Distinct regions in the 3' untranslated region are responsible for targeting and stabilizing utrophin transcripts in skeletal muscle cells.
In this study, we have sought to determine whether utrophin transcripts are targeted to a distinct subcellular compartment in skeletal muscle cells, and have examined the role of the 3' untranslated region (UTR) in regulating the stability and localization of utrophin transcripts. Our results show that utrophin transcripts associate preferentially with cytoskeleton-bound polysomes via actin microfilaments. Because this association is not evident in myoblasts, our findings also indicate that the localization of utrophin transcripts with cytoskeleton-bound polysomes is under developmental influences. Transfection of LacZ reporter constructs containing the utrophin 3'UTR showed that this region is critical for targeting chimeric mRNAs to cytoskeleton-bound polysomes and controlling transcript stability. Deletion studies resulted in the identification of distinct regions within the 3'UTR responsible for targeting and stabilizing utrophin mRNAs. Together, these results illustrate the contribution of posttranscriptional events in the regulation of utrophin in skeletal muscle. Accordingly, these findings provide novel targets, in addition to transcriptional events, for which pharmacological interventions may be envisaged to ultimately increase the endogenous levels of utrophin in skeletal muscle fibers from Duchenne muscular dystrophy (DMD) patients.
Gramolini
A O
AO
Department of Cellular and Molecular Medicine, Faculty of Medicine, and Center for Neuromuscular Disease, University of Ottawa, Canada.
Bélanger
G
G
Jasmin
B J
BJ
D020413:3' Untranslated Regions / Q000494:pharmacology*; D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000209:etiology; D011132:Polyribosomes / Q000378:metabolism; D021381:Protein Transport; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution; D049411:Utrophin
D020413:3' Untranslated Regions; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C483600:Utrn protein, mouse; D049411:Utrophin