Yamaguchi Suguru, Ishihara Hisamitsu, Yamada Takahiro, Tamura Akira, Usui Masahiro, Tominaga Ryu, Munakata Yuichiro, Satake Chihiro, Katagiri Hideki, Tashiro Fumi, Aburatani Hiroyuki, Tsukiyama-Kohara Kyoko, Miyazaki Jun-ichi, Sonenberg Nahum, Oka Yoshitomo
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Cell Metab. 2008 Mar;7(3):269-76. doi: 10.1016/j.cmet.2008.01.008.
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 MIN6 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.
内质网（ER）应激介导的细胞凋亡可能在胰腺β细胞数量减少中起关键作用，这有助于糖尿病的发展。在此，我们表明，mRNA 5'帽结合蛋白真核起始因子4E（eIF4E）的抑制因子4E-BP1的诱导参与了内质网应激下β细胞的存活。在几种糖尿病小鼠模型中，内质网应激下胰岛中4E-BP1的表达增加。编码4E-BP1的Eif4ebp1基因被揭示为转录因子ATF4的直接靶点。Eif4ebp1基因的缺失增加了MIN6β细胞和小鼠胰岛对内质网应激介导的细胞凋亡的敏感性，这伴随着翻译控制的失调。此外，Eif4ebp1缺失加速了糖尿病小鼠模型中的β细胞丢失并加剧了高血糖症。因此，4E-BP1的诱导有助于内质网应激期间β细胞稳态的维持，并且是糖尿病的潜在治疗靶点。
