Abstract
Gq-protein-coupled receptor (GqPCR) signalling is associated with the induction of cardiac myocyte hypertrophy, which is characterized by an increase in expression of immediate early genes via activation of pre-existing transcription factors. Here, we explore the role of MSK1 and MAPK signalling pathways in the regulation of the immediate early gene c-jun. The results provide further support for the role of MSK1 in cardiac myocyte hypertrophy and indicate that PE activates distinct signalling mechanisms which culminate with a complex activation of c-jun. ERK1/2 and JNKs are the principal kinases responsible for phosphorylation of c-Jun, whereas c-jun mRNA and protein up-regulation by PE is mediated by multiple signalling pathways that include MSK1, ERK1/2, p38-MAPK and JNKs. These signalling mechanisms seem to be critical to the phenotypic changes of cardiac myocytes in response to hypertrophic stimulation.
Similar content being viewed by others
References
Sugden PH, Clerk A (1998) Cellular mechanisms of cardiac hypertrophy. J Mol Med 76:725–742. doi:10.1007/s001090050275
Lazou A, Sugden PH, Clerk A (1998) Activation of Mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart. Biochem J 332:459–465
Bogoyevitch M, Glennon P, Andersson M et al (1994) Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. J Biol Chem 269:1110–1119
Clerk A, Michael A, Sugden PH (1998) Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal ventricular myocytes by the G-protein-coupled receptor agonists endothelin-1 and phenylephrine; a role in cardiac myocyte hypertrophy? J Cell Biol 142:523–535. doi:10.1083/jcb.142.2.523
Ramirez M, Sah V, Zhao X et al (1997) The MEKK-JNK pathway is stimulated by α1-adrenergic receptor and Ras activation is associated with in vitro and in vivo cardiac hypertrophy. J Biol Chem 272:14057–14061. doi:10.1074/jbc.272.22.14057
Markou T, Lazou A (2002) Phosphorylation and activation of mitogen- and stress-activated protein kinase-1 in adult rat cardiac myocytes by G-protein coupled receptor agonists requires both extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Biochem J 365:757–763
Deak M, Clifton A, Lucqocq J et al (1998) Mitogen-and stress-activated kinase 1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17:4426–4441. doi:10.1093/emboj/17.15.4426
Markou T, Hadzopoulou-Cladaras M, Lazou A (2004) Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways. J Mol Cell Cardiol 37:1001–1011. doi:10.1016/j.yjmcc.2004.08.002
Raivich G, Behrens A (2006) Role of the AP-1 transcription factor c-Jun in developing, adult and injured brain. Prog Neurobiol 78:347–363. doi:10.1016/j.pneurobio.2006.03.006
Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20:2378–2389. doi:10.1038/sj.onc.1204381
Minden A, Lin A, Smeal T et al (1994) c-Jun N-terminal phosphorylation correlates with activation of the JNK subgroup but not the ERK subgroup of mitogen-activated protein kinases. Mol Cell Biol 14:6683–6688
Dignam J, Lebwvitz R, Roeder R (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489. doi:10.1093/nar/11.5.1475
Clerk A, Cullingford TE, Fuller SJ et al (2007) Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol 212:311–322. doi:10.1002/jcp.21094
Pulverer BJ, Kyriakis M, Avruch J et al (1991) Phosphorylation of c-jun mediated by MAP kinases. Nature 353:670–674. doi:10.1038/353670a0
Nadruz W Jr, Kobarg CB, Kobarg J et al (2004) c-Jun is regulated by combination of enhanced expression and phosphorylation in acute-overloaded rat heart. Am J Physiol 286(2):H760–H767
Yue TL, Gu JL, Wang C et al (2000) Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiac myocyte hypertrophy. J Biol Chem 275:37895–37901. doi:10.1074/jbc.M007037200
Clerk A, Aggeli I-K, Stathopoulou K et al (2006) Peptide growth factors signal differentially through protein kinase C to extracellular signal-regulated kinase in neonatal cardiac myocytes. Cell Signal 18:225–235. doi:10.1016/j.cellsig.2005.04.005
Sugden PH (2001) Signaling pathways in cardiac myocyte hypertrophy. Ann Med 33:611–622
Sugden PH, Clerk A (1998) “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 83:345–352
Gillespie-Brown J, Fuller SJ, Bogoyevitch MA et al (1995) The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiac myocytes. J Biol Chem 270:28092–28096. doi:10.1074/jbc.270.47.28092
Omura T, Yoshiyama M, Yoshida K et al (2002) Dominant negative mutant of c-Jun inhibits cardiac myocyte hypertrophy induced by endothelin 1 and phenylephrine. Hypertension 39:81–86. doi:10.1161/hy0102.100783
Clerk A, Kemp TJ, Harrison JG et al (2002) Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein. Biochem J 368:101–110. doi:10.1042/BJ20021083
Zhu F, Zhang Y, Bode AM et al (2004) Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Carcinogenesis 25:1847–1852. doi:10.1093/carcin/bgh202
Aggeli I-K, Gaitanaki C, Beis I (2006) Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced up-regulation of heme oxygenase-1 mRNA in H9c2 cells. Cell Signal 18:1801–1812. doi:10.1016/j.cellsig.2006.02.001
Harrison JG, Sugden PH, Clerk A (2004) Endothelin-1 promotes phosphorylation of CREB transcription factor in primary cultures of neonatal rat cardiac myocytes: implications for the regulation of c-jun expression. Biochim Biophys Acta 1644:17–25. doi:10.1016/j.bbamcr.2003.10.008
Marinissen MJ, Chiariello M, Pallane M et al (1999) A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38 s, and extracellular signal-regulated kinase 5. Mol Cell Biol 19:4289–4301
Spruill LS, McDermott PJ (2006) Regulation of c-jun mRNA expression in adult cardiocytes by MAP kinase interacting kinase-1 (MNK1). FASEB J 20:2133–2135. doi:10.1096/fj.06-6245fje
Waskiewicz AJ, Flynn A, Proud CG et al (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:909–920. doi:10.1093/emboj/16.8.1909
Fuchs SY, Fried VA, Ronai Z (1998) Stress-activated kinases regulate protein stability. Oncogene 1:1483–1490. doi:10.1038/sj.onc.1202184
Davies SP, Reddy H, Caivano M et al (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105. doi:10.1042/0264-6021:3510095
Bain J, Plater L, Elliott M et al (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315. doi:10.1042/BJ20070797
Acknowledgements
This work was partially supported by a grant from Empirikion Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Markou, T., Cieslak, D., Gaitanaki, C. et al. Differential roles of MAPKs and MSK1 signalling pathways in the regulation of c-Jun during phenylephrine-induced cardiac myocyte hypertrophy. Mol Cell Biochem 322, 103–112 (2009). https://doi.org/10.1007/s11010-008-9945-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-008-9945-8