Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

Chen, Ming; Yi, Bing; Sun, Jianxin

doi:10.1074/jbc.m114.577494

Cited by 42 publications

(40 citation statements)

References 47 publications

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“…Direct interaction of GATA4 with NFAT has been shown to synergistically regulate the hypertrophic gene expression in the heart (31,32). In addition, the transcriptional activity of GATA4 is regulated by posttranslational modifications, such as phosphorylation, acetylation, and methylation (4,37,38). Both MAP kinase and phosphatidylinositol (PI) 3-kinase/Akt/glycogen synthase kinase (GSK) pathways can phosphorylate GATA4 and regulate its transcriptional activity in the heart (4, 39).…”

Section: Discussionmentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (␤-AR) activation. However, the functional significance of Nur77 in ␤-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time-and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the ␤-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure. Cardiac hypertrophy is an adaptive process in response to various physiological or pathological stimuli associated with neurohumoral activation, elevated wall stress, and changes in volume load (1). Although initially adaptive, persistent hypertrophy induced by pathological conditions like myocardial infarction and hypertension has detrimental consequences on the heart and eventually progresses to heart failure, a major cause of death and disability in the industrialized world (1). At cellular and molecular levels, cardiac hypertrophy is characterized by increased myocyte size, sarcomerogenesis, and reexpression of a set of fetal genes, such as the atrial natriuretic factor, B-type natriuretic peptide, and ␤-myosin heavy chain genes, which are coordinately controlled by a subset of hypertrophy-responsive transcription factors, including myocyte enhancer factor 2 (MEF2), nuclear factor of activated T cells (NFAT), and GATA4 (2, 3) (4). Depending on the upstream hypertrophic stimuli, these transcriptional regulators can be directly phosphorylated or dephosphorylated by protein kinases, such as mitogen-activated protein (MAP) kinase and protein kinases A and C, as well as the calcium-activated phosphatase calcineurin, to facilitate hypertrophic gene expression (5-9). Disruption and/or attenuation of the activities of these transcription factors could serve as a potential therapeutic approach in terms of inhibiting the hypertrophic responses in the heart (10-12).NR4A receptors are immediate early genes that are regulated by various ...

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Section: Discussionmentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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“…Conversely, phosphorylation of MEP50 on T5 increases the methyltransferase activity of PRMT5–MEP50 toward H4 [118], potentially by increased affinity for histone substrates. Finally, PRMT5 can influence the activity of other enzymes, as PRMT5 methylation of the transcription factor GATA4 inhibits p300-mediated GATA4 acetylation [119]. …”

Section: Introductionmentioning

confidence: 99%

“…Strikingly, this arginine methylation enhanced NaV1.5 cell surface localization and current density, showing that this regulation may be a previously unknown component of heart health and disease [157]. PRMT5 also was shown to interact with GATA4 in cardiomyocytes and methylated it on three Arg residues, inhibiting the ability of GATA4 to promote transcriptional activation [119]. …”

Section: Introductionmentioning

confidence: 99%

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Stopa

Krebs

Shechter

2015

Cell. Mol. Life Sci.

366

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Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymo-logical studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

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“…Metabolites either participating in or that are products of cellular methylation reactions are shifted during mucosal inflammatory responses . The role of methylation in inflammation has been investigated in human diseases characterized by inflammatory disorders . In TLR4‐mediated signaling, both membrane protein carboxyl methylation and histone methylation are critical for transcriptional activation of LPS‐induced proinflammatory gene expressions .…”

Section: Introductionmentioning

confidence: 99%

Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF‐κB in glomerular mesangial cells

Tsai

Lee

Chen

et al. 2018

J of Cellular Biochemistry

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Lipopolysaccharide (LPS) released from gram-negative bacteria stimulates immune responses in infected cells. Epigenetic modifications such as DNA methylation and protein methylation modulate LPS-induced innate immune gene expressions. Expression of the Klotho protein decreased with LPS treatment in rats. In a cellular model, information regarding the effect of LPS on Klotho expression was meager. In the present study, we demonstrated that LPS triggered global DNA and protein methylation in glomerular mesangial MES-13 cells. LPS upregulated protein expressions of enzymes central to cellular methylation reactions, especially protein arginine methyltransferase 6 (PRMT6) in MES-13 cells. Expression of the Klotho protein was diminished by LPS and was restored by 5-Aza-2'-deoxycytidine (5-Aza-2'-dc), AMI-1, and ammonium pyrrolidinedithiocarbamate (PDTC), but not adenosine aldehyde (AdOx). NF-κB was identified as a substrate for arginine methylation and interacted with PRMT6 in MES-13 cells. Inhibition of PRMT activity by AMI-1 blocked LPS-induced NF-κB nuclear translocation in MES-13 cells. Our data indicate that NF-κB negatively regulated Klotho expression with an interaction with PRMT6, which was upregulated by LPS in MES-13 cells.

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Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

Cited by 42 publications

References 47 publications

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF‐κB in glomerular mesangial cells

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