LymphedemaV1, Main, Curation, bibRecord, 002044

Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis

Identifieur interne : 002044 ( Main/Curation ); précédent : 002043; suivant : 002045

Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis

Auteurs : Wassim A. Basheer [États-Unis] ; Brett S. Harris [États-Unis] ; Heather L. Mentrup [États-Unis] ; Measho Abreha [États-Unis] ; Elizabeth L. Thames [États-Unis] ; Jessica B. Lea [États-Unis] ; Deborah A. Swing [États-Unis] ; Neal G. Copeland [États-Unis] ; Nancy A. Jenkins [États-Unis] ; Robert L. Price [États-Unis] ; Lydia E. Matesic [États-Unis]

Source :

Journal of molecular and cellular cardiology [ 0022-2828 ] ; 2015.

RBID : PMC:4641030

Abstract

Gap junctions (GJ) are intercellular channels composed of connexin subunits that play a critical role in a diverse number of cellular processes in all tissue types. In the heart, GJs mediate electrical coupling between cardiomyocytes and display mislocalization and/or downregulation in cardiac disease (a process known as GJ remodeling), producing an arrhythmogenic substrate. The main constituent of GJs in the ventricular myocardium is connexin 43 (Cx43), an integral membrane protein that is rapidly turned over and shows decreased expression or function with age. We hypothesized that Wwp1, an ubiquitin ligase whose expression in known to increase in aging-related pathologies, may regulate Cx43 in vivo by targeting it for ubiquitylation and degradation and yield tissue-specific Cx43 loss of function phenotypes. When Wwp1 was globally overexpressed in mice under the control of a β-actin promoter, the highest induction of Wwp1 expression was observed in the heart which was associated with a 90% reduction in cardiac Cx43 protein levels, left ventricular hypertrophy (LVH), and the development of lethal ventricular arrhythmias around 8 weeks of age. This phenotype was completely penetrant in two independent founder lines. Cardiomyocyte-specific overexpression of Wwp1 confirmed that this phenotype was cell autonomous and delineated Cx43-dependent and –independent roles for Wwp1 in arrhythmogenesis and LVH, respectively. Using a cell-based system, it was determined that Wwp1 co-immunoprecipitates with and ubiquitylates Cx43, causing a decrease in the steady state levels of Cx43 protein. These findings offer new mechanistic insights into the regulation of Cx43 which may be exploitable in various gap junctionopathies.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641030

DOI: 10.1016/j.yjmcc.2015.09.004
PubMed: 26386426
PubMed Central: 4641030

Links toward previous steps (curation, corpus...)

to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :003292
to stream Pmc, to step Curation: Pour aller vers cette notice dans l'étape Curation :003291
to stream Pmc, to step Checkpoint: Pour aller vers cette notice dans l'étape Curation :001441
to stream Ncbi, to step Merge: Pour aller vers cette notice dans l'étape Curation :007902
to stream Ncbi, to step Curation: Pour aller vers cette notice dans l'étape Curation :007902
to stream Ncbi, to step Checkpoint: Pour aller vers cette notice dans l'étape Curation :007902
to stream Main, to step Merge: Pour aller vers cette notice dans l'étape Curation :002047

Links to Exploration step

PMC:4641030

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis</title>
<author><name sortKey="Basheer, Wassim A" sort="Basheer, Wassim A" uniqKey="Basheer W" first="Wassim A." last="Basheer">Wassim A. Basheer</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Harris, Brett S" sort="Harris, Brett S" uniqKey="Harris B" first="Brett S." last="Harris">Brett S. Harris</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425</wicri:regionArea>
<wicri:noRegion>SC 29425</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mentrup, Heather L" sort="Mentrup, Heather L" uniqKey="Mentrup H" first="Heather L." last="Mentrup">Heather L. Mentrup</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Abreha, Measho" sort="Abreha, Measho" uniqKey="Abreha M" first="Measho" last="Abreha">Measho Abreha</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Thames, Elizabeth L" sort="Thames, Elizabeth L" uniqKey="Thames E" first="Elizabeth L." last="Thames">Elizabeth L. Thames</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lea, Jessica B" sort="Lea, Jessica B" uniqKey="Lea J" first="Jessica B." last="Lea">Jessica B. Lea</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Swing, Deborah A" sort="Swing, Deborah A" uniqKey="Swing D" first="Deborah A." last="Swing">Deborah A. Swing</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Copeland, Neal G" sort="Copeland, Neal G" uniqKey="Copeland N" first="Neal G." last="Copeland">Neal G. Copeland</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Jenkins, Nancy A" sort="Jenkins, Nancy A" uniqKey="Jenkins N" first="Nancy A." last="Jenkins">Nancy A. Jenkins</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Price, Robert L" sort="Price, Robert L" uniqKey="Price R" first="Robert L." last="Price">Robert L. Price</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209</wicri:regionArea>
<wicri:noRegion>SC 29209</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Matesic, Lydia E" sort="Matesic, Lydia E" uniqKey="Matesic L" first="Lydia E." last="Matesic">Lydia E. Matesic</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26386426</idno>
<idno type="pmc">4641030</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641030</idno>
<idno type="RBID">PMC:4641030</idno>
<idno type="doi">10.1016/j.yjmcc.2015.09.004</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">003292</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003292</idno>
<idno type="wicri:Area/Pmc/Curation">003291</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">003291</idno>
<idno type="wicri:Area/Pmc/Checkpoint">001441</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">001441</idno>
<idno type="wicri:Area/Ncbi/Merge">007902</idno>
<idno type="wicri:Area/Ncbi/Curation">007902</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">007902</idno>
<idno type="wicri:doubleKey">0022-2828:2015:Basheer W:cardiomyocyte:specific:overexpression</idno>
<idno type="wicri:Area/Main/Merge">002047</idno>
<idno type="wicri:Area/Main/Curation">002044</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis</title>
<author><name sortKey="Basheer, Wassim A" sort="Basheer, Wassim A" uniqKey="Basheer W" first="Wassim A." last="Basheer">Wassim A. Basheer</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Harris, Brett S" sort="Harris, Brett S" uniqKey="Harris B" first="Brett S." last="Harris">Brett S. Harris</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425</wicri:regionArea>
<wicri:noRegion>SC 29425</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mentrup, Heather L" sort="Mentrup, Heather L" uniqKey="Mentrup H" first="Heather L." last="Mentrup">Heather L. Mentrup</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Abreha, Measho" sort="Abreha, Measho" uniqKey="Abreha M" first="Measho" last="Abreha">Measho Abreha</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Thames, Elizabeth L" sort="Thames, Elizabeth L" uniqKey="Thames E" first="Elizabeth L." last="Thames">Elizabeth L. Thames</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lea, Jessica B" sort="Lea, Jessica B" uniqKey="Lea J" first="Jessica B." last="Lea">Jessica B. Lea</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Swing, Deborah A" sort="Swing, Deborah A" uniqKey="Swing D" first="Deborah A." last="Swing">Deborah A. Swing</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Copeland, Neal G" sort="Copeland, Neal G" uniqKey="Copeland N" first="Neal G." last="Copeland">Neal G. Copeland</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Jenkins, Nancy A" sort="Jenkins, Nancy A" uniqKey="Jenkins N" first="Nancy A." last="Jenkins">Nancy A. Jenkins</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mouse Cancer Genetics Program, The National Cancer Institute at Frederick, Frederick, MD 21702</wicri:regionArea>
<wicri:noRegion>MD 21702</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Price, Robert L" sort="Price, Robert L" uniqKey="Price R" first="Robert L." last="Price">Robert L. Price</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209</wicri:regionArea>
<wicri:noRegion>SC 29209</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Matesic, Lydia E" sort="Matesic, Lydia E" uniqKey="Matesic L" first="Lydia E." last="Matesic">Lydia E. Matesic</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biological Sciences, University of South Carolina, Columbia, SC 29208</wicri:regionArea>
<wicri:noRegion>SC 29208</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of molecular and cellular cardiology</title>
<idno type="ISSN">0022-2828</idno>
<idno type="eISSN">1095-8584</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P2">Gap junctions (GJ) are intercellular channels composed of connexin subunits that play a critical role in a diverse number of cellular processes in all tissue types. In the heart, GJs mediate electrical coupling between cardiomyocytes and display mislocalization and/or downregulation in cardiac disease (a process known as GJ remodeling), producing an arrhythmogenic substrate. The main constituent of GJs in the ventricular myocardium is connexin 43 (Cx43), an integral membrane protein that is rapidly turned over and shows decreased expression or function with age. We hypothesized that Wwp1, an ubiquitin ligase whose expression in known to increase in aging-related pathologies, may regulate Cx43 <italic>in vivo</italic>
 by targeting it for ubiquitylation and degradation and yield tissue-specific Cx43 loss of function phenotypes. When Wwp1 was globally overexpressed in mice under the control of a β-actin promoter, the highest induction of <italic>Wwp1</italic>
 expression was observed in the heart which was associated with a 90% reduction in cardiac Cx43 protein levels, left ventricular hypertrophy (LVH), and the development of lethal ventricular arrhythmias around 8 weeks of age. This phenotype was completely penetrant in two independent founder lines. Cardiomyocyte-specific overexpression of Wwp1 confirmed that this phenotype was cell autonomous and delineated Cx43-dependent and –independent roles for Wwp1 in arrhythmogenesis and LVH, respectively. Using a cell-based system, it was determined that Wwp1 co-immunoprecipitates with and ubiquitylates Cx43, causing a decrease in the steady state levels of Cx43 protein. These findings offer new mechanistic insights into the regulation of Cx43 which may be exploitable in various gap junctionopathies.</p>
</div>
</front>
</TEI>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Main/Curation

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002044 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/Main/Curation/biblio.hfd -nk 002044 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Wicri/Sante
   |area=    LymphedemaV1
   |flux=    Main
   |étape=   Curation
   |type=    RBID
   |clé=     PMC:4641030
   |texte=   Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Curation/RBID.i   -Sk "pubmed:26386426" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Curation/biblio.hfd   \
       | NlmPubMed2Wicri -a LymphedemaV1

This area was generated with Dilib version V0.6.31.
Data generation: Sat Nov 4 17:40:35 2017. Site generation: Tue Feb 13 16:42:16 2024

	Serveur d'exploration sur le lymphœdème
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.

Serveur d'exploration sur le lymphœdème

Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis

Cardiomyocyte-Specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis

Source :

Abstract

Links toward previous steps (curation, corpus...)

Links to Exploration step

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki