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)

J Biol Chem. 1997 Jan 3;272(1):138-45. doi: 10.1074/jbc.272.1.138.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Glucagon / pharmacology
  • Insulin / pharmacology*
  • Insulin / physiology*
  • Insulin-Like Growth Factor Binding Protein 1 / genetics*
  • Insulin-Like Growth Factor Binding Protein 4 / genetics*
  • Liver / metabolism
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Organometallic Compounds / pharmacology*
  • Phenanthrolines / pharmacology*
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Polyenes / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Sirolimus
  • Wortmannin

Substances

  • Androstadienes
  • Enzyme Inhibitors
  • Insulin
  • Insulin-Like Growth Factor Binding Protein 1
  • Insulin-Like Growth Factor Binding Protein 4
  • Organometallic Compounds
  • Phenanthrolines
  • Polyenes
  • RNA, Messenger
  • bisperoxo(1,10-phenanthroline)oxovanadate(1-)
  • Dexamethasone
  • Glucagon
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • Protein Tyrosine Phosphatases
  • Sirolimus
  • Wortmannin