Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin

Insulin regulates the synthesis of several proteins in a variety of tissues 1 . Before techniques were available to quantify the amount of specific mRNAs, insulin was thought to regulate the synthesis of proteins by influencing the rate of translation of a fixed amount of mRNA. A very different interpretation is called for by experiments which show that insulin alters the amount of several specific mRNAs 2–5 , but little is known about the mechanism. Insulin decreases the rate of synthesis of the critical gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in both liver 6 and H4IIE heptoma cells 7,8 . We recently showed that insulin acts directly on H4IIE cells to decrease mRNA PEPCK activity without any other hormone intermediaries 8 . This effect is mediated by the insulin receptor and occurs at insulin concentrations which are well within the physiological range (10 −12 –10 −9 M) 8 . Here we extend these studies to show that insulin specifically inhibits transcription of the PEPCK gene. This inhibition results in a rapid decrease in the concentration of nuclear PEPCK transcripts which is followed, in turn, by a proportionate decline in cytoplasmic mRNA PEPCK and synthesis of the protein.