Abstract
Aim:
Activating transcription factor 6 (ATF6) is a key signal transducer of endoplasmic reticulum stress (ER stress). This study was conducted to clarify the potential role of ATF6 in the insulin signaling pathway under chronic ER stress.
Methods:
ER stress of HEK293 cells was induced with tunicamycin (2 μg/mL). The cells were transfected with ATF6α or ATF6β. The phosphorylation level of insulin receptor (IR) was analyzed using Western blot. The changes in ER stress and ERK signaling pathways were explored using Western blot and quantitative real-time PCR.
Results:
Tunicamycin-induced chronic ER stress attenuated IR tyrosine phosphorylation in a time-dependent manner, whereas over-expression of ATF6 protected IR from desensitization. ATF6 modulation of IR suppression was associated with insulin-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 (10 μmol/L) mimicked the effect of ATF6 over-expression and restored the insulin-stimulated IR phosphorylation. The treatment of the cells with the ERK activator epidermal growth factor (EGF, 200 ng/mL) decreased the protection effect of ATF6 on IR.
Conclusion:
Our results demonstrate that ATF6 may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.
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Acknowledgements
We gratefully acknowledge Prof Kazutoshi MORI for the plasmids of pcDNA3.1-hATF6α and pcDNA3.1-hATF6β. This work was supported by the State Key Program of Basic Research of China (No 2010CB912501 and 2007CB914304), the National Natural Science Foundation of China (No 90713046 and 30890044), Shanghai Basic Research Project from the Shanghai Science and Technology Commission (No 11ZR1444500) and Open Research Fund of the Key Laboratory of Biotherapy, West China Hospital, West China Medicine School, Sichuan University (No SKLB200901).
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Supplementary figures are available at Acta Pharmacologica Sinica website of NPG.
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Supplementary Figure 1
GRP78 protein level responded to tunicamycin stimulation more potentially in ATF6 over-expression stable cells than in control cells. (DOC 70 kb)
Supplementary Figure 2
ATF6 protected AKT phosphorylation from desensitization induced by tunicamycin incubation. (DOC 137 kb)
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Tang, X., Shen, H., Chen, J. et al. Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway. Acta Pharmacol Sin 32, 1138–1147 (2011). https://doi.org/10.1038/aps.2011.75
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DOI: https://doi.org/10.1038/aps.2011.75
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