ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress.
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.
Yamaguchi
Suguru
S
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Ishihara
Hisamitsu
H
Yamada
Takahiro
T
Tamura
Akira
A
Usui
Masahiro
M
Tominaga
Ryu
R
Munakata
Yuichiro
Y
Satake
Chihiro
C
Katagiri
Hideki
H
Tashiro
Fumi
F
Aburatani
Hiroyuki
H
Tsukiyama-Kohara
Kyoko
K
Miyazaki
Jun-ichi
J
Sonenberg
Nahum
N
Oka
Yoshitomo
Y
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D039642:Eukaryotic Initiation Factors; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D013312:Stress, Physiological / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D015854:Up-Regulation; D014929:Wolfram Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C081452:Atf4 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D008565:Membrane Proteins; D010750:Phosphoproteins; C114987:wolframin protein; D051701:Activating Transcription Factor 4