Cargando…

Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4

Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes h...

Descripción completa

Detalles Bibliográficos
Autores principales: Backs, Johannes, Worst, Barbara C., Lehmann, Lorenz H., Patrick, David M., Jebessa, Zegeye, Kreusser, Michael M., Sun, Qiang, Chen, Lan, Heft, Claudia, Katus, Hugo A., Olson, Eric N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206346/
https://www.ncbi.nlm.nih.gov/pubmed/22042619
http://dx.doi.org/10.1083/jcb.201105063
_version_ 1782215416481841152
author Backs, Johannes
Worst, Barbara C.
Lehmann, Lorenz H.
Patrick, David M.
Jebessa, Zegeye
Kreusser, Michael M.
Sun, Qiang
Chen, Lan
Heft, Claudia
Katus, Hugo A.
Olson, Eric N.
author_facet Backs, Johannes
Worst, Barbara C.
Lehmann, Lorenz H.
Patrick, David M.
Jebessa, Zegeye
Kreusser, Michael M.
Sun, Qiang
Chen, Lan
Heft, Claudia
Katus, Hugo A.
Olson, Eric N.
author_sort Backs, Johannes
collection PubMed
description Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects.
format Online
Article
Text
id pubmed-3206346
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-32063462012-04-30 Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4 Backs, Johannes Worst, Barbara C. Lehmann, Lorenz H. Patrick, David M. Jebessa, Zegeye Kreusser, Michael M. Sun, Qiang Chen, Lan Heft, Claudia Katus, Hugo A. Olson, Eric N. J Cell Biol Research Articles Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects. The Rockefeller University Press 2011-10-31 /pmc/articles/PMC3206346/ /pubmed/22042619 http://dx.doi.org/10.1083/jcb.201105063 Text en © 2011 Backs et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Backs, Johannes
Worst, Barbara C.
Lehmann, Lorenz H.
Patrick, David M.
Jebessa, Zegeye
Kreusser, Michael M.
Sun, Qiang
Chen, Lan
Heft, Claudia
Katus, Hugo A.
Olson, Eric N.
Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title_full Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title_fullStr Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title_full_unstemmed Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title_short Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4
title_sort selective repression of mef2 activity by pka-dependent proteolysis of hdac4
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206346/
https://www.ncbi.nlm.nih.gov/pubmed/22042619
http://dx.doi.org/10.1083/jcb.201105063
work_keys_str_mv AT backsjohannes selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT worstbarbarac selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT lehmannlorenzh selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT patrickdavidm selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT jebessazegeye selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT kreussermichaelm selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT sunqiang selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT chenlan selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT heftclaudia selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT katushugoa selectiverepressionofmef2activitybypkadependentproteolysisofhdac4
AT olsonericn selectiverepressionofmef2activitybypkadependentproteolysisofhdac4