Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element.
Insulin rapidly and completely inhibits expression of the hepatic insulin-like growth factor binding protein-1 (IGFBP-1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. This inhibition is mediated through a phosphatidyl inositol 3-kinase-dependent regulation of a DNA element, termed the thymine-rich insulin response element, found within the promoters of each of these genes. This has led to the conclusion that these three promoters are regulated by insulin using the same molecular mechanism. However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Here, we present further evidence that different regulatory pathways mediate the insulin regulation of these promoters. Importantly, we identify a protein phosphatase activity in the pathway connecting mTOR to the IGFBP-1 promoter. These data have major implications for the development of molecular therapeutics for the treatment of insulin-resistant states such as diabetes and hypertension.
Patel
Satish
S
Department of Pharmacology and Neurosciences, University of Dundee, Ninewells Medical School and Hospital, Dundee 108-8639, UK.
Lipina
Christopher
C
Sutherland
Calum
C
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007328:Insulin / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics; D051381:Rats; D020218:Response Elements; D017385:Sequence Homology; D058570:TOR Serine-Threonine Kinases; D013941:Thymine
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D013941:Thymine