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Regulation of microRNA 183 by cyclooxygenase 2 in liver is DEAD-box helicase p68 (DDX5) dependent: Role in insulin signaling

AutorMotiño, Omar ; Francés, Daniel E.; Mayoral, Rafael ; Castro-Sánchez, Luis; Fernández-Velasco, María ; Boscá, Lisardo ; García-Monzón, Carmelo; Brea, Rocío; Casado, Marta ; Agra, Noelia ; Martín-Sanz, Paloma
Fecha de publicación2015
EditorAmerican Society for Microbiology
CitaciónMolecular and Cellular Biology 35(14): 2554-2567 (2015)
ResumenCyclooxygenase (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.
URIhttp://hdl.handle.net/10261/124590
DOI10.1128/MCB.00198-15
Identificadoresdoi: 10.1128/MCB.00198-15
issn: 0270-7306
e-issn: 1098-5549
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