THE MITOGEN-ACTIVATED PROTEIN-KINASE KINASE MEK1 STIMULATES A PATTERNOF GENE-EXPRESSION TYPICAL OF THE HYPERTROPHIC PHENOTYPE IN RAT VENTRICULAR CARDIOMYOCYTES

Citation
J. Gillespiebrown et al., THE MITOGEN-ACTIVATED PROTEIN-KINASE KINASE MEK1 STIMULATES A PATTERNOF GENE-EXPRESSION TYPICAL OF THE HYPERTROPHIC PHENOTYPE IN RAT VENTRICULAR CARDIOMYOCYTES, The Journal of biological chemistry, 270(47), 1995, pp. 28092-28096
Citations number
78
Categorie Soggetti
Biology
ISSN journal
00219258
Volume
270
Issue
47
Year of publication
1995
Pages
28092 - 28096
Database
ISI
SICI code
0021-9258(1995)270:47<28092:TMPKMS>2.0.ZU;2-P
Abstract
Adult mammalian ventricular cardiomyocytes are terminally differentiat ed cells that enlarge adaptively by hypertrophy. In this situation, ge nes normally expressed in the fetal ventricular cardiomyocyte (e.g. at rial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), and skeletal muscle (SkM) alpha-actin) are re-expressed, and there is tra nsient expression of immediate early genes (e.g. c-fos), Using appropr iate reporter plasmids, we studied the effects of transfection of the constitutively active or dominant negative mitogen-activated protein k inase kinase MEK1 on ANF, beta-MHC, and SkM alpha-actin promoter activ ities in cultured ventricular cardiomyocytes, ANF expression was stimu lated (maximally 75-fold) by the hypertrophic agonist phenylephrine in a dose-dependent manner (EC(50), 10 mu M), and this stimulation was i nhibited by dominant negative MEK1, Cotransfection of dominant negativ e MEK1 with a dominant negative mitogen-activated protein kinase (extr acellular signal-regulated protein kinase (ERK2)) increased this inhib ition. Transfection with constitutively active MEK1 constructs doubled ANF promoter activity, The additional cotransfection of wild-type ERK 2 stimulated ANF promoter activity by about 5-fold. Expression of beta -MHC and SkM alpha-actin was also stimulated. Promoter activity regula ted by activator protein-1 or c-fos serum response element consensus s equences was also increased, We conclude that the MEK1/ERK2 cascade ma y play a role in regulating gene expression during hypertrophy.