Journal article
Translational Regulation of Utrophin by miRNAs
PloS one, Vol.6(12), e29376
2011
Abstract
Background
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified.
Methodology/Principal Findings
Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ~99% in C2C12 cells and is mediated by both the 5′- and 3′-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR-206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells.
Conclusions/Significance
The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA-mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD.
Details
- Title
- Translational Regulation of Utrophin by miRNAs
- Authors/Creators
- A.C. Wilber (Author/Creator)U. Basu (Author/Creator) - University of PennsylvaniaO. Lozynska (Author/Creator) - University of PennsylvaniaC. Moorwood (Author/Creator) - University of PennsylvaniaG. Patel (Author/Creator) - University of PennsylvaniaS.D. Wilton (Author/Creator) - The University of Western AustraliaT.S. Khurana (Author/Creator) - University of Pennsylvania
- Publication Details
- PloS one, Vol.6(12), e29376
- Publisher
- Public Library of Science
- Identifiers
- 991005541679407891
- Copyright
- © 2011 Basu et al.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Biochemistry & Molecular Biology
- ESI research areas
- Molecular Biology & Genetics