期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 27, 页码 19773-19784出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.457622
关键词
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资金
- Universidad Nacional del Sur [PGI 24/B179]
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT-2010-0936]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) [PIP 11220090100687]
- Fundacion Florencio Fiorini
The PI3K/Akt pathway is a key component in synaptic plasticity and neuronal survival. The aim of this work was to investigate the participation of the PI3K/Akt pathway and its outcome on different molecular targets such as glycogen synthase kinase 3 beta (GSK3 beta) and Forkhead box-O (FoxO) transcription factors during mild oxidative stress triggered by iron overload. The exposure of mouse hippocampal neurons (HT22) to different concentrations of Fe2+ (25-200 mu M) for 24 h led us to define a mild oxidative injury status (50 mu M Fe2+) in which cell morphology showed changes typical of neuronal damage with increased lipid peroxidation and cellular oxidant levels but no alteration of cellular viability. There was a simultaneous increase in both Akt and GSK3 beta phosphorylation. Levels of phospho-FoxO3a (inactive form) increased in the cytosolic fraction of cells treated with iron in a PI3K-dependent manner. Moreover, PI3K and Akt translocated to the nucleus in response to oxidative stress. Iron-overloaded cells harboring a constitutively active form of Akt showed decreased oxidants levels. Indeed, GSH synthesis under oxidative stress conditions was regulated by activated Akt. Our results show that activation of the PI3K/Akt pathway during iron-induced neurotoxicity regulates multiple targets such as GSK3 beta, FoxO transcriptional activity, and glutathione metabolism, thus modulating the neuronal response to oxidative stress.
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