoxicity in PC12 cells and decreased the cellular protein and phosphorylation levels of Akt in a concentration- and exposure time-dependent manner. This downregulation was blocked by the proteasome inhibitor MG132 and the Akt-specific inhibitor LY294002. In addition, an in vivo ubiquitination assay revealed that the degradation of Akt was mediated by the ubiquitin-mediated proteasome pathway and further demonstrated that this ubiquitination was dependent on the phosphorylation status of Akt. Furthermore, the exogenously overexpressed active form of Akt, but not its inactive form, induced resistance to H2O2-mediated cell death. These results suggested that H2O2-induced cytotoxicity was mediated by active Akt degradation.read more
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References
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Journal ArticleDOI
Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
Anne Brunet,Azad Bonni,Michael J. Zigmond,Michael Z. Lin,Peter Juo,Linda Hu,Michael J. Anderson,Karen C. Arden,John Blenis,Michael E. Greenberg +9 more
TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
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Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery
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TL;DR: It is shown that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival.
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