INHIBITORS OF SIGNALING IDENTIFY DIFFERENTIAL CONTROL PROCESSES RESPONSIBLE FOR SELECTIVE EFFECTS OF INSULIN ON THE EXPRESSION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE AND GENE-33 IN RAT H4 HEPATOMA-CELLS

Gene 33 and phosphoenolpyruvate carboxykinase (PEPCK) present excellent model systems for the analysis of the differential control of hepatic gene expression by the insulin-regulated signal-transduction pathway(s). We have analysed the importance of specific components in the insulin-regulated transduction pathway(s) towards enhanced gene expression (gene 33) and inhibited gene expression (PEPCK) by examination of the influence of selective inhibitors. Rapamycin, which inhibits the 70 kDa 56 kinase (p70(rsk)) does not influence the actions of insulin on gene 33 or PEPCK; thus the kinase p70(rsk) appears to play no direct role in the regulation of expression of these two hepatic genes. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, differentiates between processes involved in insulin regulation of gene 33 and PEPCK mRNA expression. Although the actions of insulin on gene 33 expression are abolished by wortmannin, the actions of insulin on PEPCK expression are insensitive to wortmannin. The existence of wortmannin-sensitive and rapamycin/wortmannin-insensitive pathways for transducing insulin signals to factors controlling gene expression, and the differential actions on specific genes, presents an initial step towards deciphering the linkage between signalling components and selective control of gene expression.