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Molecular and Cellular Biology, October 2000, p. 7583-7590, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functional Conservation of Regulatory Elements in the pdx-1 Gene: PDX-1 and Hepatocyte Nuclear Factor 3beta Transcription Factors Mediate beta -Cell-Specific Expression

Sonya Marshak, Etty Benshushan, Michal Shoshkes, Leora Havin, Erol Cerasi, and Danielle Melloul*

Department of Endocrinology & Metabolism, Hadassah University Hospital, 91120 Jerusalem, Israel

Received 2 February 2000/Returned for modification 15 March 2000/Accepted 21 July 2000

The PDX-1 transcription factor plays a key role in pancreatic development and in the regulation of the insulin gene in the adult beta  cell. As its functions appear to be similar in humans and mice, we analyzed the functional conservation of homologous sequences important for the maintenance and the cell-specific regulation of the pdx-1 gene. Apart from the proximal promoter region, three highly homologous (PH1 to PH3) sequences were apparent in the human and mouse 5' flanking regions of the gene. By transient transfections in beta  and non-beta cells, we show that mainly PH1 and PH2 preferentially confer beta -cell-specific activation on a heterologous promoter. DNase I footprinting and binding analyses revealed that both bind to and are transactivated by hepatocyte nuclear factor 3beta (HNF-3beta ). Furthermore, the PH1 enhancer element also binds the PDX-1 transcription factor itself, which acts cooperatively with adjacent HNF-3beta to regulate its transcriptional potency. This finding suggests a possible autoregulatory loop as a mechanism for PDX-1 to control its own expression.

* Corresponding author. Mailing address: Department of Endocrinology & Metabolism, Hadassah University Hospital, P.O. Box 12 000, Jerusalem, 91120 Israel. Phone: 972-2-677 83 98. Fax: 972-2-643 79 40. E-mail: Danielle{at}md2.huji.ac.il.

Molecular and Cellular Biology, October 2000, p. 7583-7590, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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