The effect of phorbol esters and diacylglycerol on expression of the phosphoenolpyruvate carboxykinase (GTP) gene in rat hepatoma H4IIE cells.

Abstract

The effect of the tumor promoter phorbol 12-myristate 13-acetate (PMA) on expression of the P-enolpyruvate carboxykinase gene was studied in rat hepatoma H4IIE cells. Like insulin, PMA provokes a concentration and time-dependent decrease of mRNA coding for that enzyme that is due to an inhibition of P-enolpyruvate carboxykinase gene transcription. This effect of PMA is rapid, reversible, specific for phorbol esters known to be active in other systems, and it does not require on-going protein synthesis. PMA overrides the stimulatory effects cAMP and glucocorticoid analogs have on the transcription of this gene. A synthetic diacylglycerol, sn-1,2-dioctanoylglycerol, also inhibits P-enolpyruvate carboxykinase gene transcription. These effects of PMA and synthetic diacylglycerol are specific, since neither affected total mRNA synthesis. We conclude that diacylglycerol and phorbol esters, specific stimulators of protein kinase C, inhibit the transcription of P-enolpyruvate carboxykinase gene in H4IIE cells. The findings support the hypothesis that diacylglycerols generated in the plasma membrane can act as an intracellular signal that regulates specific gene expression.