A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart

Junmei Ye, Miriam Llorian, Maria Cardona, Anthony Rongvaux, Rana S. Moubarak, Joan X. Comella, Rhonda Bassel-Duby, Richard A. Flavell, Eric N. Olson, Christopher W J Smith, Daniel Sanchis

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1682-1691
Number of pages10
JournalJournal of cell science
Volume126
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • Cardiomyocyte
  • Differentiation
  • Gene expression
  • Myocyte enhancer factor-2
  • Polypyrimidine tract binding protein

ASJC Scopus subject areas

  • Cell Biology

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    Ye, J., Llorian, M., Cardona, M., Rongvaux, A., Moubarak, R. S., Comella, J. X., Bassel-Duby, R., Flavell, R. A., Olson, E. N., Smith, C. W. J., & Sanchis, D. (2013). A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart. Journal of cell science, 126(7), 1682-1691. https://doi.org/10.1242/jcs.121384