SH2B1beta經由PI3K-AKT-FoxO與MEK-ERK1/2-FoxO途徑降低由氧化壓力所誘導之細胞死亡現象

SH2B1β reduces oxidative stress-induced cell death through PI2K-AKT-FoxO and MEK-ERK1/2-FoxO pathways

許惠蒨(Hui-Chien Hsu)

指導教授 ： 陳令儀

國立清華大學/生命科學院/分子醫學研究所/碩士(2009年)

摘要

Oxidative stress is widely implicated in the neuronal cell death which is associated with many diseases and neuronal degenerative disorders such as Parkinson’s, Alzheimer’s and Huntington’s diseases. Reactive oxygen species including hydrogen peroxide are generated during oxidative stress and cause cell damage. Among many intracellular signaling molecules induced by oxidative stress, three subfamilies of MAP (mitogen-activated protein) kinases (MAPKs) which are sensitive to ROS have been identified: extracellular-signal regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38MAPK. These kinases are activated in response to oxidative stress, and each of them plays different roles in cell survival/death. Phosphatidylinositol 3-Kinase (PI3K)-AKT (PKB) pathway is another important survival pathway that is induced by oxidative stress. Forkhead transcription factors, downstream target of AKT, regulate several pro-apoptotic genes, such as Fas ligand and Bim, that lead to cell death. SH2B1beta, an adaptor protein, is a signaling molecule which is reported to enhance nerve growth factor (NGF)-mediated neuronal differentiation in PC12 cells and is required for the survival of sympathetic neurons. In this thesis, I tested the role of SH2B1beta in oxidative stress-induced response. My data suggest that SH2B1beta reduces H2O2-induced cell death through enhancing and prolonging the activation of MAPKs and AKT. In addition, we demonstrated that both AKT and ERK1/2 are capable of phosphorylating the FKHR/FoxO1 and FKHRL1/FoxO3 in response to H2O2. We further provided evidence showing that SH2B1beta promotes survival through PI3K-AKT-FoxO pathway at low dosage of H2O2 while, at high dosage, SH2B1beta uses MEK-ERK1/2-FoxO pathway to reduce cell death.

關鍵字

氧化壓力

並列摘要

無資料

並列關鍵字

oxidative stress ； FoxO transcription factors ； PC12

參考文獻

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