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

12 Citations (Scopus)

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

Fingerprint

Polypyrimidine Tract-Binding Protein
CASP8 and FADD-Like Apoptosis Regulating Protein
Caspases
Histone Deacetylases
Tropomyosin
MEF2 Transcription Factors
Proteins
Proteasome Inhibitors
Muscle Development
RNA Precursors
Alternative Splicing
Muscle Cells
Myocardium
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart. / Ye, Junmei; Llorian, Miriam; Cardona, Maria; Rongvaux, Anthony; Moubarak, Rana S.; Comella, Joan X.; Bassel-Duby, Rhonda; Flavell, Richard A.; Olson, Eric N.; Smith, Christopher W J; Sanchis, Daniel.

In: Journal of Cell Science, Vol. 126, No. 7, 01.04.2013, p. 1682-1691.

Research output: Contribution to journalArticle

Ye, J, Llorian, M, Cardona, M, Rongvaux, A, Moubarak, RS, Comella, JX, Bassel-Duby, R, Flavell, RA, Olson, EN, Smith, CWJ & 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, vol. 126, no. 7, pp. 1682-1691. https://doi.org/10.1242/jcs.121384
Ye, Junmei ; Llorian, Miriam ; Cardona, Maria ; Rongvaux, Anthony ; Moubarak, Rana S. ; Comella, Joan X. ; Bassel-Duby, Rhonda ; Flavell, Richard A. ; Olson, Eric N. ; Smith, Christopher W J ; Sanchis, Daniel. / A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart. In: Journal of Cell Science. 2013 ; Vol. 126, No. 7. pp. 1682-1691.
@article{678a34f2190e43e8acf972ff805644ff,
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.",
keywords = "Cardiomyocyte, Differentiation, Gene expression, Myocyte enhancer factor-2, Polypyrimidine tract binding protein",
author = "Junmei Ye and Miriam Llorian and Maria Cardona and Anthony Rongvaux and Moubarak, {Rana S.} and Comella, {Joan X.} and Rhonda Bassel-Duby and Flavell, {Richard A.} and Olson, {Eric N.} and Smith, {Christopher W J} and Daniel Sanchis",
year = "2013",
month = "4",
day = "1",
doi = "10.1242/jcs.121384",
language = "English (US)",
volume = "126",
pages = "1682--1691",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "7",

}

TY - JOUR

T1 - A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart

AU - Ye, Junmei

AU - Llorian, Miriam

AU - Cardona, Maria

AU - Rongvaux, Anthony

AU - Moubarak, Rana S.

AU - Comella, Joan X.

AU - Bassel-Duby, Rhonda

AU - Flavell, Richard A.

AU - Olson, Eric N.

AU - Smith, Christopher W J

AU - Sanchis, Daniel

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

KW - Cardiomyocyte

KW - Differentiation

KW - Gene expression

KW - Myocyte enhancer factor-2

KW - Polypyrimidine tract binding protein

UR - http://www.scopus.com/inward/record.url?scp=84877943805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877943805&partnerID=8YFLogxK

U2 - 10.1242/jcs.121384

DO - 10.1242/jcs.121384

M3 - Article

C2 - 23424201

AN - SCOPUS:84877943805

VL - 126

SP - 1682

EP - 1691

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 7

ER -