title: miR-204 Targets PERK and Regulates UPR Signaling and β-Cell Apoptosis.
abstract: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of diabetes and the associated β-cell apoptosis. Although microRNAs (miRNAs) have been widely studied in various diseases including diabetes, the role of miRNAs in ER stress and β-cell apoptosis has only started to be elucidated. We recently showed that diabetes increases β-cell miR-204 and have now discovered that miR-204 directly targets the 3'untranslated region of protein kinase R-like ER kinase (PERK), 1 of the 3 ER transmembrane sensors and a key factor of the unfolded protein response (UPR). In addition, by using primary human islets, mouse islets, and INS-1 β-cells, we found that miR-204 decreased PERK expression as well as its downstream factors, activating transcription factor 4 and CCAAT enhancer-binding protein homologous protein, whereas it had no effect on the other 2 ER transmembrane sensors, activating transcription factor 6 and inositol-requiring enzyme-1α. Interestingly, we discovered that miR-204 also inhibited PERK signaling in the context of ER stress, and this exacerbated ER stress-induced β-cell apoptosis. This effect could be mimicked by PERK inhibitors supporting the notion that the miR-204-mediated inhibition of PERK and UPR signaling was conferring these detrimental effects on cell survival. Taken together, we have identified PERK as a novel target of miR-204 and show that miR-204 inhibits PERK signaling and increases ER stress-induced cell death, revealing for the first time a link between this miRNA and UPR.
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182.
authors.forename: Guanlan
authors.initials: G
authors.lastname: Xu
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182.
authors.forename: Junqin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182.
authors.forename: Gu
authors.initials: G
authors.lastname: Jing
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182.
authors.forename: Truman B
authors.initials: TB
authors.lastname: Grayson
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182.
authors.forename: Anath
authors.initials: A
authors.lastname: Shalev
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; D035683:MicroRNAs; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C549404:MIRN204 microRNA, human