Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling.
Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling.
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DOI：
10.1016/j.cmet.2012.03.008
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发表时间：
2012-04-04
期刊：
影响因子：
29
通讯作者：
Puigserver P
中科院分区：
文献类型：
--
作者：
Blättler SM;Cunningham JT;Verdeguer F;Chim H;Haas W;Liu H;Romanino K;Rüegg MA;Gygi SP;Shi Y;Puigserver P
雷帕霉素及其衍生物是用于组织移植和癌症治疗的mTOR抑制剂。接受这些抑制剂治疗的患者中有一定比例会出现糖尿病样症状，但其分子机制尚不清楚。我们在这里表明，长期雷帕霉素治疗小鼠导致胰岛素抵抗，抑制胰岛素/IGF信号传导和该途径中相关的基因，如IGFs，IRS 1/2和AKT。重要的是，骨骼肌特异性YY 1基因敲除小鼠受到保护，免受雷帕霉素诱导的糖尿病样症状。这种保护作用是由胰岛素/IGF信号的过度激活引起的，与野生型小鼠相比，这种级联反应中的基因增加，不受雷帕霉素抑制。从机制上讲，雷帕霉素诱导YY 1去磷酸化和招募胰岛素/IGF基因的启动子，这促进了与polycomb蛋白-2辅阻遏物的相互作用。这与H3 K27三甲基化相关，导致基因表达和胰岛素信号转导减少。这些结果对雷帕霉素在人类疾病和生物学过程中的作用有影响，例如长寿。
Rapamycin and derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice leads to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as IGFs, IRS1/2 and AKTs. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increases in genes in this cascade that, in contrast to wild-type mice, were not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 tri-methylation leading to decreases in gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes, such as longevity.
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