Role of oxidative stress and the JNK pathway in diabetes

研究表明，氧化应激和c-Jun n -末端激酶（JNK）通路的激活可诱导胰腺转录因子PDX-1的核胞质易位，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之间发挥中介作用。氧化应激条件下，胰腺β细胞系HIT-T15中Foxol的胞内定位由细胞质向细胞核转变。JNK的过表达也诱导了Foxol的核定位，但相反，JNK的抑制降低了氧化应激诱导的Foxol核定位，提示JNK通路参与了Foxol易位。此外，氧化应激或JNK通路的激活降低了HIT细胞中Akt的活性，导致Foxol在核定位后磷酸化降低。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对Foxol的抑制保留了氧化应激条件下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-胞质易位。

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.