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.
Patel
S
S
Division of Cell Signalling, School of Life Sciences, WTB/MSI Complex, University of Dundee, Dundee DD1 5EH, UK.
Lochhead
P A
PA
Rena
G
G
Sutherland
C
C
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016895:Culture Media, Serum-Free; D000242:Cyclic AMP / Q000737:chemistry / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D007328:Insulin / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000071161:Forkhead Box Protein O1
D001549:Benzamides; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016895:Culture Media, Serum-Free; D000242:Cyclic AMP; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D005952:Glucose-6-Phosphatase; D038362:Glycogen Synthase Kinase 3; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C069767:phosphoenolpyruvate carboxylase kinase