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Gene Review

Myef2  -  myelin basic protein expression factor 2,...

Mus musculus

Synonyms: 9430071B01, Kiaa1341, MEF-2, Mef2, MyEF-2, ...
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Disease relevance of Myef2


High impact information on Myef2

  • The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression [6].
  • Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression [7].
  • Paradoxically, MEF2 transcriptional activity, revealed by the expression of a MEF2-dependent transgene, was enhanced in the hearts of Mef2a-mutant mice, reflecting the transcriptional activation of residual MEF2D [8].
  • We generated mice deficient in MEF2A, the predominant Mef2 gene product expressed in post-natal cardiac muscle [8].
  • Ectopically expressed mouse Twist (Mtwist) was shown to inhibit myogenesis by blocking DNA binding by MyoD, by titrating E proteins, and by inhibiting trans-activation by MEF2 [9].

Chemical compound and disease context of Myef2


Biological context of Myef2

  • In this report, we describe the molecular cloning and characterization of myelin gene expression factor-2 (Myef-2), a protein isolated from mouse brain that binds specifically to single-stranded DNA derived from the MB1 element and represses transcription of the MBP gene in transient transfection assay [11].
  • The myogenic basic helix-loop-helix (bHLH) and MEF2 transcription factors are expressed in the myotome of developing somites and cooperatively activate skeletal muscle gene expression [9].
  • Recent studies have revealed multiple signaling systems that stimulate and inhibit myogenesis by altering MEF2 phosphorylation and its association with other transcriptional cofactors [12].
  • Activation of muscle-specific genes by members of the myocyte enhancer factor 2 (MEF2) and MyoD families of transcription factors is coupled to histone acetylation and is inhibited by class II histone deacetylases (HDACs) 4 and 5, which interact with MEF2 [13].
  • Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis [14].

Anatomical context of Myef2

  • Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD [15].
  • Members of the MyoD and MEF2 families of transcription factors associate combinatorially to control myoblast specification, differentiation and proliferation [12].
  • By using immune electron microscopy and Western blot analysis on subcellular fractions, MEF2 was shown to be tightly associated with cytoskeleton membrane components [1].
  • A single MEF-2 site is a major positive regulatory element required for transcription of the muscle-specific subunit of the human phosphoglycerate mutase gene in skeletal and cardiac muscle cells [16].
  • In particular, MEF-2 binding activity was up-regulated in 10T1/2 cells stably transfected with a MyoD expression vector only after these cells fused and differentiated into skeletal myotubes [17].

Associations of Myef2 with chemical compounds

  • The ability of HDAC4 and -5 to inhibit MEF2 is blocked by phosphorylation of these HDACs at two conserved serine residues, which creates docking sites for the intracellular chaperone protein 14-3-3 [13].
  • During muscle regeneration, the enhancer activity was markedly inhibited by cancellation of the binding sites of MEF2, MyoD, or thyroid hormone receptors [18].
  • Chromatin immunoprecipitation demonstrated the in vivo recruitment of MEF2 and CARM1 to the endogenous muscle creatine kinase promoter in a differentiation-dependent manner [19].
  • Glutathione S-transferase pulldown and immunoprecipitation demonstrate that the repression mechanism involves direct interactions between MEF2 proteins and HDAC7 and is associated with the ability of MEF2 to interact with the N-terminal 121 amino acids of HDAC7 that encode repression domain 1 [20].
  • In the presence of cycloheximide, AVP up-regulates the expression of MEF2, but not of myogenin, indicating that the synthesis of a protein intermediate is not necessary for MEF2 induction [21].

Physical interactions of Myef2

  • These results support a model of transcriptional activation and stabilization of myogenin expression in which DNA-bound MEF2 recruits myogenic bHLH factors into an active but E1A-sensitive transcription factor complex [2].
  • During muscle differentiation, repression of gene transcription by MEF-2/HDAC complexes is relieved due to calcium/calmodulin-dependent (CaM) kinase-induced translocation of HDAC4 and HDAC5 to the cytoplasm [22].

Regulatory relationships of Myef2

  • Thus, the MRF4 promoter is regulated by the MEF2 and basic helix-loop-helix MRF protein family through a cross-regulatory circuitry [23].
  • We also observed that abrogation of p38 MAPK signaling blocks MEF2 activation using a MEF2 transgenic 'sensor' mouse [24].
  • Co-transfection of Gtx prevented the serum-induced activation of the MEF-2-containing reporter genes [25].
  • Furthermore, BMP-2 stimulated specific protein.DNA complex formation when an MEF-2 DNA recognition element was used as probe [26].

Other interactions of Myef2

  • Myef-2 mRNA is developmentally regulated in mouse brain; its peak expression occurs at postnatal day 7, prior to the onset of MBP expression [11].
  • The myogenin promoter contains two essential elements; an E-box and an A/T rich element that bind MRF and MEF2 transcription factors, respectively [15].
  • We propose a mechanism in which the inhibition of myogenesis by TGF-beta is mediated through MEF2 localization to the cytoplasm, thus preventing it from participating in an active transcriptional complex [1].
  • Located within the proximal promoter are a single MEF2 site and E box that are required for maximum MRF4 expression [23].
  • Enhancement by PC4 of MyoD-dependent activation of muscle gene promoters occurs selectively through MEF2 binding sites [27].

Analytical, diagnostic and therapeutic context of Myef2


  1. Inhibition of myogenesis by transforming growth factor beta is density-dependent and related to the translocation of transcription factor MEF2 to the cytoplasm. De Angelis, L., Borghi, S., Melchionna, R., Berghella, L., Baccarani-Contri, M., Parise, F., Ferrari, S., Cossu, G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  2. Transcriptional activation of the myogenin gene by MEF2-mediated recruitment of myf5 is inhibited by adenovirus E1A protein. Johanson, M., Meents, H., Ragge, K., Buchberger, A., Arnold, H.H., Sandmöller, A. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  3. Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2. Nakagawa, O., Arnold, M., Nakagawa, M., Hamada, H., Shelton, J.M., Kusano, H., Harris, T.M., Childs, G., Campbell, K.P., Richardson, J.A., Nishino, I., Olson, E.N. Genes Dev. (2005) [Pubmed]
  4. Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice. Xu, J., Gong, N.L., Bodi, I., Aronow, B.J., Backx, P.H., Molkentin, J.D. J. Biol. Chem. (2006) [Pubmed]
  5. MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. Kolodziejczyk, S.M., Wang, L., Balazsi, K., DeRepentigny, Y., Kothary, R., Megeney, L.A. Curr. Biol. (1999) [Pubmed]
  6. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Zhang, C.L., McKinsey, T.A., Chang, S., Antos, C.L., Hill, J.A., Olson, E.N. Cell (2002) [Pubmed]
  7. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Lin, J., Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z., Boss, O., Michael, L.F., Puigserver, P., Isotani, E., Olson, E.N., Lowell, B.B., Bassel-Duby, R., Spiegelman, B.M. Nature (2002) [Pubmed]
  8. Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Naya, F.J., Black, B.L., Wu, H., Bassel-Duby, R., Richardson, J.A., Hill, J.A., Olson, E.N. Nat. Med. (2002) [Pubmed]
  9. Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist. Spicer, D.B., Rhee, J., Cheung, W.L., Lassar, A.B. Science (1996) [Pubmed]
  10. Cooperative transcriptional activation by the neurogenic basic helix-loop-helix protein MASH1 and members of the myocyte enhancer factor-2 (MEF2) family. Black, B.L., Ligon, K.L., Zhang, Y., Olson, E.N. J. Biol. Chem. (1996) [Pubmed]
  11. Identification of a sequence-specific single-stranded DNA binding protein that suppresses transcription of the mouse myelin basic protein gene. Haas, S., Steplewski, A., Siracusa, L.D., Amini, S., Khalili, K. J. Biol. Chem. (1995) [Pubmed]
  12. MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Naya, F.J., Olson, E. Curr. Opin. Cell Biol. (1999) [Pubmed]
  13. The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Zhang, C.L., McKinsey, T.A., Olson, E.N. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  14. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Okamoto, S., Li, Z., Ju, C., Scholzke, M.N., Mathews, E., Cui, J., Salvesen, G.S., Bossy-Wetzel, E., Lipton, S.A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD. Friday, B.B., Mitchell, P.O., Kegley, K.M., Pavlath, G.K. Differentiation (2003) [Pubmed]
  16. A single MEF-2 site is a major positive regulatory element required for transcription of the muscle-specific subunit of the human phosphoglycerate mutase gene in skeletal and cardiac muscle cells. Nakatsuji, Y., Hidaka, K., Tsujino, S., Yamamoto, Y., Mukai, T., Yanagihara, T., Kishimoto, T., Sakoda, S. Mol. Cell. Biol. (1992) [Pubmed]
  17. A novel myogenic regulatory circuit controls slow/cardiac troponin C gene transcription in skeletal muscle. Parmacek, M.S., Ip, H.S., Jung, F., Shen, T., Martin, J.F., Vora, A.J., Olson, E.N., Leiden, J.M. Mol. Cell. Biol. (1994) [Pubmed]
  18. Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle. Moreno, H., Serrano, A.L., Santalucía, T., Gumá, A., Cantó, C., Brand, N.J., Palacin, M., Schiaffino, S., Zorzano, A. J. Biol. Chem. (2003) [Pubmed]
  19. The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. Chen, S.L., Loffler, K.A., Chen, D., Stallcup, M.R., Muscat, G.E. J. Biol. Chem. (2002) [Pubmed]
  20. A dynamic role for HDAC7 in MEF2-mediated muscle differentiation. Dressel, U., Bailey, P.J., Wang, S.C., Downes, M., Evans, R.M., Muscat, G.E. J. Biol. Chem. (2001) [Pubmed]
  21. AVP induces myogenesis through the transcriptional activation of the myocyte enhancer factor 2. Scicchitano, B.M., Spath, L., Musarò, A., Molinaro, M., Adamo, S., Nervi, C. Mol. Endocrinol. (2002) [Pubmed]
  22. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. Chawla, S., Vanhoutte, P., Arnold, F.J., Huang, C.L., Bading, H. J. Neurochem. (2003) [Pubmed]
  23. Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. Naidu, P.S., Ludolph, D.C., To, R.Q., Hinterberger, T.J., Konieczny, S.F. Mol. Cell. Biol. (1995) [Pubmed]
  24. Regulation of vertebrate myotome development by the p38 MAP kinase-MEF2 signaling pathway. de Angelis, L., Zhao, J., Andreucci, J.J., Olson, E.N., Cossu, G., McDermott, J.C. Dev. Biol. (2005) [Pubmed]
  25. Gtx: a novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells of testis, has a transcriptional repressor activity in vitro for a serum-inducible promoter. Komuro, I., Schalling, M., Jahn, L., Bodmer, R., Jenkins, N.A., Copeland, N.G., Izumo, S. EMBO J. (1993) [Pubmed]
  26. Phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2 (BMP-2)-induced myocyte enhancer factor 2A-dependent transcription of BMP-2 gene in cardiomyocyte precursor cells. Ghosh-Choudhury, N., Abboud, S.L., Mahimainathan, L., Chandrasekar, B., Choudhury, G.G. J. Biol. Chem. (2003) [Pubmed]
  27. PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C. Micheli, L., Leonardi, L., Conti, F., Buanne, P., Canu, N., Caruso, M., Tirone, F. Mol. Cell. Biol. (2005) [Pubmed]
  28. Regulation of the mouse desmin gene: transactivated by MyoD, myogenin, MRF4 and Myf5. Li, H., Capetanaki, Y. Nucleic Acids Res. (1993) [Pubmed]
  29. Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. Lyons, G.E., Micales, B.K., Schwarz, J., Martin, J.F., Olson, E.N. J. Neurosci. (1995) [Pubmed]
  30. Role of myocyte-specific enhancer-binding factor (MEF-2) in transcriptional regulation of the alpha-cardiac myosin heavy chain gene. Adolph, E.A., Subramaniam, A., Cserjesi, P., Olson, E.N., Robbins, J. J. Biol. Chem. (1993) [Pubmed]
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