The forkhead transcription factor foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation
The forkhead transcription factor foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation
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DOI：
10.1074/jbc.m508510200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Yamasaki, Y
中科院分区：
文献类型：
--
作者：
Kawamori, D;Kaneto, H;Yamasaki, Y
已经显示，氧化应激和c-Jun N-末端激酶（JNK）途径的激活诱导胰腺转录因子PDX-1的核质易位，这导致胰腺β细胞功能障碍。在这项研究中，我们已经表明，叉头转录因子Foxo 1/FKHR作为JNK通路和PDX-1之间的介质发挥作用。在氧化应激条件下，Foxo 1改变了其在胰腺β细胞系HIT-T15中的细胞内定位，从细胞质到细胞核。JNK的过表达也诱导了Foxo 1的核定位，但相反，抑制JNK减少了氧化应激诱导的Foxo 1的核定位，这表明JNK通路参与了Foxo 1的易位。此外，氧化应激或JNK通路的激活降低了HIT细胞中Akt的活性，导致核定位后Foxo 1磷酸化水平降低。此外，腺病毒介导的Foxo 1过表达减少了PDX-1的核表达，而Foxo 1特异性小干扰RNA对Foxo 1的抑制在氧化应激条件下保留了PDX-1的核表达。总之，Foxo 1通过氧化应激和JNK途径参与PDX-1的核质易位。
It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic beta-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic beta-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 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 Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway.