FoxO Feedback Control of Basal IRS-2 Expression in Pancreatic β-Cells Is Distinct From That in Hepatocytes
| Autor: | Christopher J. Rhodes, Shin Tsunekawa, Isabelle Briaud, Roland Stein, Damien Demozay, Jill F. McCuaig, Domenico Accili |
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| Rok vydání: | 2011 |
| Předmět: |
Aryl hydrocarbon receptor nuclear translocator
Insulin Receptor Substrate Proteins Endocrinology Diabetes and Metabolism FOXO1 Biology Response Elements Cell Line Tissue Culture Techniques Mice 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells Internal Medicine medicine Animals Humans Insulin RNA Messenger Rats Wistar Promoter Regions Genetic Enhancer Transcription factor 030304 developmental biology Cell Nucleus Feedback Physiological 0303 health sciences Forkhead Box Protein O1 Pancreatic islets Forkhead Box Protein O3 Forkhead Transcription Factors Promoter Molecular biology IRS2 Rats Mice Inbred C57BL Protein Transport medicine.anatomical_structure Gene Expression Regulation Islet Studies Organ Specificity 030220 oncology & carcinogenesis Hepatocytes |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db11-0340 |
| Popis: | OBJECTIVE Appropriate regulation of insulin receptor substrate 2 (IRS-2) expression in pancreatic β-cells is essential to adequately compensate for insulin resistance. In liver, basal IRS-2 expression is controlled via a temporal negative feedback of sterol regulatory element–binding protein 1 (SREBP-1) to antagonize transcription factors forkhead box class O (FoxO)1/FoxO3a at an insulin response element (IRE) on the IRS-2 promoter. The purpose of the study was to examine if a similar mechanism controlled IRS-2 expression in β-cells. RESEARCH DESIGN AND METHODS IRS-2 mRNA and protein expression, as well as IRS-2 gene promoter activity, were examined in isolated rat islets. Specific transcription factor association with the IRE on the IRS-2 promoter was examined by chromatin immunoprecipitation (ChIP) assay, and their nuclear translocation was examined by immunofluorescence. A direct in vivo effect of insulin on control of IRS-2 expression in liver and pancreatic islets was also investigated. RESULTS In IRS-2 promoter-reporter assays conducted in isolated islets, removal of the IRE decreased basal IRS-2 promoter activity in β-cells up to 80%. Activation of IRS signaling in isolated rat islets by insulin/IGF-I (used as an experimental in vitro tool) or downstream constitutive activation of protein kinase B (PKB) significantly decreased IRS-2 expression. In contrast, inhibition of phosphatidylinositol 3-kinase (PI3K) or PKB significantly increased IRS-2 levels in β-cells. ChIP assays indicated that transcription factors FoxO1 and FoxO3a associated with the IRE on the IRS-2 promoter in β-cells in a PI3K/PKB–dependent manner, whereas others, such as SREBP-1, the transcription factor binding to immunoglobulin heavy chain enhancer 3′, and the aryl hydrocarbon receptor nuclear translocator (ARNT), did not. However, only FoxO3a, not FoxO1, was capable of driving IRS-2 promoter activity via the IRE in β-cells. In vivo studies showed insulin was able to suppress IRS-2 expression via activation of SREBP-1 in the liver, but this mechanism was not apparent in pancreatic islets from the same animal. CONCLUSIONS The molecular mechanism for feedback control of IRS signaling to decrease IRS-2 expression in liver and β-cells is quite distinct, with a predominant role played by FoxO3a in β-cells. |
| Databáze: | OpenAIRE |
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