炎症因子IFN-γ调控小鼠成肌细胞FoxO1乙酰化及活性的机制研究
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Effects of IFN-γ on FoxO1 acetylation and activity in mouse myoblast cells and its mechanism
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    目的:在炎症信号IFN-γ作用下,研究小鼠成肌细胞(C2C12)内FoxO1的活性和乙酰化水平的改变,探讨炎症在2型糖尿病发病过程中的机制-方法:免疫共沉淀分析Ⅲ型脱乙酰化酶沉默信息调节因子1(silent information regulator 1,SIRT1)激动剂白藜芦醇对IFN-γ升高FoxO1乙酰化水平的影响-通过荧光素酶报告基因活性实验分析IFN-γ-CⅡTA对FoxO1转录活性的影响,同时用小RNA干扰内源性CⅡTA后再检测IFN-γ作用下FoxO1转录活性的改变-结果:蛋白实验显示,IFN-γ处理后FoxO1乙酰化水平明显升高,白藜芦醇降低该效应-报告基因实验显示IFN-γ抑制野生型FoxO1的转录活性,对赖氨酸突变的FoxO1作用不大-过表达CⅡTA抑制了FoxO1靶基因FHRE启动子的活性,且在同时转染FoxO1时抑制60%左右-IFN-γ抑制FoxO1的转录活性,内源性CⅡTA干扰后再给予IFN-γ,抑制作用消失-结论:IFN-γ通过激活CⅡTA降低SIRT1酶活性,使SIRT1对FoxO1的去乙酰化作用减弱,提高了FoxO1乙酰化水平,抑制了FoxO1的转录活性-本研究为临床2型糖尿病的治疗提供了新思路-

    Abstract:

    Objective:To investigate the activity and acetylation of FoxO1 after inflammatory cytokine IFN-γ treatment in mouse myoblast cells(C2C12) and its regulatory mechanisms on T2DM. Methods:Acetylation of FoxO1 after IFN-γ and silent information regulator 1 (SIRT1) activator resveratrol treatment were evaluated by co-immunoprecipitation (co-IP) followed by Western blot. Luciferase reporter assays were performed to assess the effect of IFN-γ and C Ⅱ TA on the promoter activities of FoxO1. To evaluate whether CⅡTA was necessary for the repression of SIRT1 activity by IFN-γ,cells were transfected with C Ⅱ TA small interfering RNA(siRNA). Results:IFN-γ augmented the acetylation level of FoxO1 while down-regulated by resveratrol. IFN-γ suppressed the transcriptional activity of wild-type FoxO1,mutation of lysine residues in FoxO1 abrogated such effects. C Ⅱ TA directly inhibited FoxO1 dependent transcription and while transfected with FoxO1 simultaneously,the inhibition was up to 60%. C Ⅱ TA depletion restored FoxO1 transcriptional activity in the presence of IFN-γ. Conclusion:IFN-γ induced the expression of C Ⅱ TA,which in turn inhibited SIRT1 enzyme activity,increased the acetylation level of FoxO1,thus reduced its transcriptional activity. Therefore,our study provides a potential target for clinical intervention in T2DM.

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方明明,吴晓燕,李 平,袁艺标.炎症因子IFN-γ调控小鼠成肌细胞FoxO1乙酰化及活性的机制研究[J].南京医科大学学报(自然科学版),2016,(11):1316-1320

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  • 收稿日期:2016-05-07
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  • 在线发布日期: 2016-11-28
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