title: MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p Regulate the Expression of Proapoptotic BH3-Only Proteins DP5 and PUMA in Human Pancreatic β-Cells.
abstract: Type 1 diabetes (T1D) is an autoimmune disease leading to β-cell destruction. MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to β-cell death in T1D and their target genes remain to be clarified. We performed an miRNA expression profile on human islet preparations exposed to the cytokines IL-1β plus IFN-γ. Confirmation of miRNA and target gene modification in human β-cells was performed by real-time quantitative PCR. Single-stranded miRNAs inhibitors were used to block selected endogenous miRNAs. Cell death was measured by Hoechst/propidium iodide staining and activation of caspase-3. Fifty-seven miRNAs were detected as modulated by cytokines. Three of them, namely miR-23a-3p, miR-23b-3p, and miR-149-5p, were downregulated by cytokines and selected for further studies. These miRNAs were found to regulate the expression of the proapoptotic Bcl-2 proteins DP5 and PUMA and consequent human β-cell apoptosis. These results identify a novel cross talk between a key family of miRNAs and proapoptotic Bcl-2 proteins in human pancreatic β-cells, broadening our understanding of cytokine-induced β-cell apoptosis in early T1D.
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium fagrieco@ulb.ac.be deizirik@ulb.ac.be.
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Grieco
authors.affiliation: Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.|Umberto Di Mario ONLUS Foundation-Toscana Life Sciences Foundation, Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Sebastiani
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Juan-Mateu
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Olatz
authors.initials: O
authors.lastname: Villate
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Laura
authors.identifier: http://orcid.org/0000-0003-2931-9317
authors.initials: L
authors.lastname: Marroqui
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ladrière
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
authors.forename: Ksenya
authors.initials: K
authors.lastname: Tugay
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
authors.forename: Romano
authors.initials: R
authors.lastname: Regazzi
authors.affiliation: Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.affiliation: Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.|Umberto Di Mario ONLUS Foundation-Toscana Life Sciences Foundation, Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dotta
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium fagrieco@ulb.ac.be deizirik@ulb.ac.be.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C484586:HRK protein, human; C551557:MIRN149 microRNA, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins