Insulin-regulated gene expression

Insulin regulates the expression of more than 150 genes, indicating that th is is a major action of this hormone. At least eight distinct consensus ins ulin response sequence (IRSs) have been defined through which insulin can r egulate gene transcription. These include the serum response element, the a ctivator protein 1 ('AP-1') motif, the Ets motif, the E-box motif and the t hyroid transcription factor 2 ('TTF-2') motif. All of these IRSs mediate st imulatory effects of insulin on gene transcription. In contrast, an element with the consensus sequence T(G/A)TTT(T/G)(G/T), which we refer to as the phosphoenolpyruvate carboxykinase (PEPCK)-like motif, mediates the inhibito ry effect of insulin on transcription of the genes encoding PEPCK, insulin- like- growth-factor-binding protein 1 (IGFBP-1), tyrosine aminotransferase and the glucose-6-phosphatase (G6Pase) catalytic subunit. The forkhead tran scription factor FKHR has recently been shown to bind this PEPCK-like IRS m otif and a model has been proposed in which insulin inhibits gene transcrip tion by stimulating the phosphorylation and nuclear export of FKHR. Our res ults suggest that this model is consistent with the action of insulin on tr anscription of the gene encoding IGFBP-1 but not that of the G6Pase catalyt ic subunit. Thus, even though the IRSs in both promoters seem identical, th ey are functionally distinct. In addition, in the G6Pase catalytic subunit promoter, hepatocyte nuclear factor I ('HNF-1'), acts as an accessory facto r to enhance the effect of insulin mediated through the IRS.