The mammalian target of rapamycin signaling pathway regulates myocyte enhancer factor‐2C phosphorylation levels through integrin‐linked kinase in goat skeletal muscle satellite cells
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Abstract:
Mammalian target of rapamycin (mTOR) signaling pathway plays a key role in muscle development and is involved in multiple intracellular signaling pathways. Myocyte enhancer factor-2 (MEF2) regulates muscle cell proliferation and differentiation. However, how the mTOR signaling pathway regulates MEF2 activity remains unclear. We isolated goat skeletal muscle satellite cells (gSSCs) as model cells to explore mTOR signaling pathway regulation of MEF2C. We inhibited mTOR activity in gSSCs with PP242 and found that MEF2C phosphorylation was decreased and that muscle creatine kinase (MCK) expression was suppressed. Subsequently, we detected integrin-linked kinase (ILK) using MEF2C coimmunoprecipitation; ILK and MEF2C were colocalized in the gSSCs. We found that inhibiting mTOR activity increased ILK phosphorylation levels and that inhibiting ILK activity with Cpd 22 and knocking down ILK with small interfering RNA increased MEF2C phosphorylation and MCK expression. In the presence of Cpd 22, mTOR activity inhibition did not affect MEF2C phosphorylation. Moreover, ILK dephosphorylated MEF2C in vitro. These results suggest that the mTOR signaling pathway regulates MEF2C positively and regulates ILK negatively and that ILK regulates MEF2C negatively. It appears that the mTOR signaling pathway regulates MEF2C through ILK, further regulating the expression of muscle-related genes in gSSCs.Keywords:
Mef2
MEF2C
Integrin-linked kinase
MEF2C
Mef2
Enhancer RNAs
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Objective To explore the effects of myocyte enhancer factor 2C(MEF2C) on the expression regulation of DOK5.Methods RT-PCR was carried out to detect the tissue distribution of mouse DOK5gene and the expression level of DOK5 and MEF2C during P19CL6 cells differentiated into cardiomyocytes.The effect of MEF2C on DOK5 promoter was confirmed by co-transfection studies.Results The expression of DOK5 was rich in brain,muscle and heart.The mRNA level of DOK5 and MEF2C was enhanced during P19CL6 cells differentiation into cardiomyocytes(P0.05).Over-expression of MEF2C increased the promoter activity of DOK5.Furthermore,site-directed mutagenesis demonstrated that MEF2C was crucial for activating DOK5 promoter.ConclusionMEF2C enhanced the transcription of DOK5 through MEF2 binding site on DOK5 promoter.
MEF2C
Mef2
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Myocyte enhancer factors (MEF2s) bind to muscle-specific promoters and activate transcription. Drosophila Mef2 is essential for Drosophila heart development, however, neither MEF2C nor MEF2B are essential for the early stages of murine cardiomyogenesis. Although Mef2c-null mice were defective in the later stages of heart morphogenesis, differentiation of cardiomyocytes still occurred. Since there are four isoforms of MEF2 factors (MEF2A, MEF2B, MEF2C and MEF2D), the ability of cells to differentiate may have been confounded by genetic redundancy. To eliminate this variable, the effect of a dominant-negative MEF2 mutant (MEF2C/EnR) during cardiomyogenesis was examined in transgenic mice and P19 cells. Targeting the expression of MEF2C/EnR to cardiomyoblasts using an Nkx2-5 enhancer in the P19 system resulted in the loss of both cardiomyocyte development and the expression of GATA4, BMP4, Nkx2-5 and MEF2C. In transiently transgenic mice, MEF2C/EnR expression resulted in embryos that lacked heart structures and exhibited defective differentiation. Our results show that MEF2C, or genes containing MEF2 DNA-binding sites, is required for the efficient differentiation of cardiomyoblasts into cardiomyocytes, suggesting conservation in the role of MEF2 from Drosophila to mammals.
MEF2C
Mef2
GATA4
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A variety of cardiac transcription factors/cofactors, signaling pathways, and downstream structural genes integrate to form the regulatory hierarchies to ensure proper cardiogenesis in vertebrate. Major interaction proteins of the transcription cofactor vestigial like family member 4 (VGLL4) include myocyte enhancer factor 2 (MEF2) and TEA domain transcription factors (TEAD), both of which play important roles in embryonic cardiac development and in adulthood. In this study, we identified that the deficiency of zebrafish vgll4b paralog, a unique family member expressed in developing heart, led to an impaired valve development. Mechanistically, in vgll4b mutant embryos the disruption of Vgll4b-Mef2c complex, rather than that of Vgll4b-Tead complex, resulted in an aberrant expression of krüppel-like factor 2a (klf2a) in endocardium. Such misexpression of klf2a eventually evoked the valvulogenesis defects. Our findings suggest that zebrafish Vgll4b plays an important role in modulating the transcription activity of Mef2c on klf2a during valve development in a blood-flow-independent manner.
Mef2
MEF2C
GATA4
GATA2
GATA transcription factor
Heart development
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Mef2
MEF2C
Myogenic regulatory factors
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MEF2C
Mef2
Coding region
Homology
Myogenic regulatory factors
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Myogenic enhancer transcription factor 2c (MEF2c), one of the members of the MEF2 family of transcription factors, plays an important role in mammalian muscle development. However, the role of MEF2c in avian muscle development still remains unclear. To understand the function of MEF2c in avian muscle development, we first cloned the duck MEF2c coding domain sequence (CDS) and analyzed MEF2c expression in duck muscle tissues of embryos from 10 days of incubation to 1 week after birth using real-time PCR technology. The results showed that the duck MEF2c CDS consists of 1,398 nucleotides that encode 465 amino acids. The MEF2c duck protein contains a MADS domain, a MEF2 domain and a HJURP_C domain with high homology to related proteins in other organisms. Different expression levels of MEF2c were found in skeletal, smooth and cardiac muscle. Therefore, these results indicated that duck MEF2c has two conserved domains (a MADS and a MEF2 domain), is an indispensable regulator of muscle development, and plays an important role in the development of duck muscle.
MEF2C
Mef2
Coding region
Dysferlin
ACVR2B
Homology
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Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c -null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3 -null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.
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Myocyte enhancer factor (MEF2) are MADS box transcription factors that play important roles in the regulation of myogenesis and morphogenesis of muscle cells. MEF2 proteins are activated by mechanical overload in the heart. In this study, we found the interaction of MEF2C with the regulatory protein Ki‐1/57 using yeast two‐hybrid system. This interaction was confirmed by GST‐pull down assay in vitro and by co‐immunoprecipitation in vivo. This interaction is also dependent on pressure overload in the heart. Co‐imunoprecipitation assay with anti‐MEF2 and anti‐Ki‐1/57 antibodies demonstrated a basal association between these proteins in the left ventricles of control rats. Pressure overload caused a reduction in this association. Ki‐1/57 co‐localizes with MEF2 in the nucleus of myocytes of control rats. However, after submitting the animals to pressure overload Ki‐1/57 leaves the nucleus thereby decreasing this co‐localization. Ki‐1/57 also exerts an inhibitory effect upon MEF2C DNA binding activity. These results suggest that Ki‐1/57 is a new interacting partner of MEF2 protein and may be involved in the regulation of MEF2 at the onset of hypertrophy.
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