TY - JOUR
T1 - A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression
AU - Finlay, David
AU - Ruiz-Alcaraz, Antonio J.
AU - Lipina, Christopher
AU - Perrier, Stephane
AU - Sutherland, Calum
PY - 2006/10
Y1 - 2006/10
N2 - Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulation of this process aids the search for the defect(s) that promotes insulin-resistant states, such as diabetes mellitus. We have previously shown that the insulin regulation of hepatic IGF-binding protein-1 (IGFBP1) expression requires the 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.
AB - Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulation of this process aids the search for the defect(s) that promotes insulin-resistant states, such as diabetes mellitus. We have previously shown that the insulin regulation of hepatic IGF-binding protein-1 (IGFBP1) expression requires the 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.
U2 - 10.1677/jme.1.02084
DO - 10.1677/jme.1.02084
M3 - Article
C2 - 17032741
SN - 0952-5041
VL - 37
SP - 227
EP - 237
JO - Journal of Molecular Endocrinology
JF - Journal of Molecular Endocrinology
IS - 2
ER -