Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH2-terminal kinase
Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH2-terminal kinase
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DOI：
10.2337/diabetes.52.12.2896
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发表时间：
2003-12-01
期刊：
影响因子：
7.7
通讯作者：
Hori, M
中科院分区：
文献类型：
--
作者：
Kawamori, D;Kajimoto, Y;Hori, M
在糖尿病条件下，在胰腺β细胞中诱导氧化应激，并导致β细胞功能障碍。糖尿病动物的抗氧化剂治疗导致胰岛素生物合成的恢复并增加其控制转录因子胰腺十二指肠同源框-1（PDX-1）在胰腺β细胞中的表达。在这里，我们表明，PDX-1从细胞核易位到胰腺β细胞的细胞质中，以响应氧化应激。当氧化应激作用于β细胞衍生的HIT-T15细胞时，内源性PDX-1和外源性引入的绿色荧光蛋白标记的PDX-1都从细胞核移动到细胞质。另外，显性负性形式的c-Jun氨基末端激酶（JNK）抑制氧化应激诱导的PDX-1易位，这表明JNK在介导这一现象中的重要作用。而核定位信号（NLS）在PDX-1不受氧化应激，来普霉素B，一个经典的亮氨酸丰富的核输出信号（内斯）的特异性抑制剂，抑制氧化应激诱导的PDX-1的核质易位。此外，我们在小鼠PDX-1蛋白的位置82-94处鉴定了内斯。因此，我们目前的研究结果揭示了一种负调节PDX-1功能的新机制。内斯以氧化应激反应性、JNK依赖性方式取代NLS的功能，其鉴定支持PDX-1功能在体内的复杂调节，并且可以进一步理解糖尿病中的β细胞病理生理学。
Oxidative stress is induced in pancreatic beta-cells under diabetic conditions and causes beta-cell dysfunction. Antioxidant treatment of diabetic animals leads to recovery of insulin biosynthesis and increases the expression of its controlling transcription factor, pancreatic duodenal homeobox-1 (PDX-1), in pancreatic beta-cells. Here, we show that PDX-1 is translocated from the nuclei to the cytoplasm of pancreatic beta-cells in response to oxidative stress. When oxidative stress was charged upon beta-cell-derived HIT-T15 cells, both endogenous PDX-1 and exogenously introduced green fluorescent protein-tagged PDX-1 moved from the nuclei to the cytoplasm. The addition of a dominant negative form of c-Jun NH2-terminal kinase (JNK) inhibited oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating this phenomenon. Whereas the nuclear localization signal (NLS) in PDX-1 was not affected by oxidative stress, leptomycin B, a specific inhibitor of the classical leucine-rich nuclear export signal (NES), inhibited nucleo-cytoplasmic translocation of PDX-1 induced by oxidative stress. Moreover, we identified an NES at position 82-94 of the mouse PDX-1 protein. Thus, our present results revealed a novel mechanism that negatively regulates PDX-1 function. The identification of the NES, which overrides the function of the NLS in an oxidative stress-responsive, JNK-dependent manner, supports the complicated regulation of PDX-1 function in vivo and may further the understanding of beta-cell pathophysiology in diabetes.