The JNK pathway modulates expression and phosphorylation of 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions
The JNK pathway modulates expression and phosphorylation of 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions
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DOI：
10.1002/cbf.1667
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发表时间：
2010-07-01
影响因子：
3.6
通讯作者：
Ishihara, Hisamitsu
中科院分区：
文献类型：
--
作者：
Tominaga, Ryu;Yamaguchi, Suguru;Ishihara, Hisamitsu
压力介导的细胞凋亡可能在胰腺β细胞质量损失中发挥关键作用，从而导致糖尿病的发生。我们最近发现，翻译控制涉及翻译抑制子 eIF4E 结合蛋白-1 (4E-BP1)，它在内质网 (ER) 应激下对于 β 细胞的生存很重要。 Eif4ebp1 基因编码 4E-BP1，是转录因子激活转录因子 4 (ATF4) 的直接靶标，ATF4 是应激反应中基因表达的主要调节因子。在当前的研究中，我们研究了用亚砷酸盐处理的小鼠胰岛素瘤系 6 (MIN6) 细胞中 4E-BP1 的表达，亚砷酸盐是一种氧化应激诱导剂，也是导致 β 细胞损失的另一个因素。我们发现亚砷酸盐诱导的 4E-BP1 表达水平低于 ER 应激诱导剂毒胡萝卜素诱导的表达水平，尽管这些药物同样诱导了 ATF4。然而，与毒胡萝卜素处理的细胞相比，用亚砷酸盐处理的MIN6细胞中4E-BP1的去磷酸化形式与磷酸化形式的比例更大，该比例具有最高的活性。通过同时使用 c-Jun N 末端激酶 (JNK) 特异性抑制剂 SP600125 处理，亚砷酸盐诱导的 4E-BP1 mRNA 和蛋白质表达得到增强。该药物还抑制亚砷酸盐处理的 MIN6 细胞中去磷酸化形式的 4E-BP1 的水平。因此。氧化应激激活的 JNK 参与 MING 细胞中 4E-BP1 表达和磷酸化的调节，这可能有助于应激条件下翻译控制的微调。版权所有 (C) 2010 约翰·威利父子有限公司
Stress-mediated apoptosis may play a crucial role in loss of pancreatic beta-cell mass, contributing to the development of diabetes. We have recently identified that translational control involving the translational suppressor eIF4E binding protein-1 (4E-BP1) which is important for beta-cell survival under endoplasmic reticulum (ER) stress. The Eif4ebp1 gene, encoding 4E-BP1, is a direct target of a transcription factor activating transcription factor-4 (ATF4), a master regulator of gene expression in stress responses. In the current study, we investigated 4E-BP1 expression in mouse insulinoma line 6 (MIN6) cells treated with arsenite, an inducer of oxidative stress which is another contributor of beta-cell loss. We found that arsenite-induced 4E-BP1 expression level was lower than that induced by thapsigargin, an ER stress inducer, although ATF4 was similarly induced by these agents. The ratio of the dephosphorylated form of 4E-BP1, which has the highest activity, to phosphorylated forms was, however, greater in MIN6 cells treated with arsenite as compared to that in thapsigargin-treated cells. Arsenite-induced 4E-BP1 mRNA and protein expressions were augmented by simultaneous treatment with a c-Jun N-terminal kinase (JNK) specific inhibitor, SP600125. The agent also suppressed the level of the dephosphrylated form of 4E-BP1 in arsenite-treated MIN6 cells. Thus. JNK activated by oxidative stress is involved in the modulation of 4E-BP1 expression and phosphorylation in MING cells, which may contribute to fine tuning of translational control under stress conditions. Copyright (C) 2010 John Wiley & Sons, Ltd.