Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5

Rick B. Vega, Brooke C. Harrison, Eric Meadows, Charles R. Roberts, Philip J. Papst, Eric N. Olson, Timothy A. McKinsey

Research output: Contribution to journalArticle

390 Citations (Scopus)

Abstract

A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRMl-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.

Original languageEnglish (US)
Pages (from-to)8374-8385
Number of pages12
JournalMolecular and Cellular Biology
Volume24
Issue number19
DOIs
StatePublished - Oct 2004

Fingerprint

Histone Deacetylases
Cell Nucleus Active Transport
Cardiomegaly
Protein Kinase C
Cardiac Myocytes
Hypertrophy
Chromatin
Protamine Kinase
Cues
Heart Failure
Phosphorylation
protein kinase D
Pharmacology
Gene Expression
Enzymes
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. / Vega, Rick B.; Harrison, Brooke C.; Meadows, Eric; Roberts, Charles R.; Papst, Philip J.; Olson, Eric N.; McKinsey, Timothy A.

In: Molecular and Cellular Biology, Vol. 24, No. 19, 10.2004, p. 8374-8385.

Research output: Contribution to journalArticle

Vega, Rick B. ; Harrison, Brooke C. ; Meadows, Eric ; Roberts, Charles R. ; Papst, Philip J. ; Olson, Eric N. ; McKinsey, Timothy A. / Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 19. pp. 8374-8385.
@article{28b0b8b9572c4c53807309ec525d77ca,
title = "Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5",
abstract = "A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRMl-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.",
author = "Vega, {Rick B.} and Harrison, {Brooke C.} and Eric Meadows and Roberts, {Charles R.} and Papst, {Philip J.} and Olson, {Eric N.} and McKinsey, {Timothy A.}",
year = "2004",
month = "10",
doi = "10.1128/MCB.24.19.8374-8385.2004",
language = "English (US)",
volume = "24",
pages = "8374--8385",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "19",

}

TY - JOUR

T1 - Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5

AU - Vega, Rick B.

AU - Harrison, Brooke C.

AU - Meadows, Eric

AU - Roberts, Charles R.

AU - Papst, Philip J.

AU - Olson, Eric N.

AU - McKinsey, Timothy A.

PY - 2004/10

Y1 - 2004/10

N2 - A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRMl-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.

AB - A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRMl-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.

UR - http://www.scopus.com/inward/record.url?scp=4544315655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4544315655&partnerID=8YFLogxK

U2 - 10.1128/MCB.24.19.8374-8385.2004

DO - 10.1128/MCB.24.19.8374-8385.2004

M3 - Article

VL - 24

SP - 8374

EP - 8385

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 19

ER -