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© The Rockefeller University Press, 0021-9525/1997//115 $5.00
The Journal of Cell Biology, Volume 139, Number 1, , 1997 115-127

Article

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 {alpha}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 {alpha}-skeletal actin ({alpha}-SkA) gene. While activation of JNK and/or ERK with MEKK1COOH or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and {alpha}-SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and {alpha}-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.

Abbreviations used in this paper: {alpha}-SkA, {alpha}-skeletal actin; ANP and BNP, A- and B-type cardiac natriuretic peptides; ATF, activating transcription factor; CMV, cytomegalovirus; ERK, extracellular signal–regulated kinase; HA, hemagglutinin; hsp, heat-shock protein; JNK, NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKAP, MAPK-activated protein kinase; PE, phenylephrine.

Address all correspondence to Christopher C. Glembotski, Department of Biology, San Diego State University, San Diego, CA 92182. Tel.: (619) 594-2959. Fax: (619) 594-6200. e-mail: cglembotski{at}sunstroke.sdsu.edu

SB 203580 was a generous gift from J. Lee (SKB Pharmaceuticals, King of Prussia, PA. {alpha}-SkA–394GL was a generous gift from M.D. Schneider (Baylor College of Medicine, Houston, TX).


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