Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity

Koichiro Kuwahara, Gordon C. Teg Pipes, John McAnally, James A Richardson, Joseph A Hill, Rhonda S Bassel-Duby, Eric N Olson

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

Original languageEnglish (US)
Pages (from-to)1324-1334
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number5
DOIs
StatePublished - May 1 2007

Fingerprint

MEF2 Transcription Factors
Serum Response Factor
Microfilament Proteins
Cytoskeletal Proteins
Calcineurin
Cardiomegaly
Cytoskeleton
Cardiomyopathies
human ABRA protein
Binding Sites
Pressure
Muscles
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity. / Kuwahara, Koichiro; Teg Pipes, Gordon C.; McAnally, John; Richardson, James A; Hill, Joseph A; Bassel-Duby, Rhonda S; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 117, No. 5, 01.05.2007, p. 1324-1334.

Research output: Contribution to journalArticle

@article{13f004483b8d4c25b19c6c62ec86d7b1,
title = "Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity",
abstract = "Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.",
author = "Koichiro Kuwahara and {Teg Pipes}, {Gordon C.} and John McAnally and Richardson, {James A} and Hill, {Joseph A} and Bassel-Duby, {Rhonda S} and Olson, {Eric N}",
year = "2007",
month = "5",
day = "1",
doi = "10.1172/JCI31240",
language = "English (US)",
volume = "117",
pages = "1324--1334",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity

AU - Kuwahara, Koichiro

AU - Teg Pipes, Gordon C.

AU - McAnally, John

AU - Richardson, James A

AU - Hill, Joseph A

AU - Bassel-Duby, Rhonda S

AU - Olson, Eric N

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

AB - Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

UR - http://www.scopus.com/inward/record.url?scp=34248168531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248168531&partnerID=8YFLogxK

U2 - 10.1172/JCI31240

DO - 10.1172/JCI31240

M3 - Article

C2 - 17415416

AN - SCOPUS:34248168531

VL - 117

SP - 1324

EP - 1334

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -