Disease relevance of MEF2A

• In addition, it is speculated that p300 might modulate the activity of the TR-RxR-MEF2A complex by recruiting a hypothetical endogenous inhibitor which may act like adenovirus E1A [1].
• RECENT FINDINGS: Positional cloning based on genome-wide linkage analysis with large families identified the first non - lipid-related disease-causing gene, MEF2A (encoding a transcriptional factor), for coronary artery disease and myocardiaI infarction [2].
• These results identify a pathogenic gene for a familial vascular disease with features of CAD and implicate the MEF2A signaling pathway in the pathogenesis of CAD/MI [3].
• The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions [4].
• We examined the expression of the MEF2 genes in mouse embryonal carcinoma P19 cells before and after in vitro muscle differentiation induced by dimethyl sulfoxide (DMSO) [5].

High impact information on MEF2A

• Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins [6].
• This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors, but only one of the factors needed a transactivation domain, and only one of the factors needed to be bound to DNA [6].
• Several MEF2 co-repressors, such as Cabin1/Cain and class II histone deacetylases (HDACs), have been identified [7].
• The myocyte enhancer factor-2 (MEF2) family of transcription factors has important roles in the development and function of T cells, neuronal cells and muscle cells [7].
• Execution of the muscle differentiation program requires release of MEF2 from repression by HDACs, which are expressed constitutively in myoblasts and myotubes [8].

Chemical compound and disease context of MEF2A

• Finally, Ang II increased protein synthesis, and this increase was inhibited by infection with an adenovirus construct that expresses the dominant-negative mutant of MEF2A but not by calcineurin inhibitors [9].

Biological context of MEF2A

• However, we did identify the 21-bp MEF2A coding sequence deletion originally implicated in adCAD1 in 1 of 300 elderly control subjects without CAD [10].
• In the nucleus, HDAC4 associates with the myocyte enhancer factor MEF2A [11].
• Finally, GEF and MEF2A coimmunoprecipitated in vivo, strongly supporting a mechanism of GLUT4 transcription activation that depends on this protein-protein interaction [12].
• Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation [13].
• Using immuno-gel shift analysis and also co-immunoprecipitation studies, we show that the predominant MEF2 DNA binding complex bound to MEF2 sites from either the muscle creatine kinase or c-jun regulatory regions in C2C12 muscle cells is comprised of a MEF2A homodimer, whereas in HeLa cells, it is a MEF2A:MEF2D heterodimer [14].

Anatomical context of MEF2A

• Lack of MEF2A mutations in coronary artery disease [10].
• By immunofluorescence, we detected abundant nuclear localized MEF2A and MEF2D protein expression in HeLa cells and C2C12 muscle cells [14].
• These results demonstrate a promoter- and cell-specific functional interaction between PITX2 and MEF2A and suggest the possibility of coordinate control by these factors in the oral epithelium [15].
• In contrast to both cardiac and skeletal muscle, adipose tissue displays a selective decrease in MEF2D expression in diabetes without any significant alteration in MEF2A protein content [16].
• The MEF2A and MEF2D isoforms are differentially regulated in muscle and adipose tissue during states of insulin deficiency [16].

Associations of MEF2A with chemical compounds

• A similar activity is present in the constitutive gamma domain and serine phosphoacceptor of MEF2A [17].
• The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter [18].
• p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor [1].
• Metformin also increased mRNA expression of the MEF2 isoforms [19].
• COS cells overexpressing MEF2A alone or with one of the kinases were metabolically labeled with [32P]orthophosphate and MEF2A was immunoprecipitated using specific anti-MEF2A antibodies [20].

Physical interactions of MEF2A

• The MEF2 domain binds transcription factors MEF2A and MEF2D in vivo [12].
• Furthermore, immunodepletion of the MEF2A-MEF2D complex from control extracts abolished binding to the MEF2 element [18].
• Deletion of the GEF-binding domain (domain I) and the MEF2-binding domain prevented activation, strengthening the conclusion that promoter regulation occurs through these elements [12].
• We report that HDAC4 and MITR contain calmodulin-binding domains that overlap with their MEF2-binding domains [21].
• Here, we have characterized the complex between the MEF2-binding motif of class II HDACs and the MADS-box/MEF2S domain of MEF2B by structural and biochemical methods [22].

Enzymatic interactions of MEF2A

• Threonines 312 and 319 within the transcription activation domain of MEF2A are the regulatory sites phosphorylated by p38 [23].
• Taken together, these data demonstrate that, upon growth factor induction, BMK1 directly phosphorylates and activates three members of the MEF2 family of transcription factors thereby inducing MEF2-dependent gene expression [24].

Regulatory relationships of MEF2A

• Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays [25].
• Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together [12].
• In this study, we examined the potential role of the p38 MAP kinase pathway in regulating the other MEF2 family members [23].
• The blocking of BMK1 signaling inhibits the epidermal growth factor-dependent activation of these three MEF2 transcription factors [24].
• Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis [4].

Other interactions of MEF2A

• These results identify MEF2A as a nuclear target for HDAC4-mediated repression and suggests that compartmentalization may be a novel mechanism for controlling the nuclear activity of this new family of deacetylases [11].
• Here we show that HDAC7, a member of the class II histone deacetylases, specifically targets several members of myocyte enhancer factors, MEF2A, -2C, and -2D, and inhibits their transcriptional activity [26].
• We have examined the interaction of PITX2 isoforms with myocyte-enhancing factor 2A (MEF2A), which is a known regulator of cardiac development [15].
• A partially processed pseudogene (MEF2AP) corresponding to MEF2A was also isolated and characterized [27].
• We have shown, by using transgenic mice, that the human GLUT4 promoter is regulated through the cooperative function of two distinct regulatory elements, domain 1 and the myocyte enhancer factor 2 (MEF2) domain [12].

Analytical, diagnostic and therapeutic context of MEF2A

• PCR primers were also used to identify individual YAC clones for two of the genes, MEF2A and MEF2C, and a PCR product was used to identify cosmid clones for MEF2B [28].
• Human MEF2A was mapped by fluorescence in situ hybridization to chromosome 15q26, and MEF2AP was mapped to chromosome 1q24 --> q25 [27].
• Electrophoretic mobility shift assays revealed that nuclear extracts from diabetic animals had reduced binding to the MEF2 binding site compared with extracts from control or insulin-treated animals [18].
• Sequence analysis of human MEF2 cDNA clones suggests that they arose from alternatively spliced transcripts of four different genes, termed MEF2A-D [28].
• Northern blot analysis showed that MyoD, myf-5 and MEF2C transcripts were present in three-somite embryos, whereas myogenin and MEF2A transcripts were not detected until the 15-somite stage [29].

References