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Adult mammalian ventricular cardiomyocytes are terminally differentiated cells that enlarge adaptively by hypertrophy. In this situation, genes normally expressed in the fetal ventricular cardiomyocyte (e.g. atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), and skeletal muscle (SkM) alpha-actin) are re-expressed, and there is transient expression of immediate early genes (e.g. c-fos). Using appropriate reporter plasmids, we studied the effects of transfection of the constitutively active or dominant negative mitogen-activated protein kinase kinase MEK1 on ANF, beta-MHC, and SkM alpha-actin promoter activities in cultured ventricular cardiomyocytes. ANF expression was stimulated (maximally 75-fold) by the hypertrophic agonist phenylephrine in a dose-dependent manner (EC50, 10 microM), and this stimulation was inhibited by dominant negative MEK1. Cotransfection of dominant negative MEK1 with a dominant negative mitogen-activated protein kinase (extracellular signal-regulated protein kinase (ERK2)) increased this inhibition. Transfection with constitutively active MEK1 constructs doubled ANF promoter activity. The additional cotransfection of wild-type ERK2 stimulated ANF promoter activity by about 5-fold. Expression of beta-MHC and SkM alpha-actin was also stimulated. Promoter activity regulated by activator protein-1 or c-fos serum response element consensus sequences was also increased. We conclude that the MEK1/ERK2 cascade may play a role in regulating gene expression during hypertrophy.

Original publication

DOI

10.1074/jbc.270.47.28092

Type

Journal article

Journal

J Biol Chem

Publication Date

24/11/1995

Volume

270

Pages

28092 - 28096

Keywords

Amino Acid Sequence, Animals, Atrial Natriuretic Factor, Calcium-Calmodulin-Dependent Protein Kinases, Cardiomegaly, Cells, Cultured, Chickens, Gene Expression, Heart Ventricles, Humans, Luciferases, MAP Kinase Kinase 1, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase Kinases, Phenotype, Point Mutation, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Rabbits, Rats, Rats, Sprague-Dawley, Serine, Transfection