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)

The 5'-flanking sequence of the human alpha 1-antitrypsin (AAT) gene contains multiple cis-regulatory elements, including a distal enhancer and proximal sequences essential for its transcription in cultured hepatoma cells. To understand better the promoter specificity of the AAT gene in vivo, transgenic mice harboring the AAT-SV40 hybrid promoter or the natural AAT promoter fused to a reporter gene (CAT) were generated. Examination of CAT activity in various tissues indicated that the CAT gene was expressed primarily in the liver and also, to a lesser extent, in tissues known to express the AAT gene. In addition, the cis-acting elements of the human AAT gene were utilized to drive the transcription of the SV40 T antigen gene in transgenic mice. Hepatocellular malignancy was found in all founder animals examined, while sporadic occurrence of malignancy was also observed in stomach, pancreas, and kidney. These results verify that the 5'-flanking region of the human AAT gene contains cis-regulatory elements sufficient to confer tissue specificity in vivo.
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PMID:Tissue-specific regulation of human alpha 1-antitrypsin gene expression in transgenic mice. 278 78

In the light of recent findings concerning the importance of intermediate alpha 1-antitrypsin deficiency in the development of chronic liver disease and of hepatocellular carcinoma, we report the case of a 56-year-old woman affected by cirrhosis with significant features of liver cell dysplasia associated with intermediate alpha 1-antitrypsin deficiency (protease inhibitor SZ phenotype). In our paper we emphasize the importance of a precocious diagnosis and identification of individuals carrying the Z allele, also heterozygous.
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PMID:Alpha-1-antitrypsin protease inhibitor SZ phenotype and liver cirrhosis. 278 75

Human alpha 1-antitrypsin (AAT) is expressed in the liver, and a 318 bp fragment immediately flanking the CAP site of the gene was found to be sufficient to drive the expression of a reporter gene (CAT) specifically in hepatoma cells. The enhancing activity however, was orientation-dependent. The DNA fragment was separated into a distal region and a proximal region. A "core enhancer" sequence GTGGTTTC is present within the distal region and is capable of activity enhancement in both orientations when complemented by the proximal region in the sense orientation. The results strongly suggest that there are multiple cis-acting elements in the human AAT gene that confer cell specificity for its expression. Nuclear proteins prepared from the hepatoma cells bound specifically to the proximal region in a band-shifting assay that was resistant to competition by the globin promoter DNA. Foot-printing analysis showed a protected domain within the proximal region that contains a nearly perfect palindromic sequence TGGTTAATATTCACCA, which may be important in the regulation of AAT expression in the liver.
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PMID:Tissue-specific expression of the human alpha 1-antitrypsin gene is controlled by multiple cis-regulatory elements. 282 29

The 5' flanking region of the human alpha 1-antitrypsin (alpha 1-AT) gene contains cis-acting signals for liver-specific expression and, when fused to a reporter gene, is able to drive the expression of this gene specifically in liver cells. Here we report the results of a functional dissection of the alpha 1-AT regulatory region. The expression of the bacterial chloramphenicol-transacetylase (CAT) gene, fused to a set of alpha 1-AT 5' flanking regions shortened by progressive deletions or mutated by base pair substitutions, has been compared by transfection in HepG2 (hepatocyte) and HeLa (non-hepatocyte) human cell lines. A minimal tissue-specific element has been identified between the nucleotides -137 and -37 (from the transcriptional start site). This DNA segment activates the heterologous SV40 promoter in hepatoma cell lines but not in HeLa cells. This element contains at least two regions referred to as the A (-125/-100) and B (-84/-70) domains, both essential for transcription. There are at least two other regulatory domains located upstream of the 'minimal element'; the most active of these is located between positions -261 and -210 from the cap site. These upstream elements activate the heterologous SV40 early promoter both in hepatoma cell lines and in HeLa cells. Upon fractionation of rat liver nuclear extracts two proteins have been identified, alpha 1TF-A and alpha 1TF-B, which bind specifically to the A and B domains respectively. Transcriptionally inactive A and B domain mutants are not able to bind these proteins.
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PMID:Cis- and trans-acting elements responsible for the cell-specific expression of the human alpha 1-antitrypsin gene. 282 93

We have isolated three cDNA clones for human alpha 2-plasmin inhibitor (alpha 2-PI). Two clones are from human hepatoma cell line, Hep G2, and cover the entire protein coding region plus the 3'-flanking region up to the poly(A) sequence, and the other clone is from human liver and contains the carboxyl-terminal half. The total length of the cDNAs is 2.29 kb, corresponding to more than 95% of the full-length mRNA. alpha 2-PI seems to consist of 452 amino acid residues plus 39 amino acid residues for the signal peptide. The amino acid sequence shows 23 to 28% homology to those of five other protease inhibitors, plasminogen activator inhibitor (PAI), protein C inhibitor (PCI), alpha 1-antitrypsin (alpha 1-AT), antithrombin III (AT III), and alpha 1-antichymotrypsin (alpha 1-AC). alpha 2-PI seems to be the most distantly related among these inhibitors. Comparison of the phylogenetic trees of proteases and their inhibitors indicates that four proteases, namely elastase (or trypsin), chymotrypsin, plasminogen activator, and thrombin, may have evolved concurrently with the corresponding inhibitors. However, alpha 2-PI and PCI seem to have evolved asynchronously from their substrates. The data suggest that alpha 2-PI may originally have inhibited some protease other than plasmin, and protein C may have had an inhibitor different from the present one early in its evolutionary history.
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PMID:Structure of human alpha 2-plasmin inhibitor deduced from the cDNA sequence. 283 Feb 48

Apolipoprotein CIII (apoCIII) is a major protein constituent of triglyceride-rich lipoproteins and is synthesized primarily in the liver. Cis-acting DNA elements required for liver-specific apoCIII gene transcription were identified with transient expression assays in the human hepatoma (HepG2) and epithelial carcinoma (HeLa) cell lines. In liver cells, 821 nucleotides of the human apoCIII gene 5'-flanking sequence were required for maximum levels of gene expression, while the proximal 110 nucleotides alone were sufficient. No expression was observed in similar studies with HeLa cells. The level of expression was modulated by a combination of positive and negative cis-acting sequences, which interact with distinct sets of proteins from liver and HeLa cell nuclear extracts. The proximal positive regulatory region shares homology with similarly located sequences of other genes strongly expressed in the liver, including alpha 1-antitrypsin and other apolipoprotein genes. The negative regulatory region is strikingly homologous to the human beta-interferon gene regulatory element. The distal positive region shares homology with some viral enhancers and has properties of a tissue-specific enhancer. The regulation of the apoCIII gene is complex but shares features with other genes, suggesting shuffling of regulatory elements as a common mechanism for cell type-specific gene expression.
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PMID:Human apolipoprotein CIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factors. 283 95

We have previously described the isolation and characterization of genomic clones corresponding to the mouse alpha 1-antitrypsin gene (Krauter et al., DNA 5:29-36, 1986). In this report, we have analyzed the DNA sequences upstream of the RNA start site that direct hepatoma cell-specific expression of this gene when incorporated into recombinant plasmids. The 160 nucleotides 5' to the cap site direct low-level expression in hepatoma cells, and sequences between -520 and -160 bp upstream of the RNA start site functioned as a cell-specific enhancer of expression both with the alpha 1-antitrypsin promoter and when combined with a functional beta-globin promoter. Within the enhancer region, three binding sites for proteins present in hepatoma nuclear extracts were identified. The location of each site was positioned, using both methylation protection and methylation interference experiments. Each protein-binding site correlated with a functionally important region necessary for full enhancer activity. These experiments demonstrated a complex arrangement of regulatory elements comprising the alpha 1-antitrypsin enhancer. Significant qualitative differences exist between the findings presented here and the cis-acting elements operative in regulating expression of the human alpha 1-antitrypsin gene (Ciliberto et al., Cell 41:531-540, 1985; De Simone et al., EMBO J. 6:2759-2766, 1987).
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PMID:A cell-specific enhancer of the mouse alpha 1-antitrypsin gene has multiple functional regions and corresponding protein-binding sites. 283 57

A new human hepatocellular carcinoma (HCC) cell line, KYN-2, has been established from a surgical specimen obtained from a 52-year-old Japanese male HCC patient. The originally resected HCC was classified as pleomorphic HCC corresponding to Edmondson-Steiner's grade III with a thick trabecular to solid arrangement. The cell line has been maintained for 17 months through 35 passages. Morphologically, the KYN-2 cells have retained the characteristics of the original HCC, being pleomorphic and composed of various types such as cells with relatively small, polygonal, eosinophilic cytoplasm and oval-shaped nuclei with a marked tendency to pile up, flat cells with abundant clear cytoplasm and oval-shaped nuclei, and many multinucleated giant cells, proliferating in a pavement-like cell arrangement. Some junctional complexes and a number of microvilli are evident between the cells by electron microscopy. Functionally, these cells were found to secrete albumin, alpha 1-acid glycoprotein, alpha 1-antitrypsin, ceruloplasmin, transferrin, complement C, fibrinogen, fibronectin, prothrombin, retinol-binding protein (serum type), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), ferritin and beta 2-microglobulin in chemically defined medium (CDM). The secretion of AFP and CEA is apparently dependent upon culture medium and passage. The doubling time of cells growing in serum-containing medium at the 14th passage was 84 h, and those of cells in serum-containing medium, HB101 (serum-free medium) and CDM at late passage were 28, 68, and 42 h, respectively. Chromosome analysis revealed that the chromosome number ranged from 56 to 69 without a mode, and the presence of marker chromosomes. HB virus DNA sequence was not detected by hybridization analysis. The tumorigenicity of KYN-2 cells was identified by development of tumors in nude mice after subcutaneous injection of the cells; the tumors showed an appearance basically similar to that of the original HCC. Thus, these findings suggest that the KYN-2 cell line is available as a new human HCC cell line and should be useful for various studies on HCC.
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PMID:A new human pleomorphic hepatocellular carcinoma cell line, KYN-2. 284 82

Normal liver and differentiated hepatoma cell lines contain a nuclear factor, HNF-1, which binds functional sequences within the promoters of the alpha and beta chains of fibrinogen and alpha 1-antitrypsin. In UV cross-linking studies we find that HNF-1 has an apparent mol. wt of 92 kd in differentiated hepatocytes. Nuclear extracts from a dedifferentiated hepatoma cell line, Fao flC2 (C2), selected on the basis of morphological and biochemical dedifferentiation from Fao contains a protein, vHNF, which binds to the same DNA sequence motif as HNF-1 but has an apparent mol. wt of 72 rather than 92 kd. Mixing experiments indicate that this variant nuclear factor does not arise from HNF-1 by proteolysis. Reversion to the differentiated phenotype in C2-Rev7 (Rev7), selected by growth in glucose-free media, results in the re-expression of many liver-specific functions including the fibrinogen genes. In Rev7, HNF-1 is indistinguishable from that in the original differentiated cell line Fao. Transfection studies and nuclear run-on experiments indicate that reduced expression of fibrinogen RNA in C2 relative to Fao is related to reduced transcription. vHNF but not HNF-1 is present in somatic hybrids between fibroblasts and liver cells which show extinction of liver specific traits and it can also be detected in normal tissue, predominantly in lung nuclear extracts. Since vHNF and HNF-1 are not co-expressed yet correlate with the non-hepatic and hepatic phenotype, respectively, we suggest that the expression of these variant forms reflects determination events in establishing the hepatic phenotype.
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PMID:A variant nuclear protein in dedifferentiated hepatoma cells binds to the same functional sequences in the beta fibrinogen gene promoter as HNF-1. 284 19

We have cloned the human alpha 1-antitrypsin (alpha 1-AT) gene and identified the promoter and the transcription initiation point. The cloned gene, following transfection, is expressed in a cell-specific manner, being transcribed in a human hepatoma cell line (Hep3B) but not in HeLa cells. We show that the 5' flanking region of the alpha 1-AT gene contains DNA sequences sufficient for efficient transcription in Hep3B but not in HeLa cells. This DNA sequence also activates, in a cell-specific manner, heterologous promoters such as that of SV40; however, the effect is only obtained in one orientation, suggesting that this cis-acting cell-specific element does not share all the features generally associated with enhancers. By cotransfection-competition experiments we also show the existence of a limiting trans-acting factor, essential for the expression of the alpha 1-AT gene in Hep3B cells.
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PMID:Cell-specific expression of a transfected human alpha 1-antitrypsin gene. 298 81


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