Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression
Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression
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DOI：
10.1074/jbc.m202066200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Weir, GC
中科院分区：
文献类型：
--
作者：
Kaneto, H;Xu, G;Weir, GC
糖尿病状态下胰腺β细胞中发现的氧化应激会抑制胰岛素基因转录和分泌，但氧化应激引起的β细胞功能障碍所涉及的信号通路仍不清楚。在这项研究中，使大鼠胰岛受到氧化应激会激活 JNK、p38 MAPK 和蛋白激酶 C，然后胰岛素基因表达降低。腺病毒介导的显性失活型 (DN) JNK 过度表达，但不是 p38 MAPK 抑制剂 SB203580 或蛋白激酶 C 抑制剂 GF109203X，可以保护胰岛素基因表达和分泌免受氧化应激。此外，野生型 JNK 过度表达抑制胰岛素基因表达和分泌。这些结果与重要转录因子 PDX-1 与胰岛素启动子结合的变化相关。 DN-JNK 的腺病毒过表达在面对氧化应激时保留了 PDX-1 DNA 结合活性，而野生型 JNK 过表达降低了 PDX-1 DNA 结合活性。此外，为了检查 JNK 通路的抑制是否可以保护 β 细胞免受高血糖的毒性作用，用表达 DN-JNK 的腺病毒或对照腺病毒感染大鼠胰岛，并将其移植到链脲佐菌素诱导的糖尿病裸鼠的肾被膜下。在接受 DN-JNK 过表达胰岛的小鼠中，胰岛移植物中的胰岛素基因表达得到保留，并且与对照小鼠相比，高血糖得到改善。总之，JNK 的激活参与了氧化应激导致的胰岛素基因表达的减少，而抑制 JNK 通路可以保护 β 细胞免受氧化应激的影响。
Oxidative stress, which is found in pancreatic beta-cells in the diabetic state, suppresses insulin gene transcription and secretion, but the signaling pathways involved in the beta-cell dysfunction induced by oxidative stress remain unknown. In this study, subjecting rat islets to oxidative stress activates JNK, p38 MAPK, and protein kinase C, preceding the decrease of insulin gene expression. Adenovirus-mediated overexpression of dominant-negative type (DN) JNK, but not the p38 MAPK inhibitor SB203580 nor the protein kinase C inhibitor GF109203X, protected insulin gene expression and secretion from oxidative stress. Moreover, wild type JNK overexpression suppressed both insulin gene expression and secretion. These results were correlated with changes in the binding of the important transcription factor PDX-1 to the insulin promoter; adenoviral overexpression of DN-JNK preserved PDX-1 DNA binding activity in the face of oxidative stress, whereas wild type JNK overexpression decreased PDX-1 DNA binding activity. Furthermore, to examine whether suppression of the JNK pathway can protect beta-cells from the toxic effects of hyperglycemia, rat islets were infected with DN-JNK expressing adenovirus or control adenovirus and transplanted under renal capsules of streptozotocin-induced diabetic nude mice. In mice receiving DN-JNK overexpressing islets, insulin gene expression in islet grafts was preserved, and hyperglycemia was ameliorated compared with control mice. In conclusion, activation of JNK is involved in the reduction of insulin gene expression by oxidative stress, and suppression of the JNK pathway protects beta-cells from oxidative stress.