Document Detail

Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of conserved upstream control regions and their hepatic nuclear factor 3beta sites.
MedLine Citation:
PMID:  10652343     Owner:  NLM     Status:  MEDLINE    
To identify potential transactivators of pdx-1, we sequenced approximately 4.5 kilobases of the 5' promoter region of the human and chicken homologs, assuming that sequences conserved with the mouse gene would contain critical cis-regulatory elements. The sequences associated with hypersensitive site 1 (HSS1) represented the principal area of homology within which three conserved subdomains were apparent: area I (-2694 to -2561 base pairs (bp)), area II (-2139 to -1958 bp), and area III (-1879 to -1799 bp). The identities between the mouse and chicken/human genes are very high, ranging from 78 to 89%, although only areas I and III are present within this region in chicken. Pancreatic beta cell-selective expression was shown to be controlled by mouse and human area I or area II, but not area III, from an analysis of pdx-1-driven reporter activity in transfected beta- and non-beta cells. Mutational and functional analyses of conserved hepatic nuclear factor 3 (HNF3)-like sites located within area I and area II demonstrated that activation by these regions was mediated by HNF3beta. To determine if a similar regulatory relationship might exist within the context of the endogenous gene, pdx-1 expression was measured in embryonic stem cells in which one or both alleles of HNF3beta were inactivated. pdx-1 mRNA levels induced upon differentiation to embryoid bodies were down-regulated in homozygous null HNF3beta cells. Together, these results suggest that the conserved sequences represented by areas I and II define the binding sites for factors such as HNF3beta, which control islet beta cell-selective expression of the pdx-1 gene.
K Gerrish; M Gannon; D Shih; E Henderson; M Stoffel; C V Wright; R Stein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-03-02     Completed Date:  2000-03-02     Revised Date:  2011-06-01    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3485-92     Citation Subset:  IM    
Department of Molecular Physiology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AF192495;  AF192496;  AF194114
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MeSH Terms
Base Sequence
Cells, Cultured
DNA-Binding Proteins / genetics*,  metabolism
Hepatocyte Nuclear Factor 3-beta
Homeodomain Proteins / biosynthesis,  genetics
Islets of Langerhans / physiology*
Molecular Sequence Data
Nuclear Proteins / genetics*,  metabolism
Sequence Alignment
Trans-Activators / biosynthesis,  genetics*
Transcription Factors / genetics,  metabolism
Transcription, Genetic*
Grant Support
Reg. No./Substance:
0/DNA-Binding Proteins; 0/FOXA2 protein, human; 0/Foxa2 protein, mouse; 0/Homeodomain Proteins; 0/Nuclear Proteins; 0/Trans-Activators; 0/Transcription Factors; 0/pancreatic and duodenal homeobox 1 protein; 135845-92-0/Hepatocyte Nuclear Factor 3-beta

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