| DOI | Resolve DOI: https://doi.org/10.1074jbcM804518200 |
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| Author | Search for: Lu, Yifan; Search for: Tian, Chai; Search for: Danialou, Gawiyou; Search for: Gilbert, Rénald1; Search for: Petrof, Basil J.; Search for: Karpati, George; Search for: Nalbantoglu, Josephine |
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| Affiliation | - National Research Council Canada. NRC Biotechnology Research Institute
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| Format | Text, Article |
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| Subject | biotechnology; deficiency; dystrophin; in vitro; muscle fibers; muscles; muscular dystrophies; pathology; proteins; transcription factors; vitro; zinc; up-regulation |
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| Abstract | Duchenne muscular dystrophy is caused by a genetic defect in the dystrophin gene. The absence of dystrophin results in muscle fiber necrosis and regeneration, leading to progressive muscle fiber loss. Utrophin is a close analogue of dystrophin. A substantial, ectopic expression of utrophin in the extrasynaptic sarcolemma of dystrophin-deficient muscle fibers can prevent deleterious effects of dystrophin deficiency. An alternative approach for the extrasynaptic up-regulation of utrophin involves the augmentation of utrophin transcription via the endogenous utrophin A promoter using custom-designed transcriptional activator proteins with zinc finger (ZFP) motifs. We tested a panel of custom-designed ZFP for their ability to activate the utrophin A promoter. Expression of one such ZFP efficiently increased, in a time-dependent manner, utrophin transcript and protein levels both in vitro and in vivo. In dystrophic mouse (mdx) muscles, administration of adenoviral vectors expressing this ZFP led to significant enhancement of muscle function with decreased necrosis, restoration of the dystrophin-associated proteins, and improved resistance to eccentric contractions. These studies provide evidence that specifically designed ZFPs can act as strong transcriptional activators of the utrophin A promoter. These may thus serve as attractive therapeutic agents for dystrophin deficiency states such as Duchenne muscular dystrophy. |
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| Publication date | 2008-10-21 |
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| Publisher | American Society for Biochemistry and Molecular Biology |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| NRC number | NRCC 47829 |
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| NPARC number | 12400996 |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 1ce58674-c7d4-48ff-a4b3-4d8c6e417e29 |
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| Record created | 2009-10-02 |
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| Record modified | 2020-04-15 |
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