Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway  

作　　者：Xuan TANG Hong SHEN Jing CHEN Xu WANG Yu ZHANG Li-li CHEN Vatcharin RUKACHAISIRIKUL Hua-liang JIANG Xu SHEN 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Department of Oral and Maxillofacial Surgery, Ninth People＇s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China [3]Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Thailand

出　　处：《Acta Pharmacologica Sinica》2011年第9期1138-1147,共10页中国药理学报（英文版）

摘　　要：Aim： Activating transcription factor 6 （ATF6） is a key signal transducer of endoplasmic reticulum stress （ER stress）. This study was con- ducted 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 pg/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 extra- cellular signal-regulated kinase （ERK） phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 （10 pmol/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.Aim： Activating transcription factor 6 （ATF6） is a key signal transducer of endoplasmic reticulum stress （ER stress）. This study was con- ducted 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 pg/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 extra- cellular signal-regulated kinase （ERK） phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 （10 pmol/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.

关 键 词：activating transcription factor 6 ER stress insulin receptor MEK/ERK pathway type 2 diabetes 

分 类 号：Q578[生物学—生物化学] Q257