scholarly journals Hepatic Nuclear Factor-3 (HNF-3 or Foxa2) Regulates Glucagon Gene Transcription by Binding to the G1 and G2 Promoter Elements

2002 ◽  
Vol 16 (1) ◽  
pp. 170-183 ◽  
Author(s):  
Benoit R. Gauthier ◽  
Valerie M. Schwitzgebel ◽  
Maia Zaiko ◽  
Aline Mamin ◽  
Beate Ritz-Laser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Gene Transcription ◽  
Endocrine Pancreas ◽  
Gene Promoter ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Specific Element ◽  
The Third ◽  
Transactivation Potential

Abstract Glucagon gene expression in the endocrine pancreas is controlled by three islet-specific elements (G3, G2, and G4) and theα -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)β, 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-3α and -β 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-3α or -β. We show that both HNF-3β and -α 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.

scholarly journals Type I Protein C Deficiency Caused by Disruption of a Hepatocyte Nuclear Factor (HNF)-6/HNF-1 Binding Site in the Human Protein C Gene Promoter

1998 ◽  
Vol 273 (17) ◽  
pp. 10168-10173 ◽  
Author(s):  
C. Arnold Spek ◽  
Vincent J. Lannoy ◽  
Frédéric P. Lemaigre ◽  
Guy G. Rousseau ◽  
Rogier M. Bertina ◽  
...  
Keyword(s):  
Binding Site ◽  
Protein C ◽  
Gene Promoter ◽  
Human Protein ◽  
Type I ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Protein C Deficiency

scholarly journals Regulation of lactase–phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2

1997 ◽  
Vol 322 (3) ◽  
pp. 833-838 ◽  
Author(s):  
Jesper T. TROELSEN ◽  
Cathy MITCHELMORE ◽  
Nikolaj SPODSBERG ◽  
Anette M. JENSEN ◽  
Ove NORÉN ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Intestine ◽  
Binding Site ◽  
Electrophoretic Mobility Shift Assay ◽  
Gene Transcription ◽  
Transcriptional Activity ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Cis Element ◽  
Mobility Shift Assay

Lactase–phlorizin hydrolase is exclusively expressed in the small intestine and is often used as a marker for the differentiation of enterocytes. The cis-element CE-LPH1 found in the lactase–phlorizin hydrolase promoter has previously been shown to bind an intestinal-specific nuclear factor. By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1. A mutation in CE-LPH1, which does not affect Cdx-2 binding, results in a higher transcriptional activity, indicating that the CE-LPH1 site contains other binding site(s) in addition to the Cdx-2-binding site.

Disruption of a binding site for hepatocyte nuclear factor 1 in the protein C gene promoter is associated with hereditary thrombophilia

1994 ◽  
Vol 3 (12) ◽  
pp. 2147-2152 ◽  
Author(s):  
Lutz-Peter Berg ◽  
Deborah A. Scopes ◽  
Anwar Alhaq ◽  
Vijay V. Kakkar ◽  
David N. Cooper
Keyword(s):  
Binding Site ◽  
Protein C ◽  
Gene Promoter ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hereditary Thrombophilia ◽  
Nuclear Factor 1

scholarly journals The MODY1 Gene for Hepatocyte Nuclear Factor 4α and a Feedback Loop Control COUP-TFII Expression in Pancreatic Beta Cells

2008 ◽  
Vol 28 (14) ◽  
pp. 4588-4597 ◽  
Author(s):  
Anaïs Perilhou ◽  
Cécile Tourrel-Cuzin ◽  
Pili Zhang ◽  
Ilham Kharroubi ◽  
Haiyan Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Secretion ◽  
Binding Site ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Gene Promoter ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

ABSTRACT Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4α (HNF4α) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4α activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4α with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4α transactivation of COUP-TFII. The dominant negative suppression of HNF4α function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4α mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4α by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4α mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4α/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.

Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells

1992 ◽  
Vol 12 (4) ◽  
pp. 1708-1718
Author(s):  
M Mietus-Snyder ◽  
F M Sladek ◽  
G S Ginsburg ◽  
C F Kuo ◽  
J A Ladias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Protein ◽  
Lipid Binding ◽  
Hepatic Tissue ◽  
Nuclear Factor ◽  
Apolipoprotein Ai ◽  
Hepatocyte Nuclear Factor ◽  
Apolipoprotein Ciii ◽  
Caco2 Cells ◽  
Hepatocyte Nuclear Factor 4

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.

The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element

1993 ◽  
Vol 13 (2) ◽  
pp. 1183-1193
Author(s):  
J Dalmon ◽  
M Laurent ◽  
G Courtois
Keyword(s):  
Binding Site ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Constitutive Expression ◽  
Nuclear Proteins ◽  
Functional Coupling ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tissue Specific ◽  
Nuclear Factor 1

Acute-phase reactants are liver proteins whose synthesis is positively or negatively regulated during inflammation. The main mediators of this phenomenon are glucocorticoids and interleukin-6 (IL-6), a pleiotropic cytokine that also controls hematopoiesis. Functional analysis of several acute-phase reactant promoter regions has identified two major DNA motifs used by IL-6-regulated genes. The first one corresponds to a CTGG(G/A)AA sequence, and the other is a binding site for members of the C/EBP family of nuclear proteins. We have previously shown that the human beta fibrinogen (beta Fg) promoter contains an IL-6-responsive region, located between bp -150 and -67 (P. Huber, M. Laurent, and J. Dalmon, J. Biol. Chem. 265:5695-5701, 1990). In this study, using DNase I footprinting, mobility shift assays, and mutagenesis, we demonstrate that at least three subdomains of this region are necessary to observe a full response to IL-6. The most distal contains a CTGGGAA motif, and its mutation inhibits IL-6 stimulation. Another, which is able to interact with several distinct nuclear proteins, among them members of the C/EBP family, is dispensable for IL-6 induction but plays an important role in the constitutive expression of beta Fg. Finally, a proximal hepatocyte nuclear factor 1 binding site, already described as the major determinant of beta Fg tissue-specific expression, is also required for IL-6 stimulation. These results indicate a complex interplay between nuclear proteins within the beta Fg IL-6-responsive region and suggest a tight functional coupling between the tissue-specific and inducible elements.

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