Regulation of pdx-1 Gene Expression

Abstract

The homeodomain-containing transcription factor pan-creatic duodenal homeobox 1 (PDX-1) plays a key role in pancreas development and in-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-cell-specific enhanc-ers 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-cell-specific expression on a reporter gene, albeit to different extents. A number of transcription factors binding to and modulating the transcrip-tional activity of the regulatory elements were identified, such as hepatocyte nuclear factor (HNF)-3, HNF-1, 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. Diabetes 51 (Suppl. 3):S320-S325, 2002