Document Detail


Inhibition of Hes1 activity in gall bladder epithelial cells promotes insulin expression and glucose responsiveness.
MedLine Citation:
PMID:  19935883     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The biliary system has a close developmental relationship with the pancreas, evidenced by the natural occurrence of small numbers of biliary-derived beta-cells in the biliary system and by the replacement of biliary epithelium with pancreatic tissue in mice lacking the transcription factor Hes1. In normal pancreatic development, Hes1 is known to repress endocrine cell formation. Here we show that glucose-responsive insulin secretion can be induced in biliary epithelial cells when activity of the transcription factor Hes1 is antagonised. We describe a new culture system for adult murine gall bladder epithelial cells (GBECs), free from fibroblast contamination. We show that Hes1 is expressed both in adult murine gall bladder and in cultured GBECs. We have created a new dominant negative Hes1 (DeltaHes1) by removal of the DNA-binding domain, and show that it antagonises Hes1 function in vivo. When DeltaHes1 is introduced into the GBEC it causes expression of insulin RNA and protein. Furthermore, it confers upon the cells the ability to secrete insulin following exposure to increased external glucose. GBEC cultures are induced to express a wider range of mature beta cell markers when co-transduced with DeltaHes1 and the pancreatic transcription factor Pdx1. Introduction of DeltaHes1 and Pdx1 can therefore initiate a partial respecification of phenotype from biliary epithelial cell towards the pancreatic beta cell.
Authors:
R A Coad; J R Dutton; D Tosh; J M W Slack
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry and cell biology = Biochimie et biologie cellulaire     Volume:  87     ISSN:  1208-6002     ISO Abbreviation:  Biochem. Cell Biol.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-25     Completed Date:  2010-03-04     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  8606068     Medline TA:  Biochem Cell Biol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  975-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism*
Cell Culture Techniques
Cells, Cultured
Epithelial Cells / cytology,  metabolism*
Gallbladder / cytology*
Glucose / metabolism*
Homeodomain Proteins / genetics,  metabolism*
Humans
Insulin / metabolism*
Insulin-Secreting Cells / metabolism
Mice
Molecular Sequence Data
Phenotype
Grant Support
ID/Acronym/Agency:
G0300415//Medical Research Council; G0500220//Medical Research Council; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Hes1 protein, mouse; 0/Homeodomain Proteins; 0/Insulin; IY9XDZ35W2/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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