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Diabetes 51:S320-S325, 2002
© 2002 by the American Diabetes Association, Inc.

Section 2: Beta-Cell Genes: Functional Aspects

Regulation of pdx-1 Gene Expression

Danielle Melloul, Sonya Marshak, and Erol Cerasi

From the Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel

The homeodomain-containing transcription factor pancreatic duodenal homeobox 1 (PDX-1) plays a key role in pancreas development and in ß-cell function. Upstream sequences of the gene up to about -6 kb show islet-specific activity in transgenic mice. Attempts to identify functional regulatory elements involved in the controlled expression of the pdx-1 gene led to the identification of distinct distal ß-cell-specific enhancers in human and rat genes. Three additional sequences, conserved between the mouse and the human 5'-flanking regions, two of which are also found in the chicken gene, conferred ß-cell-specific expression on a reporter gene, albeit to different extents. A number of transcription factors binding to and modulating the transcriptional activity of the regulatory elements were identified, such as hepatocyte nuclear factor (HNF)-3ß, HNF-1{alpha}, SP1/3, and, interestingly, PDX-1 itself. A fourth conserved region was localized to the proximal promoter around an E-box motif and was found to bind members of the upstream stimulatory factor (USF) family of transcription factors. We postulate that disruption of pdx-1 cis-acting regulatory sequences and/or mutations or functional impairment of transcription factors controlling the expression of the gene can lead to diabetes.


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Copyright © 2002 by the American Diabetes Association.