title: Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes.
abstract: The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes.
authors.affiliation: Department of Clinical Molecular Medicine, Division of Diabetes, Digestive, and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Miyake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005246:Feedback; D015870:Gene Expression / Q000187:drug effects*; D005941:Glucokinase / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005941:Glucokinase; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; C497389:Srebf1 protein, rat; C494920:Akt1 protein, rat