J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/10/115/13 $2.00
Volume 139, Number 1, October 6, 1997 115-127

A Role for the p38 Mitogen-activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-specific Gene Expression

Dietmar Zechner, Donna J. Thuerauf, Deanna S. Hanford, Patrick M. McDonough, and Christopher C. Glembotski

Department of Biology and Molecular Biology Institute, San Diego State University, San Diego, California 92182

Three hallmark features of the cardiac hypertrophic growth program are increases in cell size, sarcomeric organization, and the induction of certain cardiac-specific genes. All three features of hypertrophy are induced in cultured myocardial cells by ₁- adrenergic receptor agonists, such as phenylephrine (PE) and other growth factors that activate mitogen- activated protein kinases (MAPKs). In this study the MAPK family members extracellular signal-regulated kinase (ERK), c-jun NH₂-terminal kinase (JNK), and p38 were activated by transfecting cultured cardiac myocytes with constructs encoding the appropriate kinases possessing gain-of-function mutations. Transfected cells were then analyzed for changes in cell size, sarcomeric organization, and induction of the genes for the A- and B-type natriuretic peptides (NPs), as well as the -skeletal actin (-SkA) gene. While activation of JNK and/or ERK with MEKK1_COOH or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and -SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and -Ska promoter activities by up to 130-fold, and elicited sarcomeric organization in a manner similar to PE. Moreover, all three growth features induced by MKK6 (Glu) or PE were blocked with the p38-specific inhibitor, SB 203580. These results demonstrate novel and potentially central roles for MKK6 and p38 in the regulation of myocardial cell hypertrophy.

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• Thuerauf, D. J., Arnold, N. D., Zechner, D., Hanford, D. S., DeMartin, K. M., McDonough, P. M., Prywes, R., Glembotski, C. C. (1998). p38 Mitogen-activated Protein Kinase Mediates the Transcriptional Induction of the Atrial Natriuretic Factor Gene through a Serum Response Element. A POTENTIAL ROLE FOR THE TRANSCRIPTION FACTOR ATF6. J. Biol. Chem. 273: 20636-20643 [Abstract] [Full Text]  
• Clerk, A., Michael, A., Sugden, P. H. (1998). Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein-coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy?. JCB 142: 523-535 [Abstract] [Full Text]  
• Adams, J. W., Sah, V. P., Henderson, S. A., Brown, J. H. (1998). Tyrosine Kinase and c-Jun NH2-Terminal Kinase Mediate Hypertrophic Responses to Prostaglandin F2{alpha} in Cultured Neonatal Rat Ventricular Myocytes. Circ. Res. 83: 167-178 [Abstract] [Full Text]  
• Sadoshima, J. (1998). Versatility of the Angiotensin II Type 1 Receptor. Circ. Res. 82: 1352-1355 [Full Text]  
• Ross, R. S., Pham, C., Shai, S.-Y., Goldhaber, J. I., Fenczik, C., Glembotski, C. C., Ginsberg, M. H., Loftus, J. C. (1998). ß1 Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes. Circ. Res. 82: 1160-1172 [Abstract] [Full Text]  
• Ushio-Fukai, M., Alexander, R. W., Akers, M., Griendling, K. K. (1998). p38 Mitogen-activated Protein Kinase Is a Critical Component of the Redox-sensitive Signaling Pathways Activated by Angiotensin II. ROLE IN VASCULAR SMOOTH MUSCLE CELL HYPERTROPHY. J. Biol. Chem. 273: 15022-15029 [Abstract] [Full Text]  
• Nemoto, S., Sheng, Z., Lin, A. (1998). Opposing Effects of Jun Kinase and p38 Mitogen-Activated Protein Kinases on Cardiomyocyte Hypertrophy. Mol. Cell. Biol. 18: 3518-3526 [Abstract] [Full Text]  
• Aoki, H., Izumo, S., Sadoshima, J. (1998). Angiotensin II Activates RhoA in Cardiac Myocytes : A Critical Role of RhoA in Angiotensin II–Induced Premyofibril Formation. Circ. Res. 82: 666-676 [Abstract] [Full Text]  
• Zechner, D., Craig, R., Hanford, D. S., McDonough, P. M., Sabbadini, R. A., Glembotski, C. C. (1998). MKK6 Activates Myocardial Cell NF-kappa B and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner. J. Biol. Chem. 273: 8232-8239 [Abstract] [Full Text]  
• Clerk, A., Fuller, S. J., Michael, A., Sugden, P. H. (1998). Stimulation of "Stress-regulated" Mitogen-activated Protein Kinases (Stress-activated Protein Kinases/c-Jun N-terminal Kinases and p38-Mitogen-activated Protein Kinases) in Perfused Rat Hearts by Oxidative and Other Stresses. J. Biol. Chem. 273: 7228-7234 [Abstract] [Full Text]  
• Wang, Y., Su, B., Sah, V. P., Brown, J. H., Han, J., Chien, K. R. (1998). Cardiac Hypertrophy Induced by Mitogen-activated Protein Kinase Kinase 7, a Specific Activator for c-Jun NH2-terminal Kinase in Ventricular Muscle Cells. J. Biol. Chem. 273: 5423-5426 [Abstract] [Full Text]  
• Hoover, H. E., Thuerauf, D. J., Martindale, J. J., Glembotski, C. C. (2000). alpha B-crystallin Gene Induction and Phosphorylation by MKK6-activated p38. A POTENTIAL ROLE FOR alpha B-CRYSTALLIN AS A TARGET OF THE p38 BRANCH OF THE CARDIAC STRESS RESPONSE. J. Biol. Chem. 275: 23825-23833 [Abstract] [Full Text]  
• Gabai, V. L., Meriin, A. B., Yaglom, J. A., Wei, J. Y., Mosser, D. D., Sherman, M. Y. (2000). Suppression of Stress Kinase JNK Is Involved in HSP72-mediated Protection of Myogenic Cells from Transient Energy Deprivation. HSP72 ALLEVIATES THE STRESS-INDUCED INHIBITION OF JNK DEPHOSPHORYLATION. J. Biol. Chem. 275: 38088-38094 [Abstract] [Full Text]  
• Lim, H. W., New, L., Han, J., Molkentin, J. D. (2001). Calcineurin Enhances MAPK Phosphatase-1 Expression and p38 MAPK Inactivation in Cardiac Myocytes. J. Biol. Chem. 276: 15913-15919 [Abstract] [Full Text]  
• Craig, R., Wagner, M., McCardle, T., Craig, A. G., Glembotski, C. C. (2001). The Cytoprotective Effects of the Glycoprotein 130 Receptor-coupled Cytokine, Cardiotrophin-1, Require Activation of NF-kappa B. J. Biol. Chem. 276: 37621-37629 [Abstract] [Full Text]  
• Taylor, J. M., Rovin, J. D., Parsons, J. T. (2000). A Role for Focal Adhesion Kinase in Phenylephrine-induced Hypertrophy of Rat Ventricular Cardiomyocytes. J. Biol. Chem. 275: 19250-19257 [Abstract] [Full Text]  
• Craig, R., Larkin, A., Mingo, A. M., Thuerauf, D. J., Andrews, C., McDonough, P. M., Glembotski, C. C. (2000). p38 MAPK and NF-kappa B Collaborate to Induce Interleukin-6 Gene Expression and Release. EVIDENCE FOR A CYTOPROTECTIVE AUTOCRINE SIGNALING PATHWAY IN A CARDIAC MYOCYTE MODEL SYSTEM. J. Biol. Chem. 275: 23814-23824 [Abstract] [Full Text]  

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