Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcriptional activation of myc family proto-oncogenes through the insertion of viral sequences is the predominant mechanism by which woodchuck hepatitis virus (WHV) induces liver tumors in chronically infected animals. The main target is N-myc2, a functional retroposon of the N-myc gene, but c-myc and N-myc are also marginally involved. Here we identify a major, liver-specific regulatory element in the WHV genome (We2) which efficiently activates the N-myc2 promoter in cultured hepatoma cells. In the context of the episomal viral genome, We2 governs the production of pregenomic RNA and thus plays a central role in the control of viral replication. We2 activity is primarily controlled by the liver-enriched HNF1 and HNF4 transcription factors, although NF1 and Oct proteins were also shown to bind in a central region. The expression of HNF1 and HNF4 appears to be maintained in woodchuck tumors. Thus, We2 is a prime candidate for controlling myc gene cis activation during WHV-induced hepatocarcinogenesis.
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PMID:The HNF1/HNF4-dependent We2 element of woodchuck hepatitis virus controls viral replication and can activate the N-myc2 promoter. 897 Sep 82

The capacity of the liver-enriched transcription factor hepatocyte nuclear factor 4 (HNF4) to direct redifferentiation of dedifferentiated rat hepatoma cells was investigated by stable transfection of epitope-tagged HNF4 cDNA into H5 variant cells. HNF4-producing cells expressed the previously silent HNF1 gene and showed activation of some hepatic functions, including alpha1-antitrypsin, beta-fibrinogen, and transthyretin, but not of the endogenous HNF4 gene. Expression of the other hepatocyte-enriched transcription factors was not modified. Treatment of the HNF4tag-expressing cells with dexamethasone induced expression of the transgene by 10-fold, resulting in enhanced expression of target genes of both glucocorticoid hormones and HNF4. The set of activated hepatic genes was extended by treatment of cells with the demethylating agent 5-azacytidine followed by selection in dexamethasone-containing glucose-free medium. Some of the colonies that developed reexpressed the entire set of hepatic functions tested. Fusion of HNF4tag-producing H5 cells with well-differentiated Fao cells showed that only those hybrids which maintained expression of HNF4tag were protected from complete extinction, including that of the Fao HNF4 gene. Thus, H5 cells must produce an extinguisher of the HNF4 gene. In addition, this result implies that HNF4 itself, or its target HNF1, is a positive regulator of HNF4. In conclusion, HNF4tag expression overcomes repression of the hepatic phenotype of the H5 cell without abolishing its potential to extinguish an active genome. Taken together, these results predict that expression of HNF4 should be sufficient to establish heritable expression of many parameters of the hepatic differentiated state.
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PMID:Hepatocyte nuclear factor 4 expression overcomes repression of the hepatic phenotype in dedifferentiated hepatoma cells. 912 39

Liver-enriched trans-acting factors hepatocyte nuclear factor-1 alpha (HNF1 alpha) and -4 (HNF4) are components of a transcriptional activation pathway that is thought to play a major role in hepatic gene activation. We previously described the isolation and characterization of distinct classes of hepatoma variants which lack the HNF4-->HNF1 alpha pathway (1). In order to determine the influence of the HNF4-->HNF1 alpha pathway on hepatic gene expression, genetic rescue experiments were done using hepatoma variant line H11 as a model system. Results suggest that this pathway is required for basal expression of a number of endogenous hepatocyte-specific genes. Complementation groups were established by fusion of H11 cells with other variant lines. Lastly, introduction of human chromosome 20 (containing the HNF4 locus) or randomly-marked human chromosomes into H11 cells failed to rescue the hepatic phenotype, suggesting that what appears to be a 'simple' defect may involve multiple genetic loci.
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PMID:Selective loss of the hepatic phenotype due to the absence of a transcriptional activation pathway. 933 Jun 30

The thyroid hormone (T3) was shown to down regulate the level of alpha-foetoprotein (AFP) mRNA in hepatoma cells HepG2. Recombinant plasmids containing segments from the mouse AFP gene promoter were transfected in HepG2 cells and transient expression assays showed that the T3 inhibitory effect depends on the sequence limited by positions -80 and -38, upstream from the TATA box. This sequence is able to confer T3 sensitivity to a heterologous promoter and contains a putative T3-responsive element, as well as likely CEBP- and HNF1-responsive elements. These observations suggest that T3 is a good candidate for hormonal control of the AFP gene expression and especially for the neonatal shut off of the gene.
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PMID:The thyroid hormone down-regulates the mouse alpha-foetoprotein promoter. 948 9

alpha-Fetoprotein (AFP), a protein highly induced during fetal liver development, is down-regulated by retinoids in the human hepatoma cell line Hep3B, in contrast to up-regulation observed in other cell types. Previously, we have documented that such up-regulation involves direct effects through cis-retinoid X receptor-binding sites in the AFP enhancer. In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts. Deletion analysis of the upstream regulatory region of the AFP gene revealed that cis-acting sites required for down-regulation resided near the promoter. Gel mobility shift assays for factors binding to key elements in the AFP promoter region demonstrated that hepatocyte nuclear factor (HNF) 1 binding was diminished in nuclear extracts from RA-treated cells. In addition, HNF4, which is not known to bind to the AFP promoter but does regulate HNF1, was also diminished. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP.
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PMID:Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. 979 24

A double mutation which converts nucleotide 1765 from A to T and nucleotide 1767 from G to A is frequently found in the hepatitis B virus (HBV) genome isolated from HBV patients with chronic hepatitis symptoms. This double mutation is located in the core promoter that controls the transcription of the precore RNA and the core RNA. In addition, this double mutation also resides in the X protein coding sequence, converting codon 130 from Lys to Met and codon 131 from Val to Ile. Previous studies indicate that this double mutation removes a nuclear receptor binding site in the core promoter, suppresses specifically precore RNA transcription, and enhances viral replication. In this study, we further investigated how this double mutation suppresses precore RNA transcription. We found that this double mutation not only removed the nuclear receptor binding site but also created an HNF1 transcription factor binding site. Further transfection studies using Huh7 hepatoma cells indicate that the removal of the nuclear receptor binding site has no effect on the transcription of HBV RNAs, the two-codon change in the X protein sequence suppresses the transcription of both precore and core RNAs, and the creation of the HNF1 binding site restores the core RNA level. Hence, the specific suppression of precore RNA transcription by this frequent double-nucleotide mutation is the combined result of multiple factors.
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PMID:Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. 988 27

The hepatocyte nuclear factor (HNF)4alpha, a member of the nuclear receptor superfamily, regulates genes that play a critical role in embryogenesis and metabolism. Recent studies have shown that mutations in the human HNF4alpha gene cause a rare form of type 2 diabetes, maturity onset diabetes of the young (MODY1). To investigate the properties of these naturally occurring HNF4alpha mutations we analysed five MODY1 mutations (R154X, R127W, V255M, Q268X and E276Q) and one other mutation (D69A), which we found in HepG2 hepatoma cells. Activation of reporter genes in transfection assays and DNA binding studies showed that the MODY1-associated mutations result in a variable reduction in function, whereas the D69A mutation showed an increased activity on some promoters. None of the MODY mutants acted in a dominant negative manner, thus excluding inactivation of the wild-type factor as a critical event in MODY development. A MODY3-associated mutation in the HNF1alpha gene, a well-known target gene of HNF4alpha, results in a dramatic loss of the HNF4 binding site in the promoter, indicating that mutations in the HNF4alpha gene might cause MODY through impaired HNF1alpha gene function. Based on these data we propose a two-hit model for MODY development.
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PMID:Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree. 1060 40

The endostatin precursor collagen XVIII is expressed at high levels in human livers, the main source being hepatocytes. We have studied the regulatory elements in the promoter 2 of the Col18a1 gene that directs the transcription of the NC1-517 variant of collagen alpha1(XVIII), which is the main form expressed in the liver. The 5'-flanking region of Col18a1 gene was cloned, and a series of 5'-deletions from -3286 bp to +285 bp were linked to the luciferase reporter gene. Transfection experiments in HepG2 cells allowed to identify a silencer-like element containing putative HNF1 and HNF3 sites and activator elements containing stretches of GC-rich sequences. Another putative HNF3 site in close apposition to a NF1/CTF site was localized upstream of the silencer-like element. Cotransfection experiments showed that the Col18a1 promoter 2 was transactivated by Sp1 and HNF3alpha. Gel-shift analyses showed that HNF3, NF1/CTF, and Sp1-like sites specifically recognized nuclear factors. Super-shift experiments indicated that HNF3beta was the major form of HNF3 interacting with the HNF3/NF1 site. The well-differentiated hepatoma cell line mhATFS315 transfected with a truncated form of HNF3beta, which competitively blocks HNF3 transactivating activity, expressed the Col18a1gene at a very low level. Taken together, these data strongly suggest that Col18a1 is a liver-specific gene. Furthermore, gel-shift analyses performed with nuclear factors prepared from well-differentiated hepatocellular carcinomas showed increased HNF3/NF1 binding activity compared with normal livers. Consequently, the precursor of endostatin might be differently expressed according to the differentiated and/or transformed state of hepatocytes.
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PMID:The promoter of the long variant of collagen XVIII, the precursor of endostatin, contains liver-specific regulatory elements. 1109 45

We have characterized a 700 bp enhancer element around -6 kb relative to the HNF4alpha1 transcription start. This element increases activity and confers glucocorticoid induction to a heterologous as well as the homologous promoters in differentiated hepatoma cells and is transactivated by HNF4alpha1, HNF4alpha7, HNF1alpha and HNF1beta in dedifferentiated hepatoma cells. A 240 bp sub-region conserves basal and hormone-induced enhancer activity. It contains HNF1, HNF4, HNF3 and C/EBP binding sites as shown by DNase I footprinting and electrophoretic mobility shift assays using nuclear extracts and/or recombinant HNF1alpha and HNF4alpha1. Mutation analyses showed that the HNF1 site is essential for HNF1alpha transactivation and is required for full basal enhancer activity, as is the C/EBP site. Glucocorticoid response element consensus sites which overlap the C/EBP, HNF4 and HNF3 sites are crucial for optimal hormonal induction. We present a model that accounts for weak expression of HNF4alpha1 in the embryonic liver and strong expression in the newborn/adult liver via the binding sites identified in the enhancer.
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PMID:An enhancer element 6 kb upstream of the mouse HNF4alpha1 promoter is activated by glucocorticoids and liver-enriched transcription factors. 1152 18

We have uncovered a fundamental difference in the regulation of the rodent and the human phenylalanine hydroxylase (PAH) genes: expression of human PAH is independent of glucocorticoids and/or cAMP in contrast to the mouse gene which is not only highly inducible but dependent upon hormones for expression. Nevertheless, the two genes do exhibit similarities: DNaseI hypersensitive sites are identically located in the regulatory regions, and the sequences around these sites are partially conserved and associated with regulatory elements sharing similar function. In transient transfections, the human proximal promoter is tissue-specific and presents significant activity compared to the extremely low and ubiquitous activity of the mouse promoter. DNA fragments corresponding to the two upstream hypersensitive sites of both genes have enhancer activity that depends upon the liver-enriched transcription factor binding sites for hepatocyte nuclear factor (HNF) 1 and/or CCAAT/enhancer binding protein (C/EBP). While expression of the rodent gene relies upon two modules in the HSIII enhancer, one activated by HNF1 and C/EBP and the other required for the hormone response, the human equivalent has conserved only the liver-specific transcription factor binding module. Even though the more proximal enhancer is not necessary for full reporter gene activity in transient transfection assays in Pah-expressing hepatoma cells, this enhancer could be required in both species for activation during development.
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PMID:Conserved as well as divergent regulatory elements account for expression of the human and rodent phenylalanine hydroxylase genes. 1167 21


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