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Title:
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A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart
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Author:
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Ye, Junmei; Llorian, Miriam; Cardona, Maria; Rongvaux, Anthony; Moubarak, Rana S.; Comella i Carnicé, Joan Xavier; Bassel-Duby, Rhonda; Flavell, Richard A.; Olson, Eric N.; Smith, Christopher W. J.; Sanchis, Daniel
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Notes:
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Polypyrimidine 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.
This 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. |
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Subject(s):
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-Cardiomyocyte
-Myocyte Enhancer Factor-2
-Morfogènesi
-Expressió gènica |
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Rights:
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(c) Company of Biologists Ltd., 2013
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Document type:
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article
publishedVersion |
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Published by:
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Company of Biologists Ltd.
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