Abstract
Duchenne muscular dystrophy is a fatal childhood disease caused by mutations that abolish the expression of dystrophin in muscle. Utrophin is a paralogue of dystrophin and can functionally replace it in skeletal muscle. A potential therapeutic approach is to increase utrophin levels in muscle. One way to achieve this aim is to increase the expression of the utrophin gene at a transcriptional level via promoter activation. In this study, we have shown that utrophin A mRNA levels can be induced by okadaic acid in murine myogenic C2C12 cells. We have found that a utrophin A promoter reporter can be induced by Sp1 in C2C12 myoblasts, but not in myotubes. This activation can be enhanced by okadaic acid treatment. Our data suggest that this induction is due to Sp1 phosphorylation during myogenesis and thus, utrophin expression in muscle could be regulated by treatment with phosphatase inhibitors. Control of utrophin promoter activation could then be used to increase the expression of utrophin, and thus ameliorate the symptoms of Duchenne muscular dystrophy.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence / genetics
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Line
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Cytoskeletal Proteins / genetics*
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Humans
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Membrane Proteins / genetics*
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Mice
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Molecular Sequence Data
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscular Dystrophy, Duchenne / genetics
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Muscular Dystrophy, Duchenne / metabolism
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Muscular Dystrophy, Duchenne / therapy
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Myoblasts, Skeletal / drug effects*
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Myoblasts, Skeletal / metabolism
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Okadaic Acid / pharmacology*
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / metabolism
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Phosphorylation
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Promoter Regions, Genetic / genetics*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Sp1 Transcription Factor / genetics
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Sp1 Transcription Factor / metabolism
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Sp1 Transcription Factor / pharmacology
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Up-Regulation / drug effects*
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Up-Regulation / genetics
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Utrophin
Substances
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Membrane Proteins
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RNA, Messenger
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Sp1 Transcription Factor
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Utrn protein, mouse
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Utrophin
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Okadaic Acid
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Phosphoric Monoester Hydrolases