Antagonistic effects of phorbol esters on insulin regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) but not glucose-6-phosphatase gene expression

Glucose-6-phosphatase (G6Pase) and insulin-like growth factor-binding prote in-1 (IGFBP-1) genes contain a homologous promoter sequence that is require d for gene repression by insulin. Interestingly, this element interacts wit h members of the forkhead family of transcription factors [e.g. HNF3 (hepat ic nuclear factor 3), FKHR (forkhead in rhabdomyosarcoma)] in vitro, while insulin promotes the phosphorylation and inactivation of FKHR in a phosphat idylinositol 3-kinase- and protein kinase B (PKB)-dependent manner. This me chanism has been proposed to underlie insulin action on G6Pase and IGFBP-1 gene transcription. However, we find that treatment of cells with phorbol e sters mimics the effect of insulin on G6Pase, but not IGFBP-1, gene express ion. Indeed, phorbol ester treatment actually blocks the ability of insulin to repress IGFBP-1 gene expression. In addition, the action of phorbol est ers is significantly reduced by inhibition of the p42/p44 mitogen-activated protein (MAP) kinase pathway. However insulin-induced phosphorylation of P KB or FKHR is not affected by the presence of phorbol esters. Therefore we suggest that activation of p42/p44 MAP kinases will reduce the sensitivity of the IGFBP-1 gene promoter, but not the G6Pase gene promoter, to insulin. Importantly, the activation of PKB and phosphorylation of FKHR is not, in itself, sufficient to reduce IGFBP-1 gene expression in the presence of pho rbol esters.