The adaptor protein SH2B1β reduces hydrogen peroxide-induced cell death in PC12 cells and hippocampal neurons

In this study, we investigated the role of SH2B1β in oxidative stress-induced cell death. Our results suggest that overexpressing SH2B1β reduced H2O2-induced, caspase 3-dependent apoptosis in PC12 cells and hippocampal neurons. In response to H2O2, overexpressing SH2B1β enhanced PI3K (phosphatidylinositol 3-kinas)-AKT (protein kinase B) and MEK (MAPK/ERK kinase)-extracellular-signal regulated kinases 1 and 2 (ERK1/2) signaling pathways. We further demonstrated that SH2B1β was able to reduce H2O2-induced nuclear localization of FoxO1 and 3a transcription factors, which lie downstream of PI3K-AKT and MEK-ERK1/2 pathways. Moreover, overexpressing SH2B1β reduced the expression of Fas ligand (FasL), one of the target genes of FoxOs.Overexpressing the adaptor protein SH2B1β enhanced H2O2-induced PI3K-AKT and MEK-ERK1/2 signaling, reduced nucleus-localized FoxOs and the expression of a pro-apoptotic gene, FasL.Oxidative stress resulting from overload of toxic reactive oxygen species (ROS) is common in the etiology of human diseases. It has been implicated in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease [1-4]. It also contributes to acute damage resulting from hypoxic-reperfusion conditions after trauma or stroke [5,6]. The accumulation of ROS, such as hydrogen peroxide (H2O2), leads to various forms of reversible and irreversible oxidative modification of proteins, lipids and DNA, accounting for cellular damage [7]. Depending on the extent of oxidative stress, it can induce proliferation, growth arrest, senescence, apoptosis (programmed cell death) or necrosis [8-11].A number of signaling pathways are evolved to protect cells from ROS-induced damages, including phosphatidylinositol 3-kinase (PI3K)-AKT pathway, mitogen-activated protein kinases (MAPKs) pathways, and phospholipase Cγ (PLCγ) signaling [12-20]. PI3K-AKT pathway predominantly acts to promote cell survival. The three family members of MAPKs are