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Induction of the ChREBP? Isoform Is Essential for Glucose-Stimulated ?-Cell Proliferation.


ABSTRACT: Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic ?-cells in rodents and humans. The full-length isoform (ChREBP?) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBP?) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBP? has not been described in ?-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBP? is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBP? transcripts without affecting ChREBP? 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 ?-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBP? contributes to glucose-stimulated gene expression and proliferation in ?-cells, with recruitment of ChREBP? to tissue-specific elements of the ChREBP? isoform promoter.

SUBMITTER: Zhang P 

PROVIDER: S-EPMC4657577 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Zhang Pili P   Kumar Anil A   Katz Liora S LS   Li Lucy L   Paulynice Martine M   Herman Mark A MA   Scott Donald K DK  

Diabetes 20150917 12


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 n  ...[more]

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