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MYL2  -  myosin, light chain 2, regulatory, cardiac...

Homo sapiens

 
 
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Disease relevance of MYL2

  • To investigate the role of cardiac MLC2, we have isolated a full-length cDNA clone for human ventricular MLC2 and produced a full-length and N-terminal deleted MLC2 polypeptides in Escherichia coli using the bacterial expression vector pT7-7 system [1].
  • Angiotensin II (Ang II), a potent agonist of hypertrophy, causes induction of the MLC-2v gene transcription, which correlates well with the enhanced binding of Nishéd-nuclear factor of the activated T cells-p300 complex to IRE in the gel mobility shift assay [2].
  • These results together have thus established a transcriptional role of IRE as a direct target sequence of Ang II-mediated signaling that appears to be pivotal in the mechanism underlying the up-regulation of the MLC-2v gene during cardiac hypertrophy [2].
  • The assay is based on a Green Fluorescent Protein (GFP) reporter under the transcriptional control of the 250 bp MLC-2v promoter expressed in pluripotent P19 embryonal carcinoma cells [3].
 

High impact information on MYL2

  • Pivotal in this process is phosphorylation of myosin light chain-2 (MLC2) by Rho kinase (ROCK) downstream of Rho activation, which generates the contractile force necessary to drive disassembly of epithelial cell-cell junctions and cell-matrix adhesions at the rear of migrating cells [4].
  • Endosomes generate localized Rho-ROCK-MLC2-based contractile signals via Endo180 to promote adhesion disassembly [4].
  • An AAV vector, MLCVEGF, with 250 bp of the MLC-2v promoter and nine copies of the hypoxia-response element driving VEGF expression, was constructed [5].
  • Expression of cardiac transcription factors Mef2c, GATAs, myocardin and Nkx2.5 was not affected by cell expression of mutated MLC2v [6].
  • A dramatic decrease in expression of mRNAs encoding alpha-actin, MLC2a and MLC2v was observed in R58QMLC2vGFP EBs [6].
 

Chemical compound and disease context of MYL2

 

Biological context of MYL2

 

Anatomical context of MYL2

  • Adipose tissue-derived stem cells (ADSCs) were transduced with two different lentiviral vectors simultaneously: (1) a lentiviral vector expressing eGFP controlled by the Nkx2.5 promoter and (2) a lentiviral vector expressing DsRed2 controlled by the myosin light chain-2v promoter (MLC-2v) [10].
  • ES cell lines engineered to express a wild-type (MLC2vGFP) or a mutated form (R58QMLC2vGFP) of ventricular myosin light chain 2 (MLC2v) fused to GFP were differentiated into cardiomyocytes within embryoid bodies (EBs) [6].
  • The selective increase in ventricular myosin light chain-2 (MLC2) in hypertrophied heart muscle has been implicated as a compensatory feature of myosin, but its relevance to myosin function is not known [1].
  • The results demonstrated that the bacterially produced full-length human cardiac MLC2 exchanges effectively with the native MLC2 and binds with specificity to MHC and to intact myofibrils [1].
  • Thus, it appears that a negative regulatory mechanism accounts for the lack of expression of the cardiac MLC-2 gene in skeletal muscle and that the CSS element and its binding proteins are important functional components of the regulatory apparatus which ensures the developmental program for cardiac tissue-specific gene expression [11].
 

Associations of MYL2 with chemical compounds

  • Losartan, an antagonist of Ang II receptor (AT1), abolishes the agonist-dependent stimulation of IRE/protein interaction and the consequent increase in MLC-2v gene transcription [2].
  • In contrast to our findings in atrial muscle strips, we observed no increase in MLC2v phosphorylation after PE in human ventricular muscle strips and wortmannin failed to inhibit PE-induced force of contraction [12].
  • Myoblasts were simultaneously identified using a MoAb directed against myosin light chains 1 and 2 (MLC1 and MLC2) and a combination of biotin-labelled sheep anti-mouse Ig antibody and Texas Red labelled streptavidin [13].
  • The observed 1.4- to 1.6-fold increase in shortening velocity appears to reflect 1.2- to 9.0-fold increases in the protein levels of fast-type MLC2, glycolytic enzymes, and creatine kinase, and 0.2- to 0.3-fold decreases in slow-type troponins T1 and T2 [14].
  • In situ phosphorylation of cardiomyocytes with calyculin A, a protein phosphatase inhibitor, resulted in an increase in the phosphorylation stiochiometry of TnT (0.3 to 0.5 (67%)), TnI (2.6 to 3.6 (38%)), and MLC2 (0.4 to 1.7 (325%)) [15].
 

Other interactions of MYL2

  • Deletion of the element B sequence alone from the cardiac MLC-2 promoter causes, as does that of the MEF-2 site from other promoters and the enhancer of skeletal muscle genes, a marked reduction of transcription [16].
  • Conversely, no changes were found in alpha cardiac actin and myosin light chain 2 (MLC2) expression [17].
  • Based on these findings, we propose that in chicken cardiac myocytes, the regulation of MLC-2v promoter by Jun may occur via its interaction with other proteins, possibly of the leucine zipper family [18].
  • In the ventricular cardiocytes there is re-expression of the fetal atrial natriuretic factor (ANF) gene and upregulation of its myosin light chain-2 (MLC-2v) [18].
 

Analytical, diagnostic and therapeutic context of MYL2

References

  1. Interaction of a conserved peptide domain in recombinant human ventricular myosin light chain-2 with myosin heavy chain. Wadgaonkar, R., Shafiq, S., Rajmanickam, C., Siddiqui, M.A. Cell. Mol. Biol. Res. (1993) [Pubmed]
  2. A ternary complex of transcription factors, Nishéd and NFATc4, and co-activator p300 bound to an intronic sequence, intronic regulatory element, is pivotal for the up-regulation of myosin light chain-2v gene in cardiac hypertrophy. Mathew, S., Mascareno, E., Siddiqui, M.A. J. Biol. Chem. (2004) [Pubmed]
  3. A P19Cl6 GFP reporter line to quantify cardiomyocyte differentiation of stem cells. Moore, J.C., Spijker, R., Martens, A.C., de Boer, T., Rook, M.B., van der Heyden, M.A., Tertoolen, L.G., Mummery, C.L. Int. J. Dev. Biol. (2004) [Pubmed]
  4. Endosomes generate localized Rho-ROCK-MLC2-based contractile signals via Endo180 to promote adhesion disassembly. Sturge, J., Wienke, D., Isacke, C.M. J. Cell Biol. (2006) [Pubmed]
  5. Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Su, H., Joho, S., Huang, Y., Barcena, A., Arakawa-Hoyt, J., Grossman, W., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Fine-tuning in Ca2+ homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells. Grey, C., Méry, A., Pucéat, M. Hum. Mol. Genet. (2005) [Pubmed]
  7. Cardiac hypertrophy: signal transduction, transcriptional adaptation, and altered growth control. Wagner, M., Mascareno, E., Siddiqui, M.A. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
  8. Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Kabaeva, Z.T., Perrot, A., Wolter, B., Dietz, R., Cardim, N., Correia, J.M., Schulte, H.D., Aldashev, A.A., Mirrakhimov, M.M., Osterziel, K.J. Eur. J. Hum. Genet. (2002) [Pubmed]
  9. Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart. Morano, I., Hädicke, K., Haase, H., Böhm, M., Erdmann, E., Schaub, M.C. J. Mol. Cell. Cardiol. (1997) [Pubmed]
  10. Genetically selected stem cells from human adipose tissue express cardiac markers. Bai, X., Pinkernell, K., Song, Y.H., Nabzdyk, C., Reiser, J., Alt, E. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  11. Tissue-specific transcription of the cardiac myosin light-chain 2 gene is regulated by an upstream repressor element. Shen, R.A., Goswami, S.K., Mascareno, E., Kumar, A., Siddiqui, M.A. Mol. Cell. Biol. (1991) [Pubmed]
  12. Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium. Grimm, M., Haas, P., Willipinski-Stapelfeldt, B., Zimmermann, W.H., Rau, T., Pantel, K., Weyand, M., Eschenhagen, T. Cardiovasc. Res. (2005) [Pubmed]
  13. Elevated MHC class I and II antigens in cultured human embryonic myoblasts following stimulation with gamma-interferon. Bao, S.S., King, N.J., dos Remedios, C.G. Immunol. Cell Biol. (1990) [Pubmed]
  14. A Proteomic Assessment of Muscle Contractile Alterations during Unloading and Reloading. Seo, Y., Lee, K., Park, K., Bae, K., Choi, I. J. Biochem. (2006) [Pubmed]
  15. Dephosphorylation specificities of protein phosphatase for cardiac troponin I, troponin T, and sites within troponin T. Jideama, N.M., Crawford, B.H., Hussain, A.A., Raynor, R.L. Int. J. Biol. Sci. (2006) [Pubmed]
  16. A new serum-responsive, cardiac tissue-specific transcription factor that recognizes the MEF-2 site in the myosin light chain-2 promoter. Zhou, M.D., Goswami, S.K., Martin, M.E., Siddiqui, M.A. Mol. Cell. Biol. (1993) [Pubmed]
  17. Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters. Di Nardo, P., Fiaccavento, R., Natali, A., Minieri, M., Sampaolesi, M., Fusco, A., Janmot, C., Cuda, G., Carbone, A., Rogliani, P., Peruzzi, G. Lab. Invest. (1997) [Pubmed]
  18. Modulation of MLC-2v gene expression by AP-1: complex regulatory role of Jun in cardiac myocytes. Goswami, S.K., Shafiq, S., Siddiqui, M.A. Mol. Cell. Biochem. (2001) [Pubmed]
  19. Dilated cardiomyopathy-associated proteins and their presentation in a WWW-accessible two-dimensional gel protein database. Pleissner, K.P., Söding, P., Sander, S., Oswald, H., Neuss, M., Regitz-Zagrosek, V., Fleck, E. Electrophoresis (1997) [Pubmed]
  20. The human adult cardiomyocyte phenotype. Bird, S.D., Doevendans, P.A., van Rooijen, M.A., Brutel de la Riviere, A., Hassink, R.J., Passier, R., Mummery, C.L. Cardiovasc. Res. (2003) [Pubmed]
 
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