Signaling Pathways through Which Insulin Regulates CCAAT/Enhancer Binding Protein α (C/EBPα) Phosphorylation and Gene Expression in 3T3-L1 Adipocytes
| Autor: | Robin L. Erickson, Nahid Hemati, Sarah E. Ross, Ormond A. MacDougald, Guy E. Groblewski |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
biology
Ccaat-enhancer-binding proteins GRB10 Insulin medicine.medical_treatment digestive oral and skin physiology Cell Biology digestive system Biochemistry Molecular biology IRS2 Dephosphorylation Insulin receptor Insulin receptor substrate biology.protein medicine biological phenomena cell phenomena and immunity Molecular Biology GLUT4 |
| Zdroj: | Journal of Biological Chemistry. 272:25913-25919 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.272.41.25913 |
| Popis: | Treatment of 3T3-L1 adipocytes with insulin (IC50 approximately 200 pM insulin) or insulin-like growth factor-1 (IC50 approximately 200 pM IGF-1) stimulates dephosphorylation of CCAAT/enhancer binding protein alpha (C/EBPalpha), a transcription factor involved in preadipocyte differentiation. As assessed by immunoblot analysis of one- and two-dimensional PAGE, insulin appears to dephosphorylate one site within p30C/EBPalpha and an additional site within p42C/EBPalpha. Consistent with insulin causing dephosphorylation of C/EBPalpha through activation of phosphatidylinositol 3-kinase, addition of phosphatidylinositol 3-kinase inhibitors (e.g. wortmannin) blocks insulin-stimulated dephosphorylation of C/EBPalpha. In the absence of insulin, wortmannin or LY294002 enhance C/EBPalpha phosphorylation. Similarly, blocking the activity of FKBP-rapamycin-associated protein with rapamycin increases phosphorylation of C/EBPalpha in the absence of insulin. Dephosphorylation of C/EBPalpha by insulin is partially blocked by rapamycin, consistent with a model in which activation of FKBP-rapamycin-associated protein by phosphatidylinositol 3-kinase results in dephosphorylation of C/EBPalpha. The dephosphorylation of C/EBPalpha by insulin, in conjunction with the insulin-dependent decline in C/EBPalpha mRNA and protein, has been hypothesized to play a role in repression of GLUT4 transcription by insulin. Consistent with this hypothesis, the decline of GLUT4 mRNA following exposure of adipocytes to insulin correlates with dephosphorylation of C/EBPalpha. However, the repression of C/EBPalpha mRNA and protein levels by insulin is blocked with an inhibitor of the mitogen-activated protein kinase pathway without blocking the repression of GLUT4 mRNA, thus dissociating the regulation of C/EBPalpha and GLUT4 mRNAs by insulin. A decline in C/EBPalpha mRNA and protein may not be required to suppress GLUT4 transcription because insulin also induces expression of the dominant-negative form of C/EBPbeta (liver inhibitory protein), which blocks transactivation by C/EBP transcription factors. |
| Databáze: | OpenAIRE |
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