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ATF4-Mediated Induction of 4E-BP1 Contributes to Pancreatic β Cell Survival under Endoplasmic Reticulum Stress

2008; Cell Press; Volume: 7; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2008.01.008

1932-7420

Suguru Yamaguchi, Hisamitsu Ishihara, Takahiro Yamada, Akira Tamura, Masahiro Usui, Ryu Tominaga, Yuichiro Munakata, Chihiro Satake, Hideki Katagiri, Fumi Tashiro, Hiroyuki Aburatani, Kyoko Tsukiyama–Kohara, Jun–ichi Miyazaki, Nahum Sonenberg, Yoshitomo Oka,

Genetics and Neurodevelopmental Disorders

Endoplasmic reticulum (ER) stress-mediated apoptosis may play a crucial role in loss of pancreatic β 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 β 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 β cells and mouse islets, which was accompanied by deregulated translational control. Furthermore, Eif4ebp1 deletion accelerated β cell loss and exacerbated hyperglycemia in mouse models of diabetes. Thus, 4E-BP1 induction contributes to the maintenance of β cell homeostasis during ER stress and is a potential therapeutic target for diabetes.