A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression.
Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulationof thisprocess aids the searchfor the defect(s) that promotesinsulin-resistant states, such asdiabetesmellitus. We havepreviously shownthat the insulin regulationof hepatic IGF-binding protein-1 (IGFBP1) expression requiresthe signalling proteins phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR). In this report, we demonstrate that activation of the mTOR pathway, without activation of its upstream regulator PI 3-kinase, reduces IGFBP1 expression. Therefore, mTOR activation is sufficient to mimic insulin regulation of this gene. However, longer exposure (>3 h) of cells to insulin reduces the importance of this pathway in insulin regulation of the gene, suggesting a temporal switch in signalling mechanisms linking insulin action to the IGFBP1 gene promoter. In contrast, the activation of PI 3-kinase is required for insulin regulation of IGFBP1 under all conditions tested. Therefore, an mTOR-independent, PI 3-kinase-dependent pathway becomes more important in IGFBP1 regulation after long exposure to insulin. This is a novel concept in insulin regulation of gene expression and demonstrates the importance of temporal analysis of signalling processes.
Finlay
David
D
Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK.
Ruiz-Alcaraz
Antonio J
AJ
Lipina
Christopher
C
Perrier
Stephane
S
Sutherland
Calum
C
D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014407:Tumor Cells, Cultured
D003513:Cycloheximide; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases