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dc.contributor.authorYe, Junmei
dc.contributor.authorLlorian, Miriam
dc.contributor.authorCardona, Maria
dc.contributor.authorRongvaux, Anthony
dc.contributor.authorMoubarak, Rana S.
dc.contributor.authorComella i Carnicé, Joan Xavier
dc.contributor.authorBassel-Duby, Rhonda
dc.contributor.authorFlavell, Richard A.
dc.contributor.authorOlson, Eric N.
dc.contributor.authorSmith, Christopher W. J.
dc.contributor.authorSanchis, Daniel
dc.date.accessioned2015-11-18T10:23:30Z
dc.date.available2015-11-18T10:23:30Z
dc.date.issued2013
dc.identifier.issn0021-9533
dc.identifier.urihttp://hdl.handle.net/10459.1/48984
dc.description.abstractPolypyrimidine tract binding protein (PTB) regulates pre-mRNA splicing, having special relevance for determining gene expression in the differentiating muscle. We have previously shown that PTB protein abundance is progressively reduced during heart development without reduction of its own transcript. Simultaneous reduction of histone deacetylase (HDAC) expression prompted us to investigate the potential link between these events. HDAC5-deficient mice have reduced cardiac PTB protein abundance, and HDAC inhibition in myocytes causes a reduction in endogenous expression of cellular FLICE-like inhibitory protein (cFLIP) and caspase-dependent cleavage of PTB. In agreement with this, cardiac PTB expression is abnormally high in mice with cardiac-specific executioner caspase deficiency, and cFLIP overexpression prevents PTB cleavage in vitro. Caspase-dependent cleavage triggers further fragmentation of PTB, and these fragments accumulate in the presence of proteasome inhibitors. Experimental modification of the above processes in vivo and in vitro results in coherent changes in the alternative splicing of genes encoding tropomyosin-1 (TPM1), tropomyosin-2 (TPM2) and myocyte enhancer factor-2 (MEF2). Thus, we report a pathway connecting HDAC, cFLIP and caspases regulating the progressive disappearance of PTB, which enables the expression of the adult variants of proteins involved in the regulation of contraction and transcription during cardiac muscle development.ca_ES
dc.description.sponsorshipThis work was partially supported by the Ministerio de Ciencia e Innovación (MICINN) [grant number SAF2010_19125 to D.S.]; the 'Ramon y Cajal' Program from MICINN (to D.S.); the Agencia de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) [grant number 2009SGR-346 to J.X.C. and D.S.]; and the Wellcome Trust [programme grant number 092900 to C.W.J.S]. R.A.F. is an investigator of the Howard Hughes Medical Institute. Work done in the laboratory of E.N.O. was supported by grants from the National Institutes of Health, the Donald W. Reynolds Center for Clinical Cardiovascular Research, the Leducq Foundation and the Robert A. Welch Foundation. Deposited in PMC for release after 6 months.
dc.language.isoengca_ES
dc.publisherCompany of Biologists Ltd.ca_ES
dc.relationMICINN/PN2008-2011/SAF2010-19125
dc.relationAGAUR/2009SGR-346
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.1242/jcs.121384ca_ES
dc.relation.ispartofJournal of Cell Science, 2013, vol. 126, núm. 7, p. 1682-1691ca_ES
dc.rights(c) Company of Biologists Ltd., 2013ca_ES
dc.subjectCardiomyocyte
dc.subjectMyocyte Enhancer Factor-2
dc.subject.otherMorfogènesi
dc.subject.otherExpressió gènica
dc.titleA pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heartca_ES
dc.typearticleca_ES
dc.identifier.idgrec019669
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess


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