Regulation of pdx-1 gene expression.
The homeodomain-containing transcription factor pancreatic duodenal homeobox 1 (PDX-1) plays a key role in pancreas development and in beta-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 beta-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 beta-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)-3beta, HNF-1alpha, 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.
Melloul
Danielle
D
Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel. danielle@md.huji.ac.il
Marshak
Sonya
S
Cerasi
Erol
E
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein