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
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cells, Cultured
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Dexamethasone / pharmacology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Glucagon / pharmacology
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Insulin / pharmacology*
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Insulin / physiology*
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Insulin-Like Growth Factor Binding Protein 1 / genetics*
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Insulin-Like Growth Factor Binding Protein 4 / genetics*
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Liver / metabolism
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Organometallic Compounds / pharmacology*
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Phenanthrolines / pharmacology*
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor) / physiology*
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Polyenes / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / physiology*
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / physiology
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RNA, Messenger / genetics
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Rats
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Rats, Sprague-Dawley
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Ribosomal Protein S6 Kinases
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Signal Transduction
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Sirolimus
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Wortmannin
Substances
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Androstadienes
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Enzyme Inhibitors
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Insulin
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Insulin-Like Growth Factor Binding Protein 1
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Insulin-Like Growth Factor Binding Protein 4
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Organometallic Compounds
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Phenanthrolines
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Polyenes
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RNA, Messenger
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bisperoxo(1,10-phenanthroline)oxovanadate(1-)
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Dexamethasone
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Glucagon
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Phosphotransferases (Alcohol Group Acceptor)
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases
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Protein Tyrosine Phosphatases
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Sirolimus
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Wortmannin