Phosphatidylinositol 3'-kinase and p70s6k are required for insulin but not bisperoxovanadium 1,10-phenanthroline (bpV(phen)) inhibition of insulin-like growth factor binding protein gene expression. Evidence for MEK-independent activation of mitogen-activated protein kinase by bpV(phen).
The hormonal regulation of insulin-like growth factor binding protein (IGFBP)-1 and -4 mRNA was compared in serum-free primary rat hepatocyte cultures. The combination of dexamethasone and glucagon (Dex/Gluc) strongly increased IGFBP-1 and IGFBP-4 mRNA levels. Insulin suppressed Dex/Gluc-stimulated IGFBP-1 but not IGFBP-4 mRNA levels. In contrast, the peroxovanadium compound, bisperoxovanadium 1,10-phenanthroline (bpV(phen)), completely abrogated Dex/Gluc induction of both IGFBP mRNA species. Wortmannin and rapamycin blocked the inhibitory effect of insulin but not that of bpV(phen) on Dex/Gluc-stimulated IGFBP mRNA. Thus, although phosphatidylinositol 3'-kinase and p70s6k are necessary for insulin-mediated transcriptional inhibition of the IGFBP-1 gene, a signaling pathway, independent of phosphatidyloinositol 3'-kinase and p70s6k, is activated by bpV(phen) and mediates IGFBP-1 as well as IGFBP-4 mRNA inhibition. Mitogen-activated protein (MAP) kinase activity induced by insulin was suppressed to below basal levels in the presence of Dex/Gluc, whereas in response to bpV(phen), MAP kinase activity was high and unaffected by Dex/Gluc, consistent with a role of MAP kinases in bpV(phen)-mediated inhibition of IGFBP mRNA. The specific MAP kinase kinase (MEK) inhibitor, PD98059, inhibited insulin but not bpV(phen)-stimulated MAP kinase activity, suggesting that MAP kinases can be activated in a MEK-independent fashion. Peroxovanadium compounds are strong inhibitors of tyrosine phosphatases, which may inhibit specific tyrosine/threonine phosphatases involved in the negative regulation of MAP kinases.
Band
C J
CJ
Polypeptide Hormone Laboratory and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
Posner
B I
BI
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009942:Organometallic Compounds / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D000077191:Wortmannin
D000730:Androstadienes; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005934:Glucagon; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018974:Insulin-Like Growth Factor Binding Protein 4; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009942:Organometallic Compounds; D010618:Phenanthrolines; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D000077191:Wortmannin; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-)