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)

Elements responsible for the transcriptional activity of the human ATP synthase beta-subunit (ATPsyn beta) gene promoter have been studied through transient expression in HepG2 hepatoma cells of a CAT gene connected with various 5'-deletion mutants of the 5'-flanking region. Promoter activity was mostly dependent upon a single CCAAT motif as well as a nearby Ets domain binding region. This last region contains two sites that bind Ets-related proteins present in liver nuclear extracts as well as recombinant purified Ets-1 protein. The ATPsyn beta promoter was trans-activated by Ets-1 and Ets-2 expression vectors, and this effect was lost when the Ets binding region was deleted. The Ets binding region of the ATPsyn beta promoter increased basal expression and conferred Ets-1- and Ets-2-dependent trans-activation to the herpes symplex thymidine kinase minimal promoter. A double-point mutation of the main Ets-binding site, which suppresses Ets binding, blocks Ets-dependent trans-activation. It is concluded that the gene for the mitochondrial ATPsyn beta is a target of transcriptional activation by members of the Ets family of transcription factors. It is suggested that Ets transcription factors may be involved in the enhanced expression of the ATPsyn beta gene in highly proliferating cells and in the coordinate transcription of nuclear genes for mitochondrial proteins.
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PMID:ETS transcription factors regulate the expression of the gene for the human mitochondrial ATP synthase beta-subunit. 779 71

Synthesis of metallothionein-I (MT-I) and heme oxygenase mRNAs is rapidly and transiently induced by H2O2 in mouse hepatoma cells (Hepa) and this effect is blocked by catalase. Menadione, which generates free radicals, also induces these mRNAs. Deletion mutagenesis revealed that a region between -42 and -153 in the mouse MT-I promoter was essential for induction of a CAT reporter gene. A multimer of a 16 bp sequence (-101 to -86) that includes an antioxidant response element and overlapping adenovirus major late transcription factor binding site elevated basal expression and allowed induction by H2O2 when inserted upstream of a minimal promoter. However, deletion of this region (-100 to -89) from the intact MT-I promoter (-153) did not completely eliminate response. Multiple copies of a metal response element also permitted response to H2O2. These results suggest that induction of MT-I gene transcription by H2O2 is mediated by at least two different elements within the proximal MT-I gene promoter and suggest a previously undescribed function of the MRE. Induction of MT gene transcription by ROS and the subsequent scavenging of ROS by the MT peptide is reminiscent of the metal regulatory loop and is consistent with the hypothesized protective functions of MT.
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PMID:Transcriptional induction of the mouse metallothionein-I gene in hydrogen peroxide-treated Hepa cells involves a composite major late transcription factor/antioxidant response element and metal response promoter elements. 780 Apr 94

The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen-inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concentrated on a potential RXR recognition site, which deviates at only one position from a perfect direct A/GGGTCA repeat spaced by one nucleotide (DR-1) and was earlier identified as a common HNF-4/COUP-TF recognition site. However, band shift analysis revealed that this imperfect DR-1 motif does not interact with RXR alpha-homodimers. In accordance with this observation we found that this regulatory element does not mediate transactivation through RXR alpha in the presence of 9-cis-RA. However, our experiments revealed another, unexpected, effect of 9-cis-RA. Instead of stimulating, 9-cis-RA attenuated estrogen-induced expression of transfected estrogen-responsive VLDL-CAT reporter plasmids. This repression appeared to take place through the main estrogen response element (ERE) of the gene. Importantly, 9-cis-RA also strongly repressed the estrogen-induced expression of the endogenous apoVLDLII gene in cultured chicken hepatoma cells.
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PMID:9-cis-retinoic acid represses estrogen-induced expression of the very low density apolipoprotein II gene. 785 23

A heterozygous T-->C transition was detected in the putative promoter region of the protein C (PROC) gene in a patient with type I protein C deficiency and a history of recurrent venous thrombosis. This mutation occurred 14 bp upstream of the transcription initiation site and within a sequence strongly homologous to the consensus binding site for the liver-enriched transcription factor, hepatocyte nuclear factor 1 (HNF-1). Transfection experiments demonstrated that a CAT reporter gene construct containing 626 bp of the putative PROC gene promoter was capable of driving CAT expression in HepG2 hepatoma cells. Levels of CAT expression from constructs bearing the mutation were found to be drastically reduced by comparison with the wild-type, consistent with the reduced plasma protein C antigen levels observed in the patient. Gel retardation and cotransfection experiments demonstrated that the mutation abolished both the binding and the transactivating ability of HNF-1 observed with the wild-type PROC gene promoter. Further, the ability of the mutation to disrupt HNF-1 binding appears to be a function not only of the nature of the nucleotide substitution and its position within the recognition sequence, but also of the relative affinity of the wild-type binding site for HNF-1. This analysis is therefore indicative of a vital role for HNF-1 in the expression of the PROC gene in vivo. Taken together with the identification of a human hepatoma cell line which contains HNF-1 but which does not express protein C, these findings are consistent with the view that HNF-1 is necessary although not sufficient for PROC gene expression in the liver.
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PMID:Disruption of a binding site for hepatocyte nuclear factor 1 in the protein C gene promoter is associated with hereditary thrombophilia. 788 11

Frequent development of subcutaneous neurogenic sarcomas was observed in a hepatocellular carcinoma-producing transgenic mouse strain harboring an albumin-promoted simian virus 40 (SV40) large T antigen gene. Found unexpectedly in 19 out of 306 mice (6.2%) by 6 months of age, all the sarcomas were similar and were characterized as neurogenic on the basis of histological features including Homer-Wright type rosette formation, the presence of dense core granules of 100-200 nm diameter under the electron microscope, expression of neuron specific enolase, S-100 protein, and catecholamines, and nerve cell-like differentiation in culture in response to But2cAMP. Immunohistochemical study revealed tiny clusters of SV40 T antigen-expressing cells with neurogenic character in normal-appearing adult mouse subcutis as candidate progenitors of the sarcomas. The tumor cells strongly expressed large T antigen but did not express albumin or albumin mRNA at the detection sensitivity used. Transient transfection assay (CAT assay), however, revealed the presence of transcriptional factor(s) acting on the albumin promoter in tumor cells. Thus, the present investigation suggested the presence of specifically differentiated neurogenic cells in the mouse subcutis with aberrant expression of the transgene.
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PMID:Subcutaneous sarcomas of probable neuronal origin in a transgenic mouse strain containing an albumin promoter-fused simian virus 40 large T antigen gene. 806 13

The expression of the gene coding for retinol-binding protein has been studied in a system of cultured human hepatoma cells exposed to retinoids. We report that the gene is positively modulated by retinol and retinoic acid in a time- and dose-dependent fashion. The stimulation at the mRNA level is paralleled by an increase of the corresponding protein that is secreted in the presence of the physiological ligand. An RBP-CAT chimeric gene, introduced by transfection, is also responsive to the treatment, showing the gene dose-dependency as the endogenous gene. These results demonstrate that retinoids up-regulate the RBP gene and that the control takes place at transcriptional level.
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PMID:Retinoids regulate expression of the retinol-binding protein gene in hepatoma cells in culture. 807 97

Here we show that insulin may play a role in the diet-induced regulation of the rat fatty acid synthase (FAS; EC 2.3.1.85). Transient transfection of human and rat hepatoma cell lines with successively deleted FAS/CAT promoter fusion plasmids was used to determine the effect of insulin on FAS promoter activity. Our results indicate the existence of cis-acting insulin-responsive elements in the FAS promoter; the position of one of these is coincident with the position of a previously determined diet-induced DNAse I hypersensitive site (HSi-1) at approximately -500 bp relative to the transcription start site of FAS mRNA.
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PMID:Insulin-responsive regions of the rat fatty acid synthase gene promoter. 809 78

The gene for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is expressed in a tissue-specific manner in the liver, kidney, and adipose tissue and is regulated by hormones including cAMP and insulin. Previous studies have shown that the CCAAT/enhancer-binding protein alpha (C/EBP alpha) binds to several sites on the PEPCK promoter and activates transcription from the promoter in hepatoma cells. Here, we report that a second member of the C/EBP family, C/EBP beta, bound to the same sites on the PEPCK promoter. However, C/EBP beta stimulated transcription primarily through the cAMP-responsive element (CRE), which maps between positions -77 to -94, but not at the more 5'-binding sites. In addition, the nuclear factor-1 site, which is immediately adjacent to the CRE in the PEPCK promoter, was also required for the full response of the promoter to cotransfected C/EBP beta. In gel mobility assays, antibodies to both C/EBP beta and the cAMP regulatory element-binding protein (CREB), but not to C/EBP alpha, "supershifted" DNA-protein complexes formed between a synthetic CRE oligomer and proteins prepared from rat liver nuclei. C/EBP beta mRNA was expressed at low levels in both the periportal and pericentral regions of the liver lobule, whereas expression of the gene for C/EBP alpha was confined to the pericentral region of the liver lobule. PEPCK gene transcription is greatest in the periportal region of the liver. CREB also bound to the CRE and stimulated transcription of a PEPCK-CAT vector in the presence of an expression vector for the catalytic subunit of protein kinase A. C/EBP beta and CREB bound to the CRE with similar affinities, both of which were greater than the affinity of C/EBP alpha. Within 90 min after the administration of dibutyryl cAMP to rats, there was a marked increase in the hepatic concentration of C/EBP beta mRNA and a decrease in the level of mRNA for C/EBP alpha. These studies indicate that C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter.
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PMID:Relative roles of CCAAT/enhancer-binding protein beta and cAMP regulatory element-binding protein in controlling transcription of the gene for phosphoenolpyruvate carboxykinase (GTP). 809 46

We have found that phenolic antioxidants specifically induce expression of the c-fos and c-jun protooncogenes. After treatment of quiescent human hepatoma HepG2 cells with butylated hydroxytoluene, butylated hydroxyanisole, or other phenolic antoxidants, the levels of c-fos and c-jun mRNAs are substantially increased. This response is antioxidant specific, dose dependent, and transient, with maximal levels at 3-6 h. The antioxidant-specific induction of c-fos/CAT promoter constructs in transient transfections indicates that at least a portion of this response is transcriptional. Deletions and point mutations map sequences required for the antioxidant response of the c-fos promoter to the serum response element. The antioxidant-specific induction of expression directed by a reporter plasmid containing four AP-1 sites and the induction of AP-1 DNA-binding activity confirm previous results indicating that antioxidant treatment increases AP-1 activity.
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PMID:Induction of c-fos and c-jun gene expression by phenolic antioxidants. 814 65

The gene coding for chicken very low density apolipoprotein II (apoVLDLII) is expressed exclusively in liver in response to estrogen. Previous work in our laboratory identified several protein binding sites, identified by the letters A to F, and their cognate factors within the first 300 bp flanking the gene. Here we present an extensive functional analysis of the apoVLDLII promoter by gene transfer experiments using a chicken hepatoma cell line and cultured non-hepatic cells. Deletion analysis revealed that the -301 to -163-bp promoter region, comprising elements E1, E2 and F, is sufficient for strong estrogen-dependent expression. Mutation analysis demonstrated that efficient transcription requires the interplay of the major estrogen response element E1 with several other cis-acting elements. Analysis of individual protein binding sites showed that element E1 is sufficient by itself to confer weak estrogen-induced transcription from the apoVLDLII promoter, and that additional promoter elements are required for full estrogen-responsiveness. Elements F and B1 were capable of strongly potentiating the activity of element E1. In general, the activity of certain cis-acting elements appeared to be strongly promoter-context dependent. Cultured non-liver cells expressed transfected VLDL-CAT reporter plasmids in the presence of cotransfected estrogen receptor expression vector in a hormone-dependent way, indicating that for the control of tissue specificity the 5'-proximal promoter region is not sufficient.
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PMID:Cis-acting elements reinforcing the activity of the estrogen-response element in the very-low-density apolipoprotein II gene promoter. 816 31


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