Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression.
Members of the Forkhead box a (Foxa) transcription factor family are expressed in the liver, pancreatic islets and intestine and both Foxa1 and Foxa2 regulate proglucagon gene transcription. As Foxa proteins exhibit overlapping DNA-binding specificities, we examined the role of Foxa3 [hepatocyte nuclear factor (HNF)-3gamma] in control of proglucagon gene expression. Foxa3 was detected by reverse transcriptase PCR in glucagon-producing cell lines and binds to the rat proglucagon gene G2 promoter element in GLUTag enteroendocrine cells. Although Foxa3 increased rat proglucagon promoter activity in BHK fibroblasts, augmentation of Foxa3 expression did not increase proglucagon promoter activity in GLUTag cells. Furthermore, adenoviral Foxa3 expression did not affect endogenous proglucagon gene expression in islet or intestinal endocrine cell lines. Although Foxa3(-/-) mice exhibit mild hypoglycaemia during a prolonged fast, the levels of proglucagon-derived peptides and proglucagon mRNA transcripts were comparable in tissues from wild-type and Foxa3(-/-) mice. These findings identify Foxa3 as a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo.
Liu
Yuanfang
Y
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, 101 College Street CCRW3-845, Toronto, Canada M5G 2C4.
Shen
Wei
W
Brubaker
Patricia L
PL
Kaestner
Klaus H
KH
Drucker
Daniel J
DJ
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics*; D051543:Hepatocyte Nuclear Factor 3-gamma; D006801:Humans; D007668:Kidney; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D010179:Pancreas / Q000378:metabolism; D052336:Proglucagon; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C496505:FOXA3 protein, human; C496506:Foxa3 protein, mouse; C496507:Foxa3 protein, rat; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011498:Protein Precursors; D014157:Transcription Factors; D051543:Hepatocyte Nuclear Factor 3-gamma; D052336:Proglucagon; D005934:Glucagon