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)

Rat hepatoma-human fibroblast hybrids of two independent lineages containing only 8-11 human chromosomes show pleiotropic extinction of thirteen out of fifteen hepatic functions examined. Reexpression of the entire group of functions most often occurs in a block, and except for one discordant subclone, correlates with loss of human chromosome 2. The extinguished cells and their reexpressing derivatives have been examined for the expression of seven liver-enriched transcription factors. C/EBP, LAP, DBP, HNF3, and vHNF1 expression are not systematically extinguished in parallel with the hepatic functions. However, HNF1 and HNF4 show a perfect correlation with phenotype: these factors are expressed only in the cells showing pleiotropic reexpression. Since recent evidence indicates that HNF4 controls HNF1 expression, it can be proposed that the HNF4 gene is the primary target of the pleiotropic extinguisher.
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PMID:HNF4 and HNF1 as well as a panel of hepatic functions are extinguished and reexpressed in parallel in chromosomally reduced rat hepatoma-human fibroblast hybrids. 849 80

We have developed a bZIP protein, GBF-F, with both dominant-negative (DN) and gain-of-function properties. GBF-F is a chimera consisting of two components: the DNA binding (basic) region from the plant bZIP protein GBF-1 (GBF) and a leucine zipper (F) designed to preferentially heterodimerize with the C/EBP alpha leucine zipper. Biochemical studies show that GBF-F preferentially forms heterodimers with C/EBP alpha and thus binds a chimeric DNA sequence composed of the half-sites recognized by the C/EBP and GBF basic regions. Transient transfections in HepG2 hepatoma cells show that both components of GBF-F are necessary for inhibition of C/EBP alpha transactivation. When the C/EBP alpha leucine zipper is replaced with that of either GCN4 or VBP, the resulting protein can transactivate a C/EBP cis-element but is not inhibited by GBF-F, indicating that the specificity of dominant-negative action is determined by the leucine zipper. All known members of the C/EBP family contain similar leucine zipper regions and are inhibited by GBF-F. GBF-F also exhibits gain-of-function properties, since, with the essential cooperation of a C/EBP family member, it can transactivate a promoter containing the chimeric C/EBP/GBF site. This protein therefore has potential utility both as a dominant-negative inhibitor of C/EBP function and as an activator protein with novel DNA sequence specificity.
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PMID:Design of a C/EBP-specific, dominant-negative bZIP protein with both inhibitory and gain-of-function properties. 856 57

The antagonistic effect of cAMP on the insulin-induced expression of fatty acid synthase (FAS) in liver could be mimicked in vitro using H4IIE hepatoma cells, both by measuring the response of the endogenous FAS gene and by assaying expression of transfected reporter genes containing promoter elements of the FAS gene. 5'-Deletion analysis and replacement mutagenesis revealed that an essential element required for cAMP antagonism of the insulin effect is an inverted CCAAT box located between nucleotides -99 and -92. DNase I foot-printing and gel shift analysis revealed that this region can bind a protein present in nuclei of liver and spleen, organs that express high and undetectable levels of FAS, respectively. This protein is not a CCAAT/enhancerbinding protein, C/EBP. Thus, the FAS gene appears unusual in that the sequence element required for transcriptional regulation by cAMP is neither a cAMP response element (CRE) nor a binding site for AP-1, AP-2, or C/EBP. These results suggest that essential to the regulation of FAS transcription by cAMP is the interaction of an inverted CCAAT box motif with a constitutively produced trans-acting factor that either itself undergoes modification in response to cAMP or associated with a protein that is produced or modified by cAMP exposure.
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PMID:Identification of an inverted CCAAT box motif in the fatty-acid synthase gene as an essential element for modification of transcriptional regulation by cAMP. 856 94

The gene encoding the rat branched-chain 2-oxo-acid dehydrogenase kinase (EC 2.7.1.115) has been isolated and partially characterized. The entire gene, including the promoter-regulatory region, spans 6 kb and contains 11 exons. The 5'-untranslated region comprising 264 bp is interrupted by intron 1 which is 581 bp in size. The complete in-frame sequence of intron 7 encodes the 49 amino acid insert previously reported to be present in the larger isoform of the rat kinase (Harris, Popov, Shimomura, Zhao, Jaskiewicz, Nanaumi and Suzuki (1992) Adv. Enzyme Regul. 32, 267-284). Sequencing of the 679 bp of the 5'-flanking region showed the absence of a canonical TATA box, similar to other branched-chain 2-oxo-acid dehydrogenase-complex genes. Several candidate cis-acting elements are present. These include CAAT boxes, Sp-1-binding sites, GCN-4 sites, CCAAT enhancer binding-protein sites (C/EBP) and glucocorticoid-responsive element (GRE) sites. Also present are a pair of direct repeats of unknown function. The luciferase-reporter assay showed that promoter activity is markedly higher in normal rat kidney (NRK-52E) cells than in rat hepatoma (FTO-2B) cells, and that the 5'-flanking region between bases -449 and +264 is both necessary and sufficient for basal transcription of the kinase gene.
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PMID:Structural organization of the rat branched-chain 2-oxo-acid dehydrogenase kinase gene and partial characterization of the promoter-regulatory region. 857 99

The gene coding for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) is expressed in all gluconeogenic tissues, but stimulation of its rate of transcription by cAMP is robust only in liver. Evidence has accumulated which suggests that a liver-enriched transcription factor, likely a member of the CCAAT/enhancer binding protein (C/EBP) family, is required along with other ubiquitously expressed transcription factors to mediate this liver-specific response to cAMP. In this study, we examined the ability of C/EBP to participate in the cAMP-mediated activation of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription in hepatoma cells. Expression of a dominant repressor of C/EBP in hepatoma cells significantly inhibited the protein kinase A-stimulated transcription of the PEPCK promoter, suggesting that a C/EBP family member was required for maximal transcriptional activation by protein kinase A. To provide additional support for this hypothesis, we prepared GAL4 fusion proteins containing C/EBP domains. Both C/EBPalpha and C/EBPbeta GAL4 fusion proteins were capable of stimulating transcription from promoters containing binding sites for the DNA-binding domain of GAL4. However, only the GAL4-C/EBPalpha fusion protein demonstrated the ability to synergize with the other transcription factors bound to the PEPCK promoter which are required to mediate cAMP responsiveness. The DNA-binding domain of C/EBPalpha was not required for this activity in hepatoma cells, although in non-hepatoma cells the basic region leucine zipper domain appeared to inhibit the ability of C/EBPalpha to participate in mediating cAMP responsiveness. These results suggest that the liver-specific nature of the cAMP responsiveness of the PEPCK promoter involves the recruitment of C/EBPalpha to the cAMP response unit.
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PMID:The alpha-isoform of the CCAAT/enhancer-binding protein is required for mediating cAMP responsiveness of the phosphoenolpyruvate carboxykinase promoter in hepatoma cells. 862 91

Three human alcohol dehydrogenase genes, ADH1, ADH2, and ADH3, were formed by tandem duplications and have diverged in their tissue-specific and developmental expression. Their proximal promoters remain 80-84% identical in sequence, approximately the same degree of identity as at synonymous sites in the coding regions of these three genes. To understand the evolution of tissue specificity, gene expression must be studied in many different cells and tissues. A systematic comparison of their promoters reveals the effects of subtle sequence differences on the binding of nuclear proteins to their cis-acting elements. There are differences in the affinity with which some proteins are bound to altered sites including C/EBP sites, USF/MLTF sites, and the G3T site (which binds Sp1). There are also differences in the sites that are occupied, e.g. CTF/NFI-related sites. These sequence differences are reflected in differences in gene expression in three cell lines. In H4IIE-C3 hepatoma cells, the ADH1 promoter was more active than the ADH2 promoter, and the ADH3 promoter was nearly nonfunctional. In HeLa cells, both ADH1 and ADH2 promoters directed expression; again the ADH3 promoter was extremely weak. None of the three promoters had much activity in CV-1 cells. Coexpression of C/EBP alpha greatly stimulated expression of the ADH1 promoter in HeLa cells and in CV-1 cells, but only weakly stimulated expression in H4IIE-C3 cells. The stimulation of the ADH1 promoter by C/EBP alpha was comparable to that of ADH2, despite the weaker binding to the C/EBP sites that flank the TATA box in ADH1. The ADH3 promoter was not greatly stimulated by C/EBP alpha, despite good binding of C/EBP alpha. These results demonstrate that small differences in the cis-acting elements affect affinity of binding by transcription factors and the pattern of gene expression.
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PMID:Gene expression in a young multigene family: tissue-specific differences in the expression of the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3. 863 48

Expression of the phenylalanine hydroxylase gene in livers and kidneys of rodents is activated at birth and is induced by glucocorticoids and cyclic AMP in the liver. Regulatory elements in a 10-kb fragment upstream of the mouse gene have been characterized. The promoter lacks TAATA and CCAAT consensus sequences and shows only extremely weak activity in transitory expression assays with phenylalanine hydroxylase-producing hepatoma cells. No key elements for regulation of promoter activity are localized within 2 kb of upstream sequences. However, a liver-specific DNase I-hypersensitive site at kb -3.5 comprises a tissue-specific and hormone-inducible enhancer. This enhancer contains multiple protein binding sites, including sites for ubiquitous factors (NF1 and AP1), the glucocorticoid receptor, and the hepatocyte-enriched transcription factors hepatocyte nuclear factor 1 (HNF1) and C/EBP. Mutation revealed that the last two sites are critical not only for basal activity but also for obtaining a maximal hormone response. Efficient transcription from the highly inducible promoter shows absolute dependence upon the enhancer at kb - 3.5, which in turn requires HNF1 and C/EBP as well as hormones. The regulatory region of the mouse phenylalanine hydroxylase gene differs totally from that of humans, even though the genes of both species are expressed essentially in the liver. Furthermore, the phenylalanine hydroxylase gene of mice shows an expression pattern very similar to those of the rodent tyrosine aminotransferase and phosphoenolpyruvate carboxykinase genes, yet each shows a different organization of its regulatory region.
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PMID:The activity of the highly inducible mouse phenylalanine hydroxylase gene promoter is dependent upon a tissue-specific, hormone-inducible enhancer. 864 24

GADD153, a ubiquitously expressed member of the CCAAT/enhancer-binding protein (C/EBP) family is induced by a wide variety of growth-arresting and DNA-damaging agents. Functionally, GADD153 has been postulated to act as a dominant-negative regulator of C/EBPs. Therefore we sought to gain evidence for interactions between GADD153 and other C/EBPs during cellular responses to stress. In this report we have demonstrated that treatment of rat pheochromocytoma PC12 cells with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153 (growth arrest and DNA damage inducible gene 153) but not other C/EBPs. Coimmunoprecipitation experiments provided evidence for the formation of endogenous GADD153-C/EBP-beta complexes in arsenite-treated cells. Additional experiments were performed to determine the role of such complexes in regulating GADD153 expression. Previous studies in our laboratory demonstrated that the GADD153 promoter contains a C/EBP binding site through which other C/EBPs interact to transactivate GADD153 expression in liver hepatoma cells. Here, we demonstrate that extracts prepared from arsenite-treated PC12 cells likewise show increased amounts of factors capable of binding to the GADD153-C/EBP site and that these complexes are comprised at least in part of C/EBP-beta. Forced expression of C/EBP-beta was found to be capable of transactivating the GADD153 promoter in PC12 cells cotransfected with plasmids expressing a GADD153 reporter gene and C/EBP-beta protein. However, overexpression of GADD153 inhibited the transactivation of the GADD153 promoter by C/EBP-beta. These findings provide evidence for an autoregulatory loop in which stress-induced GADD153 feeds back to attenuate GADD153 expression during the cellular response to stress.
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PMID:Physical and functional association between GADD153 and CCAAT/enhancer-binding protein beta during cellular stress. 866 54

A single human gene, SIAT1, encodes the beta-galactoside alpha 2,6-sialyltransferase from which multiple mRNA isoforms are generated. In rat, expression of the hepatic mRNA isoform (Form 1) has been defined with respect to the transcriptional initiation site and promoter region. We show here that a similar hepatic SIAT1 mRNA isoform exists in human. Another human mRNA isoform, a mature B-cell-specific mRNA isoform (Form 2), was previously reported. Here, we used 5'-RACE and S1 nuclease protection analysis to define the 5'-untranslated region of Form 2 human SIAT1 mRNA. We demonstrate conclusively that Form 2 mRNA is initiated from a point completely distinct from that of Form 1 mRNA. A number of cis-acting regulatory elements residing immediately 5'of the Form 2 initiation site includes AP-1, AP-2, NF-kappa B, NF-IL6, C/EBP, and CREB. A TATAA box is also present 29 bp 5' of the transcriptional initiation site. CAT reporter gene expression from serially-truncated segments of the 5'-flanking region of the Form 2 initiation site indicates that the segment between -784 and +125 was sufficient to promote high level CAT expression in Louckes, a mature B-cell line. The 5'-flanking region to the human Form 1 initiation site is competent in expression of CAT upon transfection of the fusion construct into HepG2, a human hepatoma cell line. Cellular specificity of expression is apparently retained. Louckes cells expressed CAT efficiently from Form 2 promoter but only marginally from the Form 1 promoter. In contrast, CAT expression from Form 1 promoter is more efficient than from the Form 2 promoter in HepG2 cells.
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PMID:Transcription of the beta-galactoside alpha 2,6-sialyltransferase gene in B lymphocytes is directed by a separate and distinct promoter. 872 35

Cytochromes P450 2B1 and 2B2 (CYP2B1 and CYP2B2) are well-known phenobarbital-inducible genes in rat liver. Potential transcriptional regulatory elements in the proximal promoter regions of rat CYP2B genes were analyzed by transfection in HepG2 hepatoma cells and by binding of nuclear proteins. Deletion of sequences from -1,400 to -110 had modest effects on promoter activity, but further deletion to -57 decreased the transcriptional activity by more than 90%, suggesting the presence of strong cis-acting elements in this region. Sequences similar to a basal transcription element (BTE) in CYP1A1 and a proposed phenobarbital responsive element (Barbie box) are present from -89 to -67. However, no protection was detected in these regions by DNase I footprinting assay. Instead, a region (FP1) from -64 to -45 was protected by liver nuclear extracts. Mutation of either the BTE or FP1 sequences of CYP2B1, or both, reduced transcriptional activity by 70-80% in HepG2 cells. FP1 was identified as a functional C/EBP site by co-transfection of C/EBP expression vectors and supershift assays with C/EBP antisera. Binding of liver nuclear proteins to sequences within the -110 to +1 region was not detectably altered by pretreatment of rats with phenobarbital.
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PMID:The CYP2B1 proximal promoter contains a functional C/EBP regulatory element. 876 71


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