Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy.
Shortly after birth, cardiac myocytes lose the ability to divide, and, in adult animals, heart muscle grows by a process of cellular hypertrophy where each individual cell gets larger. We have previously shown that activated Ras protein can induce markers of the hypertrophic phenotype, including atrial natriuretic factor (ANF) expression and organization of contractile proteins, and that Ras is at least partially required for the hypertrophic effect of phenylephrine. In the present study, we examine the requirement for the mitogen-activated protein kinases (MAP kinases) in the hypertrophic response induced by phenylephrine. We find that phenylephrine treatment results in the activation of the MAP kinases and that this activity is required for transactivation of the fos, ANF, and MLH promoters. However, inhibition of MAP kinases does not prevent phenylephrine-induced organization of actin. These results suggest that the signal transduction pathways leading to different hypertrophic responses diverge upstream of the MAP kinases but possibly downstream of Ras.
Thorburn
J
J
Cardiology Division, Eccles Institute of Human Genetics, University of Utah, Salt Lake City 84112.
Frost
J A
JA
Thorburn
A
A
D000199:Actins / Q000648:ultrastructure; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000473:pathology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006984:Hypertrophy; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D000199:Actins; D008934:Mitogens; D010656:Phenylephrine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate