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Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells

The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previ...

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Autores principales: Arcidiacono, Biagio, Iiritano, Stefania, Chiefari, Eusebio, Brunetti, Francesco S., Gu, Guoqiang, Foti, Daniela Patrizia, Brunetti, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292585/
https://www.ncbi.nlm.nih.gov/pubmed/25628604
http://dx.doi.org/10.3389/fendo.2014.00237
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author Arcidiacono, Biagio
Iiritano, Stefania
Chiefari, Eusebio
Brunetti, Francesco S.
Gu, Guoqiang
Foti, Daniela Patrizia
Brunetti, Antonio
author_facet Arcidiacono, Biagio
Iiritano, Stefania
Chiefari, Eusebio
Brunetti, Francesco S.
Gu, Guoqiang
Foti, Daniela Patrizia
Brunetti, Antonio
author_sort Arcidiacono, Biagio
collection PubMed
description The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS) gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production.
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spelling pubmed-42925852015-01-27 Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells Arcidiacono, Biagio Iiritano, Stefania Chiefari, Eusebio Brunetti, Francesco S. Gu, Guoqiang Foti, Daniela Patrizia Brunetti, Antonio Front Endocrinol (Lausanne) Endocrinology The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS) gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production. Frontiers Media S.A. 2015-01-13 /pmc/articles/PMC4292585/ /pubmed/25628604 http://dx.doi.org/10.3389/fendo.2014.00237 Text en Copyright © 2015 Arcidiacono, Iiritano, Chiefari, Brunetti, Gu, Foti and Brunetti. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Arcidiacono, Biagio
Iiritano, Stefania
Chiefari, Eusebio
Brunetti, Francesco S.
Gu, Guoqiang
Foti, Daniela Patrizia
Brunetti, Antonio
Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title_full Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title_fullStr Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title_full_unstemmed Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title_short Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells
title_sort cooperation between hmga1, pdx-1, and mafa is essential for glucose-induced insulin transcription in pancreatic beta cells
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292585/
https://www.ncbi.nlm.nih.gov/pubmed/25628604
http://dx.doi.org/10.3389/fendo.2014.00237
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