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Article: p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs

Titlep53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs
Authors
KeywordsMdm2
cardiomyocyte proliferation
p53
Cell cycle
Issue Date2017
Citation
Cell Cycle, 2017, v. 16, n. 17, p. 1585-1600 How to Cite?
Abstract© 2017 Taylor & Francis. Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21Cip1and p27Kip1. Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.
Persistent Identifierhttp://hdl.handle.net/10722/293035
ISSN
2023 Impact Factor: 3.4
2023 SCImago Journal Rankings: 0.947
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorStanley-Hasnain, Shanna-
dc.contributor.authorHauck, Ludger-
dc.contributor.authorGrothe, Daniela-
dc.contributor.authorAschar-Sobbi, Roozbeh-
dc.contributor.authorBeca, Sanja-
dc.contributor.authorButany, Jagdish-
dc.contributor.authorBackx, Peter H.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorBillia, Filio-
dc.date.accessioned2020-11-17T14:57:44Z-
dc.date.available2020-11-17T14:57:44Z-
dc.date.issued2017-
dc.identifier.citationCell Cycle, 2017, v. 16, n. 17, p. 1585-1600-
dc.identifier.issn1538-4101-
dc.identifier.urihttp://hdl.handle.net/10722/293035-
dc.description.abstract© 2017 Taylor & Francis. Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21Cip1and p27Kip1. Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.-
dc.languageeng-
dc.relation.ispartofCell Cycle-
dc.subjectMdm2-
dc.subjectcardiomyocyte proliferation-
dc.subjectp53-
dc.subjectCell cycle-
dc.titlep53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1080/15384101.2017.1346758-
dc.identifier.pmid28745540-
dc.identifier.pmcidPMC5587026-
dc.identifier.scopuseid_2-s2.0-85027313913-
dc.identifier.volume16-
dc.identifier.issue17-
dc.identifier.spage1585-
dc.identifier.epage1600-
dc.identifier.eissn1551-4005-
dc.identifier.isiWOS:000410724400008-
dc.identifier.issnl1551-4005-

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