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J. Biol. Chem., Vol. 276, Issue 20, 17533-17540, May 18, 2001
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From the Department of Endocrinology and Metabolism, Hebrew
University Hadassah Medical Center, 91120 Jerusalem, Israel
The PDX-1 transcription factor plays a key role
in pancreas development. Although expressed in all cells at the early
stages, in the adult it is mainly restricted to the The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) 225952.
A Pancreatic
-Cell-specific Enhancer in the Human
PDX-1 Gene Is Regulated by Hepatocyte Nuclear Factor 3
(HNF-3), HNF-1
, and SPs Transcription Factors*
-cell. To
characterize the regulatory elements and potential transcription
factors necessary for human PDX-1 gene expression in
-cells, we constructed a series of 5' and 3' deletion fragments of
the 5'-flanking region of the gene, fused to the luciferase reporter
gene. In this report, we identify by transient transfections in -
and non--cells a novel -cell-specific distal enhancer element
located between 
3.7 and 3.45 kilobases. DNase I footprinting
analysis revealed two protected regions, one binding the transcription
factors SP1 and SP3 and the other hepatocyte nuclear factor 3
(HNF-3) and HNF-1
. Cotransfection experiments suggest that
HNF-3, HNF-1, and SP1 are positive regulators of the
herein-described human PDX-1 enhancer element. Furthermore,
mutations within each motif abolished the binding of the corresponding
factor(s) and dramatically impaired the enhancer activity, therefore
suggesting cooperativity between these factors.
*
This work was supported by grants from the Juvenile Diabetes
Foundation International and the Israel Science Foundation and the
European Commission (BIOMED2).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Endocrinology
and Metabolism, Hadassah University Hospital, P. O. Box 12000, Jerusalem 91120, Israel. Tel.: 972-2-677 83 98; Fax: 972-2-643 79 40;
E-mail: Danielle@md2.huji.ac.il.
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