title: Foxa2 (HNF3beta ) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release.
abstract: The transcription factor Foxa2 is implicated in blood glucose homeostasis. Conditional expression of Foxa2 or its dominant-negative mutant DN-Foxa2 in INS-1 cells reveals that Foxa2 regulates the expression of genes important for glucose sensing in pancreatic beta-cells. Overexpression of Foxa2 results in blunted glucose-stimulated insulin secretion, whereas induction of DN-Foxa2 causes a left shift of glucose-induced insulin release. The mRNA levels of GLUT2 and glucokinase are drastically decreased after induction of Foxa2. In contrast, loss of Foxa2 function leads to up-regulation of hexokinase (HK) I and II and glucokinase (HK-IV) mRNA expression. The glucokinase and the low K(m) hexokinase activities as well as glycolysis are increased proportionally. In addition, induction of DN-Foxa2 also reduces the expression of beta-cell K(ATP) channel subunits Sur1 and Kir6.2 by 70%. Furthermore, in contrast to previous reports, induction of Foxa2 causes pronounced decreases in the HNF4alpha and HNF1alpha mRNA levels. Foxa2 fails to regulate the expression of Pdx1 transcripts. The expression of insulin and islet amyloid polypeptide is markedly suppressed after induction of Foxa2, while the glucagon mRNA levels are significantly increased. Conversely, Foxa2 is required for glucagon expression in these INS-1-derived cells. These results suggest that Foxa2 is a vital transcription factor evolved to control the expression of genes essential for maintaining beta-cell glucose sensing and glucose homeostasis.
authors.affiliation: Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, CH-1211 Geneva 4, Switzerland. Haiyan.Wang@medicine.unige.ch
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.forename: Benoit R
authors.initials: BR
authors.lastname: Gauthier
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Hagenfeldt-Johansson
authors.forename: Mariella
authors.initials: M
authors.lastname: Iezzi
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics; D005941:Glucokinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000502:physiology*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051542:Hepatocyte Nuclear Factor 3-beta; D051557:Hepatocyte Nuclear Factor 4; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis; D007328:Insulin / Q000502:physiology*; D051379:Mice; D005810:Multigene Family / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496503:Foxa2 protein, mouse; C496504:Foxa2 protein, rat; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; C496593:Hnf4a protein, mouse; C496594:Hnf4a protein, rat; D007328:Insulin; D009687:Nuclear Proteins; D010750:Phosphoproteins; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051542:Hepatocyte Nuclear Factor 3-beta; D051539:Hepatocyte Nuclear Factor 1-beta; D005934:Glucagon; D006593:Hexokinase; D005941:Glucokinase; D005947:Glucose