MEF2D Deficiency in Neonatal Cardiomyocytes Triggers Cell Cycle Re-entry and Programmed Cell Death in Vitro

Estrella, Nelsa L.; Clark, Amanda; Desjardins, Cody A.; Nocco, Sarah E.; Naya, Francisco J.

doi:10.1074/jbc.m115.666461

Cited by 23 publications

(21 citation statements)

References 48 publications

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“…MEF2D inhibition also resulted in a significant reduction in cardiomyocyte viability and increase in caspase-3 activity ( Fig. 1E), consistent with our previous analysis (24). By contrast, inhibition of MEF2C did not impair NRVM survival ( Fig.…”

Section: Neonatal Cardiomyocyte Survival Is Dependent On Mef2a or -D supporting

confidence: 91%

“…Perturbations in these processes can lead to catastrophic events, including programmed cell death. We have previously reported a requirement for MEF2A and -D in neonatal cardiomyocyte survival through their regulation of the cytoarchitecture (costamere) and cell cycle, respectively (23,24). The precise relationship between these and other MEF2 isoforms in regulating survival has not been fully explored.…”

Section: Neonatal Cardiomyocyte Survival Is Dependent On Mef2a or -D mentioning

confidence: 99%

“…Previously, we reported a function for MEF2D in cardiomyocyte survival and genomic DNA integrity (24). Based on the distinct effects of MEF2 proteins in these processes in MEF2Adeficient cardiomyocytes, we next wanted to evaluate MEF2 overexpression in MEF2D-deficient NRVMs.…”

Section: Mef2 Overexpression In Mef2d-deficient Cardiomyocytesmentioning

confidence: 99%

“…We have previously reported that neonatal cardiomyocyte homeostasis is dependent on MEF2. Cytoarchitectural (costamere/muscle focal adhesion) and cell-cycle gene programs in neonatal cardiomyocytes were shown to be regulated by MEF2A and MEF2D protein isoforms, respectively (23,24). Interestingly, defects in these distinct gene programs both led to severely impaired cardiomyocyte survival.…”

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confidence: 99%

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Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors

Desjardins

Naya

2017

Journal of Biological Chemistry

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Cardiomyocytes acquire their primary specialized function (contraction) before exiting the cell cycle. In this regard, proliferation and differentiation must be precisely coordinated for proper cardiac morphogenesis. Here, we have investigated the complex transcriptional mechanisms employed by cardiomyocytes to coordinate antagonistic cell-cycle and differentiation gene programs through the molecular dissection of the core cardiac transcription factor, MEF2. Knockdown of individual MEF2 proteins, MEF2A, -C, and -D, in primary neonatal cardiomyocytes resulted in radically distinct and opposite effects on cellular homeostasis and gene regulation. MEF2A and MEF2D were absolutely required for cardiomyocyte survival, whereas MEF2C, despite its major role in cardiac morphogenesis and direct reprogramming, was dispensable for this process. Inhibition of MEF2A or -D also resulted in the activation of cell-cycle genes and down-regulation of markers of terminal differentiation. In striking contrast, the regulation of cell-cycle and differentiation gene programs by MEF2C was antagonistic to that of MEF2A and -D. Computational analysis of regulatory regions from MEF2 isoform-dependent gene sets identified the Notch and Hedgehog signaling pathways as key determinants in coordinating MEF2 isoform-specific control of antagonistic gene programs. These results reveal that mammalian MEF2 family members have distinct transcriptional functions in cardiomyocytes and suggest that these differences are critical for proper development and maturation of the heart. Analysis of MEF2 isoform-specific function in neonatal cardiomyocytes has yielded insight into an unexpected transcriptional regulatory mechanism by which these specialized cells utilize homologous members of a core cardiac transcription factor to coordinate cell-cycle and differentiation gene programs.

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Section: Neonatal Cardiomyocyte Survival Is Dependent On Mef2a or -D supporting

confidence: 91%

Section: Neonatal Cardiomyocyte Survival Is Dependent On Mef2a or -D mentioning

confidence: 99%

Section: Mef2 Overexpression In Mef2d-deficient Cardiomyocytesmentioning

confidence: 99%

mentioning

confidence: 99%

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Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors

Desjardins

Naya

2017

Journal of Biological Chemistry

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“…Specifically, activation of PKA by catecholamine treatment or deletion of the PKA regulatory subunit I α (PKARI α ) induced apoptosis by repressing the prosurvival function of myocyte enhancer factor 2 (MEF2) [218, 220] or by enhancing CREB-binding protein (CBP) and c-Myc-dependent transcription of Bim [219]. Moreover, hypoxia/reoxygenation-induced apoptosis is mediated by downregulation of PKARI α and consequent activation of p90 ribosomal S6 Kinase 1 (RSK1) [221].…”

Section: Pkamentioning

confidence: 99%

Signaling Pathways in Cardiac Myocyte Apoptosis

Xia

Liu

Cheng

2016

BioMed Research International

133

132

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Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation.

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The Molecular and Biological Function of MEF2D in Leukemia

Zhang,

2024

Transcription Factors in Blood Cell Development

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MEF2D Deficiency in Neonatal Cardiomyocytes Triggers Cell Cycle Re-entry and Programmed Cell Death in Vitro

Cited by 23 publications

References 48 publications

Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors

Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors

Signaling Pathways in Cardiac Myocyte Apoptosis

The Molecular and Biological Function of MEF2D in Leukemia

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