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