PMID- 11875061
OWN - NLM
STAT- MEDLINE
DCOM- 20020716
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 20
DP  - 2002 May 17
TI  - Foxa2 (HNF3beta ) controls multiple genes implicated in metabolism-secretion 
      coupling of glucose-induced insulin release.
PG  - 17564-70
AB  - 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.
FAU - Wang, Haiyan
AU  - Wang H
AD  - Division of Clinical Biochemistry, Department of Internal Medicine, University 
      Medical Center, CH-1211 Geneva 4, Switzerland. Haiyan.Wang@medicine.unige.ch
FAU - Gauthier, Benoit R
AU  - Gauthier BR
FAU - Hagenfeldt-Johansson, Kerstin A
AU  - Hagenfeldt-Johansson KA
FAU - Iezzi, Mariella
AU  - Iezzi M
FAU - Wollheim, Claes B
AU  - Wollheim CB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20020301
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Foxa2 protein, mouse)
RN  - 0 (Foxa2 protein, rat)
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Hnf1a protein, mouse)
RN  - 0 (Hnf1a protein, rat)
RN  - 0 (Hnf1b protein, mouse)
RN  - 0 (Hnf4a protein, mouse)
RN  - 0 (Hnf4a protein, rat)
RN  - 0 (Insulin)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tcfl4 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 126548-29-6 (Hepatocyte Nuclear Factor 1)
RN  - 135845-92-0 (Hepatocyte Nuclear Factor 3-beta)
RN  - 138674-15-4 (Hepatocyte Nuclear Factor 1-beta)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.1.2 (Glucokinase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
MH  - DNA-Binding Proteins/genetics/*physiology
MH  - Fluorescent Antibody Technique
MH  - *Gene Expression Regulation
MH  - Glucagon/genetics
MH  - Glucokinase/biosynthesis/genetics/metabolism
MH  - Glucose/*physiology
MH  - Hepatocyte Nuclear Factor 1
MH  - Hepatocyte Nuclear Factor 1-alpha
MH  - Hepatocyte Nuclear Factor 1-beta
MH  - Hepatocyte Nuclear Factor 3-beta
MH  - Hepatocyte Nuclear Factor 4
MH  - Hexokinase/biosynthesis/genetics
MH  - Homeostasis
MH  - Insulin/*physiology
MH  - Mice
MH  - Multigene Family/*physiology
MH  - Nuclear Proteins/genetics/*physiology
MH  - Phosphoproteins/genetics
MH  - Potassium Channels, Inwardly Rectifying/genetics
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Transcription Factors/genetics
MH  - Transcriptional Activation
MH  - Tumor Cells, Cultured
EDAT- 2002/03/05 10:00
MHDA- 2002/07/18 10:01
CRDT- 2002/03/05 10:00
PHST- 2002/03/05 10:00 [pubmed]
PHST- 2002/07/18 10:01 [medline]
PHST- 2002/03/05 10:00 [entrez]
AID - S0021-9258(20)85245-4 [pii]
AID - 10.1074/jbc.M111037200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 May 17;277(20):17564-70. doi: 10.1074/jbc.M111037200. Epub 2002 
      Mar 1.