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 (MBNL1 42-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL1 42-43 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-MBNL1 42-43, succeeded in reducing the nuclear localization of both Lyn and MBNL1 42-43 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.

MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases / A. Botta, A. Malena, E. Tibaldi, L. Rocchi, E. Loro, E. Pena, L. Cenci, E. Ambrosi, M.C. Bellocchi, M.A. Pagano, G. Novelli, G. Rossi, H.L. Monaco, E. Gianazza, B. Pantic, V. Romeo, O. Marin, A.M. Brunati, L. Vergani. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 4:8(2013), pp. e770.1-e770.12. [10.1038/cddis.2013.291]

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

E. Gianazza;
2013

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 (MBNL1 42-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL1 42-43 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-MBNL1 42-43, succeeded in reducing the nuclear localization of both Lyn and MBNL1 42-43 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.
MBNL1; DM1; SFKs; muscle; pre-messenger-rna; lyn tyrosine kinase; proline-rich motif; myotonic-dystrophy; SH3 domain; lipid rafts; CTG repeat; in-vivo; C-SRC; activation
Settore BIO/10 - Biochimica
2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/226015
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