The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct
| Autor: | Christina A. Svitek, Ryan S. Streeper, Beth T. Vander Kooi, David R. Powell, James K. Oeser, Richard M. O'Brien |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Chloramphenicol O-Acetyltransferase
Transcriptional Activation Carcinoma Hepatocellular Recombinant Fusion Proteins Protein subunit medicine.medical_treatment Nerve Tissue Proteins FOXO1 Biology Biochemistry Gene Expression Regulation Enzymologic Fusion gene Mice Catalytic Domain Tumor Cells Cultured medicine Animals Humans Hypoglycemic Agents Insulin Promoter Regions Genetic Molecular Biology Transcription factor Regulation of gene expression Base Sequence Forkhead Box Protein O1 Forkhead Transcription Factors Promoter Cell Biology Molecular biology Rats DNA-Binding Proteins Insulin-Like Growth Factor Binding Protein 1 Glucose-6-Phosphatase Chromatin immunoprecipitation Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 278:11782-11793 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m212570200 |
| Popis: | Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by insulin requires two distinct promoter regions, designated A (located between -231 and -199) and B (located between -198 and -159), that together form an insulin response unit. Region A binds hepatocyte nuclear factor-1, which acts as an accessory factor to enhance the effect of insulin, mediated through region B, on G6Pase gene transcription. We have previously shown that region B binds the transcriptional activator FKHR (FOXO1a) in vitro. Chromatin immunoprecipitation assays demonstrate that FKHR also binds the G6Pase promoter in situ and that insulin inhibits this binding. Region B contains three insulin response sequences (IRSs), designated IRS 1, 2, and 3, that share the core sequence T(G/A)TTTT. However, detailed analyses reveal that these three G6Pase IRSs are functionally distinct. Thus, FKHR binds IRS 1 with high affinity and IRS 2 with low affinity but it does not bind IRS 3. Moreover, in the context of the G6Pase promoter, IRS 1 and 2, but not IRS 3, are required for the insulin response. Surprisingly, IRS 3, as well as IRS 1 and IRS 2, can each confer an inhibitory effect of insulin on the expression of a heterologous fusion gene, indicating that, in this context, a transcription factor other than FKHR, or its orthologs, can also mediate an insulin response through the T(G/A)TTTT motif. |
| Databáze: | OpenAIRE |
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