Biochemical Journal

Research article

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 protein-1 (IGFBP-1) genes contain a homologous promoter sequence that is required for gene repression by insulin. Interestingly, this element interacts with members of the forkhead family of transcription factors [e.g. HNF3 (hepatic nuclear factor 3), FKHR (forkhead in rhabdomyosarcoma)] in vitro, while insulin promotes the phosphorylation and inactivation of FKHR in a phosphatidylinositol 3-kinase- and protein kinase B (PKB)-dependent manner. This mechanism has been proposed to underlie insulin action on G6Pase and IGFBP-1 gene transcription. However, we find that treatment of cells with phorbol esters mimics the effect of insulin on G6Pase, but not IGFBP-1, gene expression. Indeed, phorbol ester treatment actually blocks the ability of insulin to repress IGFBP-1 gene expression. In addition, the action of phorbol esters is significantly reduced by inhibition of the p42/p44 mitogen-activated protein (MAP) kinase pathway. However insulin-induced phosphorylation of PKB 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 phorbol esters.

  • forkhead
  • MAP kinase
  • PKB
  • transcription


  • Abbreviations used: G6Pase, glucose-6-phosphatase; IGF, insulin-like growth factor; IGFBP-1, IGF-binding protein-1; IRE, insulin-response element; PKB, protein kinase B; PEPCK, phosphoenolpyruvate carboxykinase; PI 3-kinase, phosphoinositide 3-kinase; MAP, mitogen-activated protein; PKC, protein kinase C; 8CPT-cAMP, 8-(4-chlorophenylthio)-cAMP; p90RSK, p90 ribosomal S6 kinase; FKHR, forkhead in rhabdomyosarcoma; FKHR-L1, FKHR-like 1; AFX, ALL1 fused gene from chromosome X; GSK3, glycogen synthase kinase 3.