Hepatic nuclear factor-3 (HNF-3 or Foxa2) regulates glucagon gene transcription by binding to the G1 and G2 promoter elements.
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.
Gauthier
Benoit R
BR
Unité de Diabétologie Clinique, Centre Médical Universitaire, 1211 Genève 4, Switzerland. benoit.gauthier@medecine.unige.ch
Schwitzgebel
Valerie M
VM
Zaiko
Maia
M
Mamin
Aline
A
Ritz-Laser
Beate
B
Philippe
Jacques
J
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics* / Q000378:metabolism; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic
D000071616:CDX2 Transcription Factor; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D005934:Glucagon