title: Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling.
abstract: Cyclooxygenase (COX) catalyzes the first step in prostanoid biosynthesis and exists as two isoforms. COX-1 is a constitutive enzyme involved in physiological processes, whereas COX-2 is induced by a variety of stimuli. MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. Although it is known that COX-2 expression is regulated by miRNAs, there are no data regarding COX-2 involvement in miRNA regulation. Considering our previous results showing that COX-2 expression in hepatocytes protects against insulin resistance, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs implicated in insulin signaling in liver cells. Our results provide evidence of the molecular basis for a novel function of COX-2 in miRNA processing. COX-2 represses miRNA 23b (miR-23b), miR-146b, and miR-183 expression in liver cells by increasing the level of DEAD-box helicase p68 (DDX5) through phosphatidylinositol 3-kinase (PI3K)/p300 signaling and by modulating the enzymatic function of the Drosha (RNase type III) complex through its physical association with DDX5. The decrease of miR-183 expression promotes protection against insulin resistance by increasing insulin receptor substrate 1 (IRS1) levels. These results indicate that the modulation of miRNA processing by COX-2 is a key event in insulin signaling in liver and has potential clinical implications for the management of various hepatic dysfunctions.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: Motiño
authors.affiliation: Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Francés
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.identifier: http://orcid.org/0000-0002-6645-7172
authors.initials: R
authors.lastname: Mayoral
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castro-Sánchez
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz, IDIPAZ, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: García-Monzón
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Brea
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain Instituto de Biomedicina de Valencia, IBV-CSIC, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain nagra@iib.uam.es pmartins@iib.uam.es.
authors.forename: Noelia
authors.initials: N
authors.lastname: Agra
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain nagra@iib.uam.es pmartins@iib.uam.es.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D051546:Cyclooxygenase 2; D053487:DEAD-box RNA Helicases; D055504:Insulin Receptor Substrate Proteins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D043244:Ribonuclease III; C526292:IRS1 protein, human; C542542:MIRN146 microRNA, human; C533449:MIRN183 microRNA, human; C552430:MIRN23a microRNA, human; C517918:DROSHA protein, human