ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress
ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress
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DOI：
10.1016/j.cmet.2008.01.008
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发表时间：
2008-03-01
期刊：
影响因子：
29
通讯作者：
Oka, Yoshitomo
中科院分区：
文献类型：
--
作者：
Yamaguchi, Suguru;Ishihara, Hisamitsu;Oka, Yoshitomo
内质网(ER)应激介导的细胞凋亡可能在胰岛β细胞质量丧失中起关键作用，从而促进糖尿病的发生发展。在这里，我们证明了4E-BP1的诱导，4E-BP1是mRNA5‘帽结合蛋白真核启动因子4E(EIF4E)的抑制者，参与了内质网应激下β细胞的存活。4在内质网应激下，几种糖尿病小鼠胰岛E-BP1表达增加。编码4E-BP1的Eif4ebp1基因被发现是转录因子ATF4的直接靶标。Eif4ebp1基因的缺失增加了迷你β细胞和小鼠胰岛对内质网应激介导的凋亡的易感性，这伴随着去调控的翻译控制。此外，Eif4ebp1缺失加速了糖尿病小鼠模型中β细胞的丢失，并加剧了高血糖。因此，4E-BP1的诱导有助于维持内质网应激过程中的β细胞内环境平衡，是治疗糖尿病的潜在靶点。
Endoplasmic reticulum (ER) stress-mediated apoptosis may play a crucial role in loss of pancreatic beta cell mass, contributing to the development of diabetes. Here we show that induction of 4E-BP1, the suppressor of the mRNA 5' cap-binding protein eukaryotic initiation factor 4E (eIF4E), is involved in beta cell survival under ER stress. 4E-BP1 expression was increased in islets under ER stress in several mouse models of diabetes. The Eif4ebp1 gene encoding 4E-BP1 was revealed to be a direct target of the transcription factor ATF4. Deletion of the Eif4ebp1 gene increased susceptibility to ER stress-mediated apoptosis in MINIS beta cells and mouse islets, which was accompanied by deregulated translational control. Furthermore, Eif4ebp1 deletion accelerated beta cell loss and exacerbated hyperglycemia in mouse models of diabetes. Thus, 4E-BP1 induction contributes to the maintenance of beta cell homeostasis during ER stress and is a potential therapeutic target for diabetes.