Inhibition of Transcription of the Phosphoenolpyruvate Carboxykinase Gene by Insulin

Insulin regulates the synthesis of several proteins in a variety of tissues. 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, but little is known about the mechanism. Insulin decreases the rate of synthesis of the critical gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in both liver and H4IIE heptoma cells. We recently showed that insulin acts directly on H4IIE cells to decrease mRNAPEPCK activity without any other hormone intermediaries. This effect is mediated by the insulin receptor and occurs at insulin concentrations which are well within the physiological range range (10(-12)--10(-9) M). 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 mRNAPEPCK and synthesis of the protein.