title: A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart.
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.
authors: Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida - IRBLLEIDA, Av Rovira Roure, 80, Lleida, 25198 Spain.
authors: Junmei
authors: J
authors: Ye
authors: Miriam
authors: M
authors: Llorian
authors: Maria
authors: M
authors: Cardona
authors: Anthony
authors: A
authors: Rongvaux
authors: Rana S
authors: RS
authors: Moubarak
authors: Joan X
authors: JX
authors: Comella
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: Richard A
authors: RA
authors: Flavell
authors: Eric N
authors: EN
authors: Olson
authors: Christopher W J
authors: CW
authors: Smith
authors: Daniel
authors: D
authors: Sanchis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C490774:Tpm1 protein, mouse; D014335:Tropomyosin; D038941:Polypyrimidine Tract-Binding Protein; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: Cardiomyocyte; Differentiation; Gene expression; Myocyte Enhancer Factor-2; Polypyrimidine tract binding protein