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Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation

Carbohydrate-responsive element–binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation...

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Autores principales: Zhang, Pili, Kumar, Anil, Katz, Liora S., Li, Lucy, Paulynice, Martine, Herman, Mark A., Scott, Donald K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657577/
https://www.ncbi.nlm.nih.gov/pubmed/26384380
http://dx.doi.org/10.2337/db15-0239
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author Zhang, Pili
Kumar, Anil
Katz, Liora S.
Li, Lucy
Paulynice, Martine
Herman, Mark A.
Scott, Donald K.
author_facet Zhang, Pili
Kumar, Anil
Katz, Liora S.
Li, Lucy
Paulynice, Martine
Herman, Mark A.
Scott, Donald K.
author_sort Zhang, Pili
collection PubMed
description Carbohydrate-responsive element–binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBPβ) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBPβ has not been described in β-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBPβ is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBPβ transcripts without affecting ChREBPα expression or activity decreased glucose-stimulated expression of carbohydrate response element–containing genes and glucose-stimulated proliferation in INS-1 cells and in isolated rat islets. Quantitative chromatin immunoprecipitation, electrophoretic mobility shift assays, and luciferase reporter assays were used to demonstrate that ChREBP binds to a newly identified powerful carbohydrate response element in β-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBPβ contributes to glucose-stimulated gene expression and proliferation in β-cells, with recruitment of ChREBPα to tissue-specific elements of the ChREBPβ isoform promoter.
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spelling pubmed-46575772016-12-01 Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation Zhang, Pili Kumar, Anil Katz, Liora S. Li, Lucy Paulynice, Martine Herman, Mark A. Scott, Donald K. Diabetes Islet Studies Carbohydrate-responsive element–binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBPβ) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBPβ has not been described in β-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBPβ is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBPβ transcripts without affecting ChREBPα expression or activity decreased glucose-stimulated expression of carbohydrate response element–containing genes and glucose-stimulated proliferation in INS-1 cells and in isolated rat islets. Quantitative chromatin immunoprecipitation, electrophoretic mobility shift assays, and luciferase reporter assays were used to demonstrate that ChREBP binds to a newly identified powerful carbohydrate response element in β-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBPβ contributes to glucose-stimulated gene expression and proliferation in β-cells, with recruitment of ChREBPα to tissue-specific elements of the ChREBPβ isoform promoter. American Diabetes Association 2015-12 2015-09-17 /pmc/articles/PMC4657577/ /pubmed/26384380 http://dx.doi.org/10.2337/db15-0239 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Islet Studies
Zhang, Pili
Kumar, Anil
Katz, Liora S.
Li, Lucy
Paulynice, Martine
Herman, Mark A.
Scott, Donald K.
Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title_full Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title_fullStr Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title_full_unstemmed Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title_short Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation
title_sort induction of the chrebpβ isoform is essential for glucose-stimulated β-cell proliferation
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657577/
https://www.ncbi.nlm.nih.gov/pubmed/26384380
http://dx.doi.org/10.2337/db15-0239
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