Role of oxidative stress and the JNK pathway in diabetes

已有研究表明，氧化应激和c-jun氨基末端激酶途径的激活导致胰腺转录因子pdx-1的核质易位，从而导致胰腺β细胞功能障碍。在这项研究中，我们发现叉头转录因子Foxol/FKHR在JNK途径和PDX-1之间起到了中介作用。在氧化应激条件下，Foxol将其在胰腺β细胞系HIT-T15中的细胞内定位从胞浆改变为胞核。JNK的过表达也诱导了Foxol的核定位，但相反，JNK的抑制减少了氧化应激诱导的Foxol的核定位，提示JNK途径参与了Foxol的移位。此外，氧化应激或JNK途径的激活降低了HIT细胞中Akt的活性，导致Foxol核定位后Foxol的磷酸化减少。此外，腺病毒介导的Foxol过表达降低了PDX-1的核表达，而Foxol特异性siRNA抑制Foxol在氧化应激条件下保留了PDX-1的核表达。综上所述，Foxol通过氧化应激和JNK途径参与了PDX-1的核质转位。

It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleo-cytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic β-cell dysfunction. In this study, we show that the forkhead transcription factor Foxol/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxol changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic β-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxol, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxol, suggesting the involvement of the JNK pathway in Foxol translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxol following the nuclear localization of Foxol. Furthermore, adenovirus-mediated Foxol overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxol by Foxol-specific siRNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxol is involved in the nucleo-cytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway.