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At least 19 recordsLinked to original sources
PubMed1997

Modulation of hepatic gene expression by hepatocyte nuclear factor 1.

Hepatocyte nuclear factors 1 and 4 (HNF-1 and HNF-4) are liver-enriched transcription factors that function in the regulation of several liver-specific genes. HNF-1 activates genes containing promoters with HNF-1 binding sites. However, this factor negatively regulates its own expression and that of other HNF-4-dependent genes that lack HNF-1 binding sites in their promoter region. This repression is exerted by a direct interaction of HNF-1 with AF2, the main activation domain of HNF-4. The dual functions of gene activation and repression suggest that HNF-1 is a global regulator of the transcriptional network involved in the maintenance of hepatocyte-specific phenotype.

Animals↗
PubMed1995

The promoter of the salmon insulin-like growth factor I gene is activated by hepatocyte nuclear factor 1.

Hepatocyte nuclear factor 1 (HNF-1) was found to have a potent stimulatory action on the activity of the promoter of the salmon insulin-like growth factor I (IGF-I) gene in transient transfection experiments. This liver-enriched transcription factor was shown to bind to an element in the proximal region of the promoter with distinct nucleotide sequence homology to the HNF-1 consensus binding sequence. Mutating this sequence to a variant no longer capable of HNF-1 binding resulted in the loss of the stimulatory effect. Since the sequence of the HNF-1 binding site is conserved in all mammalian, avian, and amphibian species from which the IGF-I promoter sequences have been derived to date, we propose that HNF-1 may be an important regulator of IGF-I gene expression in all of these species.

Animals↗
PubMed1991

Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4.

Hepatocyte nuclear factor 1 (HNF-1) is a transcriptional regulatory protein possibly involved in the activation of many liver-specifically expressed genes. HNF-1 mRNA is restricted to a small number of tissues, suggesting that the HNF-1 gene itself is regulated at the transcriptional level. We have isolated and characterized the promoter region of this gene and have determined its transcriptional potential in several cell types by cell-free transcription and transient transfection experiments. In in vitro transcription assays, an HNF-1 promoter is active in nuclear extracts from liver and kidney, two tissues that contain HNF-1, but silent in nuclear extracts from spleen and lung, which are devoid of this transcription factor. Likewise, in transfection experiments, HNF-1 promoter-chloramphenicol acetyltransferase (CAT) fusion genes are expressed in Hep G2 cells, which express HNF-1, but not in mouse L cells or Hela cells, which do not express HNF-1. In both cell-free transcription and transient transfection assays, a relatively short promoter segment located between positions -82 and -40 is necessary and sufficient to direct cell type-specific HNF-1 transcription. This region contains a single site for a DNA-binding protein that has been tentatively identified as hepatocyte nuclear factor 4, a member of the steroid hormone receptor family.

Base Sequence↗
PubMed1999

Regulation of the gene for human dipeptidyl peptidase IV by hepatocyte nuclear factor 1 alpha.

Hepatocyte nuclear factor 1 was identified as the transcription factor binding to a 20 bp (-150 to -131) region of the gene for human dipeptidyl peptidase IV, which has been shown to be important for the expression of dipeptidyl peptidase IV in the human intestinal and hepatic epithelial cell lines Caco-2 and HepG2. Functional analysis of the hepatocyte nuclear factor 1 site was performed with two minimal dipeptidyl peptidase IV promoter constructs (-250 to -41, and -150 to -41) with and without a 3 bp mutation in the hepatocyte nuclear factor 1 sequence, and used in transient transfection experiments with Caco-2 cells. The results show that the mutated constructs were able to drive transcription at only 5-10% of the activity of the non-mutated controls. Co-transfection of 3T3 cells with hepatocyte nuclear factor 1 (alpha or beta) and dipeptidyl peptidase IV promoter constructs (-250 to -41 or -150 to -41) resulted in a 2.5-6-fold increase in transcription over controls with hepatocyte nuclear factor 1 alpha but not with hepatocyte nuclear factor 1 beta. The results of this study show that hepatocyte nuclear factor 1 binds to the -150 to -131 region of the human dipeptidyl peptidase IV promoter and is necessary for transcriptional activation of the gene for dipeptidyl peptidase IV.

3T3 Cells↗
PubMed1991

Promoter-specific transactivation of hepatitis B virus transcription by a glutamine- and proline-rich domain of hepatocyte nuclear factor 1.

The cloned transcription factor hepatocyte nuclear factor 1 (HNF1) transactivates transcription from the hepatitis B virus (HBV) large surface antigen promoter but does not influence the transcriptional activities of the other three HBV promoters. This indicates that this transcription factor can differentially influence the activities of the HBV promoter. By using a transient-transfection system, the major domain of the HNF1 polypeptide involved in transcriptional activation of the large surface antigen promoter in the human hepatoma cell line HepG2.1 has been mapped to a region that is rich in glutamine and proline residues (9 of 18) and is different from the previously identified regions of this factor responsible for in vitro transcriptional activation of a promoter containing human albumin promoter HNF1 binding sites. The human albumin promoter HNF1 binding site mediates transcriptional activation through the same HNF1 polypeptide domain as the HBV large surface antigen promoter HNF1 binding site in transient-transfection assays with HepG2.1 cells, suggesting that HNF1 may possess multiple transcriptional activation domains.

Animals↗
PubMed2000

Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis.

Hepatocyte nuclear factor 1 (HNF1) is a transcription factor involved in the regulation of a large set of hepatic genes, including albumin, beta-fibrinogen, and alpha1-antitrypsin. HNF1 is expressed in the liver, digestive tract, pancreas, and kidney. Mice lacking HNF1 exhibit hepatic, pancreatic, and renal dysfunctions. HNF1-deficient mice fail to express the hepatic phenylalanine hydroxylase gene, giving rise to hyperphenylalaninemia. Renal proximal tubular reabsorption of glucose, phosphate, arginine, and other metabolites is affected, producing severe renal glucosuria, phosphaturia, and amino aciduria. Homozygous mutant mice also exhibit a dramatic insulin secretion defect. This dysfunction resembles that exhibited by patients with maturity-onset diabetes mellitus of the young type 3, who carry mutations in the human HNF1 gene in the heterozygous state. These data show that HNF1 is a major regulator of glucose homeostasis, regulating the expression of genes that are expressed in the liver, kidney, and pancreas.

Animals↗
PubMed1992

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein.

The human class I alcohol dehydrogenase (ADH) gene family consists of ADH1, ADH2, and ADH3, which are sequentially activated in early fetal, late fetal, and postnatal liver, respectively. Analysis of ADH promoters revealed differential activation by several factors previously shown to control liver transcription. In cotransfection assays, the ADH1 promoter, but not the ADH2 or ADH3 promoter, was shown to respond to hepatocyte nuclear factor 1 (HNF-1), which has previously been shown to regulate transcription in early liver development. The ADH2 promoter, but not the ADH1 or ADH3 promoter, was shown to respond to CCAAT/enhancer-binding protein alpha (C/EBP alpha), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADH1, ADH2, and ADH3 promoters all responded to the liver transcription factors liver activator protein (LAP) and D-element-binding protein (DBP), which are most active in postnatal liver. For all three promoters, the activation by LAP or DBP was higher than that seen by HNF-1 or C/EBP alpha, and a significant synergism between C/EBP alpha and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBP alpha and LAP homo- and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBP alpha (i.e., -160, -120, -40, and -20 bp), but DBP bound strongly only to the site located at -40 bp relative to the transcriptional start. Mutational analysis of ADH2 indicated that the -40 bp element accounts for most of the promoter regulation by the bZIP factors analyzed. These studies suggest that HNF-1 and C/EBP alpha help establish ADH gene family transcription in fetal liver and that LAP and DBP help maintain high-level ADH gene family transcription in postnatal liver.

Alcohol Dehydrogenase↗
PubMed1993

Transcriptional regulation of the Xenopus laevis B beta fibrinogen subunit gene by glucocorticoids and hepatocyte nuclear factor 1: analysis by transfection into primary liver cells.

The blood-clotting protein fibrinogen is composed of three subunits, designated A alpha, B beta, and gamma, which are encoded by a family of related genes. As part of the acute-phase response, expression of the fibrinogen genes is coordinately regulated in the liver by glucocorticoids. To understand the factors underlying this hormonal response, we have examined control of transcription from fibrinogen gene fragments transfected into hepatocytes from the frog Xenopus laevis. This analysis is the first in any species to define transcriptional regulatory elements for the fibrinogen genes by transfection into primary liver cells, rather than liver-derived cell lines. A transfection vector was constructed containing the Xenopus B beta gene transcription start site and 1293 bp of the 5' flanking sequence linked to the firefly luciferase gene. When this construct was transfected into primary liver parenchymal cells, luciferase expression was induced approximately 14-fold by glucocorticoids, an increase similar to the transcriptional stimulation of the endogenous B beta subunit gene. DNA fragments with as little as 284 bases of upstream sequence retained full hormone responsiveness. This region contains a sequence resembling the canonical glucocorticoid response element (GRE) at bases -148 to -162. Deletions or specific point mutations eliminating this putative GRE led to complete loss of glucocorticoid inducibility. Physical association of the steroid hormone receptor with this functional GRE was demonstrated with a truncated form of the rat glucocorticoid receptor containing the DNA-binding domain. A second possible GRE at positions -526 to -540 was not hormone-responsive, in either the presence or the absence of the more proximal GRE. The regulatory region also has a sequence similar to the binding site for a liver-specific transcription factor, hepatocyte nuclear factor 1 (HNF-1), at positions -120 to -132. Specific point mutations in the HNF-1-binding site, in a construct containing a wild-type GRE, reduced promoter activity by a factor of 10, while stimulation by glucocorticoids was retained. Binding studies confirmed specific interaction between this site and the transcription factor HNF-1 alpha from mouse. Thus, we have identified a GRE sufficient to account for full glucocorticoid inducibility and an HNF-1 site close to the promoter that are major determinants of transcriptional control of the Xenopus fibrinogen B beta subunit gene in cells from normal liver tissue.

Animals↗
PubMed1993

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

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.

Animals↗
PubMed1996

Effects of diabetes mellitus on hepatocyte nuclear factor 1 decrease albumin gene transcription.

We have previously reported that albumin gene transcription is reduced in diabetes mellitus (DM). The present study explored the mechanism by which albumin gene transcription is down-regulated in DM. Deletional studies and displacement of factors binding to site B of the albumin promoter indicated that the repressive effects of DM are mediated by nuclear factors binding to this site. Since hepatocyte nuclear factor 1 (HNF1) activates albumin promoter activity and is the predominant factor binding to site B, we examined HNF1. The abundance and binding activity of HNF1 were reduced in hepatonuclear extracts from diabetic compared to control rats. However, HNF1 mRNA levels were unchanged, suggesting that the effect of DM on HNF1 is at the post-transcriptional level. Extracts from diabetic animals also contained another protein, distinct from HNF1 and vHNF1, which bound to site B in gel retardation studies. In summary, our studies demonstrate that the reduced abundance and binding activity of HNF1 correlates with decreased albumin gene transcription in DM.

Animals↗
PubMed1995

Hepatocyte nuclear factor 1 alpha activates promoter 1 of the human insulin-like growth factor I gene via two distinct binding sites.

Expression of the human insulin-like growth factor I (hIGF-I) gene is regulated in a tissue- and developmental stage-specific manner. The hIGF-I gene has two promoters, P1 and P2. P1 is the more active promoter by far in adult liver, the main endocrine source of IGF-I. Recently, we described the involvement of the CAAT/enhancer binding protein family of liver-enriched transcription factors in the regulation of the expression of IGF-I in adult liver. In this study we report on the role of another family of liver-enriched transcription factors in the regulation of IGF-I expression. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) is shown to transactivate IGF-I P1 in transient transfection experiments performed in Hep3B cells. Bandshift experiments reveal that two distinct regions in P1, located 119 and 282 nucleotides upstream of the transcription start site, can bind HNF-1 alpha with relatively high affinity. Both HNF-1-binding sites are evolutionary well conserved, emphasizing the importance of HNF-1 in the regulation of the IGF-I gene expression. Mutational analysis of the binding sites indicates that both sites are essential for maximal stimulation of P1 by HNF-1 alpha, although the largest contribution stems from the more downstream of the two HNF-1-binding sites. The latter site completely overlaps the previously described CAAT/enhancer binding protein binding site in P1. The colocalization of the binding sites, to which binding of the respective factors seems to be mutually exclusive, is suggestive of a regulatory hotspot to which members of different transcription factor families may bind depending on developmental stage and nutritional status.

Adult↗
PubMed1992

Hepatocyte nuclear factor 1 and C/EBP are essential for the activity of the human apolipoprotein B gene second-intron enhancer.

The tissue-specific transcriptional enhancer of the human apolipoprotein B gene contains multiple protein-binding sites spanning 718 bp. Most of the enhancer activity is found in a 443-bp fragment (+621 to +1064) that is located entirely within the second intron of the gene. Within this fragment, a 147-bp region (+806 to +952) containing a single 97-bp DNase I footprint exhibits significant enhancer activity. We now report that this footprint contains four distinct protein-binding sites that have the potential to bind nine distinct liver nuclear proteins. One of these proteins was identified as hepatocyte nuclear factor 1 (HNF-1), which binds with relatively low affinity to the 5' half of a 20-bp palindrome located at the 5' end of the large footprint. A binding site for C/EBP (or one of the related proteins that recognize similar sequences) was identified in the center of the 97-bp footprint. This binding site is coincident or overlaps with the binding sites for five other proteins, two of which appear to be distinct from the C/EBP-related family of proteins. The binding site for a nuclear factor designated protein I is located between the HNF-1 and C/EBP binding sites. Finally, the 3'-most 15 bp of the footprinted sequence contain a binding site for another nuclear protein, which we have called protein II. Mutations that abolish the binding of either HNF-1, protein II, or the C/EBP-related proteins severely reduce enhancer activity. However, deletion experiments demonstrated that neither the HNF-1-binding site alone, nor the combination of binding sites for HNF-1, protein I, and C/EBP, nor the C/EBP-binding site plus the protein II-binding site is sufficient to enhance transcription from a strong apolipoprotein B promoter. Rather, HNF-1 and C/EBP act synergistically with protein II to enhance transcription of the apolipoprotein B gene.

Animals↗
PubMed1997

Hepatocyte nuclear factor 1 and the glucocorticoid receptor synergistically activate transcription of the rat insulin-like growth factor binding protein-1 gene.

The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of proteins that bind IGF-I and IGF-II and modulate their biological activities. IGFBP-1 is distinctive among the IGFBPs in its rapid regulation in response to metabolic and hormonal changes. The synthetic glucocorticoid, dexamethasone, increases IGFBP-1 mRNA abundance and gene transcription in rat liver and in H4-II-E rat hepatoma cells. A glucocorticoid response element (GRE) located at nucleotide (nt) -91/-77 is required for dexamethasone to stimulate rat IGFBP-1 promoter activity in transient transfection assays in H4-II-E cells. In addition to the GRE, three accessory regulatory sites [a putative hepatocyte nuclear factor-1 (HNF-1) site (nt -62/-50), an insulin-response element (nt -108/-99), and an upstream site (nt -252/-236)] are involved in dexamethasone stimulation under some, but not all, circumstances. The present study begins to address the mechanism by which transcription factors bound to the putative HNF-1 site act synergistically with the glucocorticoid receptor (GR) bound to the GRE. In gel shift assays, HNF-1alpha and HNF-1beta in H4-II-E extracts bind to the palindromic HNF-1 site. Both half-sites are required. Overexpression of HNF-1beta enhances dexamethasone-stimulated promoter activity. Both the HNF-1 site and the GRE must be intact for stimulation to occur. By contrast, overexpression of HNF-1alpha does not enhance dexamethasone-stimulated promoter activity, although, as also observed with overexpression of HNF-1beta, it inhibits basal promoter activity. Thus, the synergistic effects of HNF-1beta and the GR on dexamethasone-stimulated promoter activity require that they are bound to the HNF-1 site and the GRE, respectively, and may involve protein-protein interactions between the transcription factors, or between them and the basal transcription machinery or a steroid receptor coactivator. Synergy between the ubiquitously expressed GR and HNF-1, which is developmentally regulated and expressed in a limited number of tissues, provides a possible mechanism for tissue- and development-specific regulation of glucocorticoid action.

Animals↗
PubMed2003

The variant hepatocyte nuclear factor 1 activates the P1 promoter of the human alpha-folate receptor gene in ovarian carcinoma.

The alpha folate receptor (alpha FR) is a membrane glycoprotein that binds folates, and mediates their uptake and that of antifolate drugs. alpha FR is absent on ovarian surface epithelium (OSE) but is detectable during early transforming events in this epithelium, with increasing expression levels in association with tumor progression. Analysis of transcriptional regulation of the alpha FR gene have revealed two promoter regions, P1 and P4, flanking exons 1 and 4, respectively, and a requirement for three SP1 sites and an INR element for optimal P4 activity. Here, we focused on the P1 transcription regulation in ovarian carcinoma cells. RNase protection assay indicated that the 5'-untranslated region is heterogeneous because of different start sites and alternative splicing of exon 3. A core region of the P1 promoter was sufficient for maximal promoter activity in ovarian carcinoma cell lines but not in OSE cells or in alpha FR-nonexpressing cell lines. Deletion and mutation analysis of this core promoter identified a cis-regulatory element at position +27 to +33 of the untranslated exon 1, which is responsible for maximum P1 activity. This element formed an abundant DNA-protein complex with nuclear proteins from ovarian cancer cells but not from other cell lines or OSE cells. Competition experiments and supershift assays demonstrated binding of the P1 cis-regulatory element by a transcription factor involved in embryonic development, the variant hepatocyte nuclear factor-1 (vHNF1). Analysis of RNA from various cell lines and surgical specimens confirmed that vHNF1 is expressed in ovarian carcinomas. Thus, vHNF1 regulates tissue-specific transcription in ovarian carcinoma.

5' Untranslated Regions↗
PubMed2002

Regulation of hepatocyte nuclear factor 1 activity by wild-type and mutant hepatitis B virus X proteins.

The hepatitis B virus (HBV) core promoter regulates the transcription of two related RNA products named precore RNA and core RNA. Previous studies indicate that a double-nucleotide mutation that occurs frequently during chronic HBV infection converts a nuclear receptor binding site in the core promoter to the binding site of the transcription factor hepatocyte nuclear factor-1 (HNF-1) and specifically suppresses the transcription of the precore RNA. This mutation also changes two codons in the overlapping X protein coding sequence. In this report, we demonstrate that the X protein and its mutant X(mt) can physically bind to HNF-1 both in vitro and in vivo. Further analyses indicate that both X and X(mt) can enhance the gene transactivation and the DNA binding activities of HNF-1. This finding demonstrates for the first time that the X protein can stimulate the DNA binding activity of a homeodomain transcription factor. Interestingly, while both X and X(mt) can stimulate the HNF-1 activities, they differ in their effects: a smaller amount of X(mt) is needed to generate greater transactivation and DNA binding activities of HNF-1. This functional difference between X and X(mt) may have important implications in HBV pathogenesis and is apparently why they have different effects on the core promoter bearing the HNF-1 binding site.

Binding Sites↗
PubMed1996

Tissue-specific expression of the nonneuronal promoter of the aromatic L-amino acid decarboxylase gene is regulated by hepatocyte nuclear factor 1.

The rat aromatic l-amino acid decarboxylase (AADC) gene contains alternative promoters which direct expression of neuronal and nonneuronal mRNAs that differ only in their 5'-untranslated regions (UTRs). We have analyzed the expression of the nonneuronal promoter of the rat AADC gene in the kidney epithelial cell line LLC-PK1 and in cells which do not express the nonneuronal form of AADC by transient transfection. These studies revealed that the first 1.1 kilobases of the nonneuronal promoter, including the nonneuronal-specific 5'-UTR (Exon 1), contains sufficient information to direct tissue-specific expression. Serial deletions of this promoter localized the cis-active element to a region between -52 and -28 base pairs upstream of the nonneuronal transcription start site. An A/T-rich sequence, within this region which we have termed KL-1, was found to bind a kidney and liver-specific factor by DNase footprint analysis and was capable of directing tissue-specific expression from a heterologous promoter. Moreover, when the KL-1 sequence was mutated in the context of the entire promoter sequence, all transcriptional activity was abolished. DNA sequence comparison revealed that the KL-1 fragment is highly homologous to the binding site for hepatocyte nuclear factor-1 (HNF-1). Mobility shift studies utilizing an antibody to HNF-1 demonstrated binding of HNF-1 to the KL-1 fragment and cotransfection of HNF-1 cDNA into cells which do not express the nonneuronal form of AADC resulted in activation of transfected AADC nonneuronal promoter constructs. These results strongly suggest that the transcription factor which regulates the tissue-specific expression of the nonneuronal form of AADC mRNA is HNF-1.

Animals↗
PubMed1993

The transactivation potential of variant hepatocyte nuclear factor 1 is modified by alternative splicing.

Two forms of the transcription factor vHNF1 (HNF1 beta or LFB3) have been previously described, derived by alternative splicing from a common premessenger RNA, and have been called vHNF1-A and vHNF1-B. vHNF1 proteins share a homologous homeo-related DNA-binding domain with the HNF1 protein, initially characterized as a liver-restricted transcription factor, and bind to a similar sequence motif. Here we demonstrate that vHNF1-A is a stronger transactivator than vHNF1-B when assayed in transient transfections using two different promoters. vHNF1-A also binds DNA with a higher affinity suggesting that a region of the protein located immediately upstream of the homeodomain can modulate the protein/DNA interaction and transactivation. Both vHNF1 transcripts were found at a constant ratio in every tissue where vHNF1 expression could be detected, using a quantitative reverse transcriptase-polymerase chain reaction.

Animals↗