Phorbol ester-induced activation of mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase and extracellular-signal-regulated protein kinase decreases glucose-6-phosphatase gene expression

Glucose-6-phosphatase (G6Pase) plays a central role in blood glucose homoeo stasis, and insulin suppresses G6Pase gene expression by the activation of phosphoinositide 3-kinase (PI 3-kinase). Here, we show that the phorbol est er PMA decreases both basal and dexamethasone/cAMP-induced expression of a luciferase gene under the control of the G6Pase promoter in transiently tra nsfected H4IIE hepatoma cells. This regulation was suppressed by the inhibi tors of the mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase (MEK), PD98059 and U0126, but not by the inhibitor of PI 3-k inase, LY294002. The co-expression of a constitutively active mutant of MEK mimicked the regulation of G6Pase promoter activity by PMA. The effect of PMA on both basal and induced G6Pase gene transcription was impaired by the overexpression of a dominant negative MEK construct, as well as by the exp ression of mitogen-activated protein kinase phosphatase-1. The mutation of the forkhead-binding sites within the insulin-response unit of the G6Pase p romoter, which decreases the effect of insulin on G6Pase gene expression, d id not alter the regulation of gene expression by PMA. The data show that P MA decreases G6Pase gene expression by the activation of MEK and extracellu lar-signal regulated protein kinase. With that, PMA mimics the effect of in sulin on G6Pase gene expression by a different signalling pathway.