Titre :
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Utrophin A is translationally regulated in regenerating skeletal muscle via an IRES dependent mechanism (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Miura P ;
Jasmin B ;
Thompson J ;
Chakkalakal J ;
Holcik M
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 114
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Langues:
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Anglais
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Mots-clés :
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colloque
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dystrophie musculaire de Duchenne
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muscle squelettique
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régénération musculaire
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utrophine
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Résumé :
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Communication n° 416. Introduction : A therapeutic strategy to treat Duchenne muscular dystrophy (DMD) is to upregulate utrophin expression in the muscles of affected patients. Our previous studies have shown that during muscle regeneration, utrophin is upregulated at the protein level without a corresponding increase in mRNA. These observations imply that translational and/or post-translational events may regulate utrophin expression. Objectives : To determine the role that the utrophin A 5'untranslated region (5'UTR) plays in the upregulation of utrophin A expression during skeletal muscle regeneration. Methods: Cardiotoxin was used to induce myonecrosis and regeneration of mouse tibialis anterior (TA) muscles. The murine 5'UTR of utrophin A was subcloned into monocistronic and bicistronic reporter constructs. Reporter analysis was carried out by RT-PCR and protein activity assays on transduced TA muscles and transfected myoblasts. Results : Utrophin A protein levels were markedly increased in regenerating TA muscle without a corresponding increase in mRNA. In control muscle, the 5'UTR of utrophin A caused an inhibitory effect on the translation of a reporter vector. This inhibitory effect was de-repressed during muscle regeneration, which suggested that utrophin A is translationally regulated via events targeting its 5'UTR. Using bicistronic reporter assays in both regenerating skeletal muscle and cultured myoblasts, we found that the utrophin A 5'UTR contains an internal ribosome entry site (IRES). Control experiments ensured that the reported IRES activity was not due to splicing or the presence of a cryptic promoter. Conclusions : We have found that the utrophin A 5'UTR contains an IRES that is activated in vivo during skeletal muscle regeneration. IRES mediated translation can at least partially account for the discordant expression of utrophin A protein and transcript during muscle regeneration.
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