The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes

Gillespie-Brown, J. , Fuller, S. J., Bogoyevitch, M. A., Cowley, S. and Sugden, P. H. (1995) The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes. Journal of Biological Chemistry, 270(47), pp. 28092-28096. (doi: 10.1074/jbc.270.47.28092)

Abstract

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), β-myosin heavy chain (β-MHC), and skeletal muscle (SkM) α-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, β-MHC, and SkM α-actin promoter activities in cultured ventricular cardiomyocytes. ANF expression was stimulated (maximally 75-fold) by the hypertrophic agonist phenylephrine in a dose-dependent manner (ECGraphic, 10 μM), 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 β-MHC and SkM α-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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Brown, Dr Judith
• Authors: Gillespie-Brown, J., Fuller, S. J., Bogoyevitch, M. A., Cowley, S., and Sugden, P. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Journal Name: Journal of Biological Chemistry
• Publisher: American Society for Biochemistry and Molecular Biology
• ISSN: 0021-9258
• ISSN (Online): 1083-351X