title: The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes.
abstract: Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Bengt-Frederik
authors.initials: BF
authors.lastname: Belgardt
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Kashan
authors.initials: K
authors.lastname: Ahmed
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Spranger
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Latreille
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Remy
authors.initials: R
authors.lastname: Denzler
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Nadiia
authors.initials: N
authors.lastname: Kondratiuk
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Ferdinand
authors.identifier: 0000000199203075
authors.initials: F
authors.lastname: von Meyenn
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Felipe Nunez
authors.initials: FN
authors.lastname: Villena
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Karolin
authors.initials: K
authors.lastname: Herrmanns
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.affiliation: Université de Lille 2, INSERM, European Genomic Institute for Diabetes, Lille Cedex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: Université de Lille 2, INSERM, European Genomic Institute for Diabetes, Lille Cedex, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: 1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: C500846:Dnajc3 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D007328:Insulin; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D051636:X-Linked Inhibitor of Apoptosis Protein