title: Converging pathways involving microRNA-206 and the RNA-binding protein KSRP control post-transcriptionally utrophin A expression in skeletal muscle.
abstract: Several reports have previously highlighted the potential role of miR-206 in the post-transcriptional downregulation of utrophin A in cultured cells. Along those lines, we recently identified K-homology splicing regulator protein (KSRP) as an important negative regulator in the post-transcriptional control of utrophin A in skeletal muscle. We sought to determine whether these two pathways act together to downregulate utrophin A expression in skeletal muscle. Surprisingly, we discovered that miR-206 overexpression in cultured cells and dystrophic muscle fibers causes upregulation of endogenous utrophin A levels. We further show that this upregulation of utrophin A results from the binding of miR-206 to conserved sites located in the 3'-UTR (untranslated region) of KSRP, thus causing the subsequent inhibition of KSRP expression. This miR-206-mediated decrease in KSRP levels leads, in turn, to an increase in the expression of utrophin A due to a reduction in the activity of this destabilizing RNA-binding protein. Our work shows that miR-206 can oscillate between direct repression of utrophin A expression via its 3'-UTR and activation of its expression through decreased availability of KSRP and interactions with AU-rich elements located within the 3'-UTR of utrophin A. Our study thus reveals that two apparent negative post-transcriptional pathways can act distinctively as molecular switches causing repression or activation of utrophin A expression.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Adel
authors.initials: A
authors.lastname: Amirouche
authors.forename: Helina
authors.initials: H
authors.lastname: Tadesse
authors.forename: Pedro
authors.initials: P
authors.lastname: Miura
authors.forename: Guy
authors.initials: G
authors.lastname: Bélanger
authors.forename: John A
authors.initials: JA
authors.lastname: Lunde
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D049411:Utrophin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C507913:Khsrp protein, mouse; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C483600:Utrn protein, mouse; D049411:Utrophin