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Scientific article
English

Hepatic nuclear factor-3 (HNF-3 or Foxa2) regulates glucagon gene transcription by binding to the G1 and G2 promoter elements

Published inMolecular endocrinology, vol. 16, no. 1, p. 170-183
Publication date2002
Abstract

Glucagon gene expression in the endocrine pancreas is controlled by three islet-specific elements (G3, G2, and G4) and the alpha-cell-specific element G1. Two proteins interacting with G1 have previously been identified as Pax6 and Cdx2/3. We identify here the third yet uncharacterized complex on G1 as hepatocyte nuclear factor 3 (HNF-3)beta, a member of the HNF-3/forkhead transcription family, which plays an important role in the development of endoderm-related organs. HNF-3 has been previously demonstrated to interact with the G2 element and to be crucial for glucagon gene expression; we thus define a second binding site for this transcription on the glucagon gene promoter. We demonstrate that both HNF-3alpha and -beta produced in heterologous cells can interact with similar affinities to either the G1 or G2 element. Pax6, which binds to an overlapping site on G1, exhibited a greater affinity as compared with HNF-3alpha or -beta. We show that both HNF-3beta and -alpha can transactivate glucagon gene transcription through the G2 and G1 elements. However, HNF-3 via its transactivating domains specifically impaired Pax6-mediated transactivation of the glucagon promoter but had no effect on transactivation by Cdx2/3. We suggest that HNF-3 may play a dual role on glucagon gene transcription by 1) inhibiting the transactivation potential of Pax6 on the G1 and G3 elements and 2) direct activation through G1 and G2.

Keywords
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Cricetinae
  • DNA-Binding Proteins/genetics/metabolism
  • Eye Proteins
  • Gene Expression Regulation
  • Glucagon/genetics/metabolism
  • Hepatocyte Nuclear Factor 3-alpha
  • Hepatocyte Nuclear Factor 3-beta
  • Homeodomain Proteins/genetics/metabolism
  • Kidney/cytology
  • Mesocricetus
  • Molecular Sequence Data
  • Nuclear Proteins/genetics/metabolism
  • Paired Box Transcription Factors
  • Promoter Regions, Genetic
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic
Citation (ISO format)
GAUTHIER, Benoît et al. Hepatic nuclear factor-3 (HNF-3 or Foxa2) regulates glucagon gene transcription by binding to the G1 and G2 promoter elements. In: Molecular endocrinology, 2002, vol. 16, n° 1, p. 170–183. doi: 10.1210/mend.16.1.0752
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Article (Published version)
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Identifiers
ISSN of the journal0888-8809
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