Role of oxidative stress and the JNK pathway in diabetes

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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.