A Pancreatic β-Cell-specific Enhancer in the Human PDX-1 Gene Is Regulated by Hepatocyte Nuclear Factor 3β (HNF-3β), HNF-1α, and SPs Transcription Factors

Etti Ben-Shushan, Sonya Marshak, Michal Shoshkes, Erol Cerasi, Danielle Melloul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

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 β-cell. To characterize the regulatory elements and potential transcription factors necessary for human PDX-1 gene expression in β-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 β- and non-β-cells a novel β-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 3β (HNF-3β) and HNF-1α. Cotransfection experiments suggest that HNF-3β, HNF-1α, 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.

Original languageAmerican English
Pages (from-to)17533-17540
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number20
DOIs
StatePublished - 18 May 2001

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