title: The JNK pathway modulates expression and phosphorylation of 4E-BP1 in MIN6 pancreatic beta-cells under oxidative stress conditions.
abstract: 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 MIN6 cells, which may contribute to fine tuning of translational control under stress conditions.
authors.affiliation: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Tominaga
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Satake
authors.forename: Masahiro
authors.initials: M
authors.lastname: Usui
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tanji
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D018053:Arsenites / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000873:Anthracenes; D018053:Arsenites; C081452:Atf4 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D051701:Activating Transcription Factor 4; C432165:pyrazolanthrone; D019284:Thapsigargin; D048031:JNK Mitogen-Activated Protein Kinases; C015001:arsenite