Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.

Botta, A., Malena, A., Tibaldi, E., Rocchi, L., Loro, E., Pena, E., et al. (2013). MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases. CELL DEATH & DISEASE, 4, e770-e770 [10.1038/cddis.2013.291].

MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases

BOTTA, ANNALISA;Bellocchi, M;NOVELLI, GIUSEPPE;ROSSI, GABRIELE;
2013-01-01

Abstract

Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.
2013
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/03 - GENETICA MEDICA
English
phosphotyrosine; humans; muscles; cell differentiation; RNA, small interfering; cell nucleus; protein binding; models, biological; protein isoforms; src homology domains; muscle fibers, skeletal; nuclear proteins; phosphorylation; RNA-binding proteins; adult; myotonic dystrophy; case-control studies; gene expression regulation; src-family kinases; protein transport
Botta, A., Malena, A., Tibaldi, E., Rocchi, L., Loro, E., Pena, E., et al. (2013). MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases. CELL DEATH & DISEASE, 4, e770-e770 [10.1038/cddis.2013.291].
Botta, A; Malena, A; Tibaldi, E; Rocchi, L; Loro, E; Pena, E; Cenci, L; Ambrosi, E; Bellocchi, M; Pagano, M; Novelli, G; Rossi, G; Monaco, H; Gianazza...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/85951
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