UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The arrangement of regulatory elements along the apolipoprotein B promoter region (positions -898 to +1) has been examined in transient transfection experiments performed in HepG2 and Hep3B (hepatic) and CaCo-2 (intestinal) cell lines, all of which express the apoB gene, and also in Chinese hamster ovary cells, which do not express the gene. The overall distribution of positive and negative regulatory segments was very similar in the two hepatoma cell lines (HepG2 and Hep3B) but different from that observed in the colon carcinoma cells (CaCo-2). Thus, whereas 260 base pairs of 5'-flanking sequence were sufficient for maximal expression of the promoter in HepG2 cells, only 139 nucleotides were required for maximal expression in CaCo-2 cells. Promoter activity in Chinese hamster ovary cells was exhibited by short constructs, with maximal activity for the -85 construct. DNase I footprinting of the apolipoprotein B promoter region using hepatic and intestinal extracts revealed multiple sites of interaction between the DNA and nuclear proteins. Gel retention experiments using the region from -262 to -88 (the region of greatest contrast between HepG2 and CaCo-2 cells) revealed interesting variations in the relative abundance of various nuclear proteins between the two cell types. A major functional difference between HepG2 and CaCo-2 cells was localized to the region between -111 and -88, which harbors the sequence TGTTTGCT, a motif present in the promoter region of several liver-specific genes. The molecular basis for the functional differences between these two cell types may be attributable to a difference in the relative abundance of three proteins that bind to sequences between -111 and -88.
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PMID:Similarities and differences in the function of regulatory elements at the 5' end of the human apolipoprotein B gene in cultured hepatoma (HepG2) and colon carcinoma (CaCo-2) cells. 166 Aug 92

Cis-acting elements involved in the control of rat alpha-fetoprotein gene expression in the liver and its modulation by glucocorticoid hormones were detected after transfection of chloramphenicol acetyltransferase constructs and their transient expression into two hepatoma cell lines. The proximal promoter region (-324 to -15) was found to contain all the information necessary for tissue-specific expression. It is also involved in the negative gene modulation by glucocorticoids and includes an activating regulatory domain allowing efficient expression in the HepG2 cells. Three regions within 7 kilobase pairs of the 5' extragenic sequences are capable of stimulating the chloramphenicol acetyltransferase activity driven by the alpha-fetoprotein promoter sequence. One of these regions, at about -2.5 kilobase pairs, contains a short indivisible 170-base pair DNA element that fulfills all the criteria of a tissue-specific enhancer, i.e. orientation and position independence, as well as cell-specific stimulation of gene expression driven by a homologous or heterologous promoter. The enhancing properties of this element are totally abolished by glucocorticoids. DNase I footprinting experiments indicate that several rat liver nuclear proteins interact with this enhancer element.
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PMID:Regulation of the rat alpha-fetoprotein gene expression in liver. Both the promoter region and an enhancer element are liver-specific and negatively modulated by dexamethasone. 168 47

The recovery of the enzyme poly(ADP-ribose) polymerase (pADPRp) in the nuclease- and 1.6 M NaCl-resistant nuclear subfraction prepared from a number of different sources was assessed by Western blotting. When rat liver nuclei were treated with DNase I and RNase A followed by 1.6 M NaCl, approximately 10% of the nuclear pADPRp was recovered in the sedimentable fraction. The proportion of pADPRp recovered with the residual fraction decreased to less than 5% of the total nuclear polymerase when nuclei were prepared in the presence of the sulfhydryl blocking reagent iodoacetamide and increased to approximately 50% of the total nuclear pADPRp when nuclei were treated with the sulfhydryl cross-linking reagent sodium tetrathionate (NaTT) prior to fractionation. To determine whether this effect of disulfide bond formation was unique to rat liver nuclei, nuclear matrix/cytoskeleton structures were prepared in situ by sequentially treating monolayers of tissue culture cells with Nonidet-P40, DNase I and RNase A, and 1.6 M NaCl (S.H. Kaufmann and J.H. Shaper (1991) Exp. Cell Res. 192, 511-523). When nuclear monolayers were prepared from HTC rat hepatoma cells, CaLu-1 human lung carcinoma cells, and CHO hamster ovary cells in the absence of NaTT, pADPRp was undetectable in the nuclease- and 1.6 M NaCl-resistant fraction. In contrast, when nuclear monolayers were isolated in the presence of NaTT, from 5% (CaLu-1) to 26% (HTC cells) of the total nuclear pADPRp was recovered with the nuclease- and salt-resistant fraction. Examination of these residual structures by SDS-polyacrylamide gel electrophoresis under nonreducing conditions suggested that pADPRp was present as a component of disulfide cross-linked complexes. Further analysis by immunofluorescence revealed that the pADPRp was diffusely distributed throughout the CaLu-1 or CHO nuclear matrix. In addition, when matrices were prepared in the absence of RNase A, pADPRp was also observed in the residual nucleoli. These observations reveal that the recovery of pADPRp with a nuclease- and salt-resistant nuclear subfraction is dependent on the source of the nuclei and on the conditions used to fractionate those nuclei. In addition, these observations raise the possibility that there might be different functional classes of pADPRp molecules within the nucleus.
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PMID:Association of poly(ADP-ribose) polymerase with the nuclear matrix: the role of intermolecular disulfide bond formation, RNA retention, and cell type. 170 86

The regulation of ornithine delta-aminotransferase (OAT) expression is poorly characterized in humans, but in rat there are tissue-specific responses to nutritional and hormonal stimuli. We analyzed 1.3 kilobases of 5'-flanking sequence and part of intron 1 of the human OAT gene and found several candidate regulatory sequences including four copies of a motif also present in the promoters of three other urea cycle-related enzymes (urea cycle element). We transfected a series of promoter deletion constructs into HepG2 (human hepatoma), H4 (rat hepatoma), and HEK (human embryonic kidney) cells and obtained maximal expression with 134 base pairs (bp) of 5'-flanking DNA. One of the urea cycle elements and the 3' end of exon 1 had positive effects on expression in all cell lines. However, mutations in a 22-bp element which overlaps the transcriptional start site decreased activity 4-fold in H4 cells only. cAMP increased endogenous OAT mRNA 4-fold in HepG2 cells and the expression of constructs containing as little as -85 bp of 5'-flanking DNA 2- 5-fold in HepG2 and H4 cells. DNase I protection analysis of the first 134 bp of 5'-flanking sequence with nuclear extracts from rat liver, rat kidney, HEK, and HepG2 cells showed two patterns of protection over one of the urea cycle elements. These studies provide the foundation for the understanding of tissue-specific regulation of OAT.
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PMID:Transcriptional analysis of the human ornithine aminotransferase promoter. 184 93

Previous studies have resulted in conflicting data regarding the recovery of the nuclear enzymes topoisomerase (topo) II and topo I in the nuclear matrix fraction. In the present study we have assessed the effect of systematically altering a single extraction procedure on the distribution of these enzymes during the subfractionation of nuclei from HTC hepatoma tissue culture cells. When nuclear monolayers (prepared by treating attached cells in situ with the neutral detergent Nonidet-P40 at 4 degrees C) were isolated in the presence of the irreversible sulfhydryl blocking reagent iodoacetamide, subsequent treatment with DNase I and RNase A followed by 1.6 M NaCl resulted in structures which were extensively depleted of intranuclear components as assessed by phase contrast microscopy and conventional transmission electron microscopy. These structures contained 12 +/- 4% of the total protein present in the original nuclear monolayers. The lamins and polypeptides with molecular weights comparable to those of actin and vimentin were the predominant polypeptides present on SDS-polyacrylamide gels. Western blotting revealed that less than 5% of the total nuclear topo II molecules were present in these structures. In contrast, when the sulfhydryl cross-linking reagent sodium tetrathionate (NaTT) was substituted for iodoacetamide, the same extraction procedure yielded structures containing components of the nucleolus and an extensive intranuclear network. These structures contained a wide variety of nonlamin, nonhistone nuclear polypeptides including 23 +/- 4% of the total nuclear topo II. SDS-polyacrylamide gel electrophoresis performed under nonreducing conditions revealed that topo II in these nuclear matrices was present as part of a large disulfide cross-linked complex. Treatment of these structures with reducing agents in 1.6 M NaCl released the topo II. In contrast, topo I did not form disulfide cross-linked oligomers and was not detectable in any of these nuclease- and salt-resistant structures prepared at 4 degrees C. To assess the effect of in vitro heat treatment on the distribution of the topoisomerases, nuclear monolayers (isolated in the absence of iodoacetamide and NaTT) were heated to 37 degrees C for 1 h prior to treatment with nucleases and 1.6 M NaCl. The resulting structures (which retained 26 +/- 5% of the total nuclear protein) were morphologically similar to the NaTT-stabilized nuclear matrices and contained 15 +/- 4% of the total nuclear topo II. High-molecular-weight disulfide cross-linked oligomers of topo II were again demonstrated. Attempts to demonstrate these disulfide cross-linked oligomers in intact cells were unsuccessful.
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PMID:Association of topoisomerase II with the hepatoma cell nuclear matrix: the role of intermolecular disulfide bond formation. 184 38

The gene coding for apolipoprotein AI (apoAI), a plasma protein involved in the transport of cholesterol and other lipids in the plasma, is expressed predominantly in liver and intestine. Previous work in our laboratory has shown that different cis-acting elements in the 5'-flanking region of the human apoAI gene control its expression in human hepatoma (HepG2) and colon carcinoma (Caco-2) cells. Hepatocyte-specific expression is mediated by elements within the -256 to -41 DNA region relative to the apoAI gene transcription start site (+1). In this study it was found that the -222 to -110 apoAI gene region is necessary and sufficient for expression in HepG2 cells. It was also found that this DNA region functions as a powerful hepatocyte-specific transcriptional enhancer. Gel retardation and DNase I protection experiments showed that HepG2 cells contain proteins that bind to specific sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within this enhancer. Site-directed mutagenesis that prevents binding of these proteins to individual or different combinations of these sites followed by functional analysis of these mutants in HepG2 cells revealed that protein binding to any one of these sites in the absence of binding to the others was not sufficient for expression. Binding to any two of these sites in any combination was sufficient for only low levels of expression. Binding to all three sites was essential for maximal expression. These results indicate that the transcriptional activity of the apoAI gene in liver cells is dependent on synergistic interactions between transcription factors bound to its enhancer.
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PMID:Synergistic interactions between transcription factors control expression of the apolipoprotein AI gene in liver cells. 184 69

We present a comparative study of the cis- and trans-acting elements governing the expression of the human transferrin (Tf) gene in two tissues, liver and testis, where Tf is expressed at various levels. We have previously identified the elements of the promoter, negative, and enhancer regions involved in the liver-specific expression of the gene. By transfection experiments of primary cultured rat Sertoli cells compared with hepatoma cells, DNase I footprinting, and gel retardation studies, we have analyzed 3.6 kilobase pairs of the Tf regulatory region. The far upstream enhancer functional in Hep3B cells is inactive in Sertoli cells; in the two cell types, different nuclear factors appear to bind to a DNA domain crucial for enhancer activity. Similar negative- and positive-acting elements are present in the distal promoter in both tissues. However different combinations of proximal promoter elements control tissue-specific expression. Liver-specific transcription is governed by the interaction of the Tf-LF1 protein and a C/EBP-related factor with the -125 to -45 region. In Sertoli cells, a -34 to -18 TATA box-binding factor is sufficient to initiate basal-level transcription. Efficient expression is achieved by the association of two factors binding either to the (-82, -1) or to the (-153, -52) region. The addition of a third adjacent element decreases the promoter activity, suggesting that the balance of three factors binding to the proximal sites regulates testis-specific expression.
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PMID:Sertoli cell-specific expression of the human transferrin gene. Comparison with the liver-specific expression. 185 57

alpha 1-Inhibitor III (alpha 1 I3), a broad range plasma proteinase inhibitor, is synthesized with striking tissue specificity in rat livers. The gene is expressed strongly in periportal hepatocytes of healthy adults and less abundantly in regions near the centrilobular vein. This expression pattern is suggestive of a concentration gradient of a blood-borne hormone that enters through the portal vein and diffuses across the lobe toward the centrilobular vein. The alpha 1 I3 gene was known to be regulated both by glucocorticoids and interleukin 6, and therefore the hypothesis was tested that the normal constitutive expression of this gene depended on glucocorticoids. alpha 1 I3 mRNA levels in the livers of hypophysectomized rats with low endogenous glucocorticoid levels were only about 20% of those in control rat livers. Injection of exogenous glucocorticoids reconstituted hepatic alpha 1 I3 mRNA levels up to 64% of their original values in a dose-dependent manner. Similarly, treatment of FAZA rat hepatoma cells with the synthetic glucocorticoid dexamethasone induced alpha 1 I3 mRNA levels in a dose-dependent manner. Taken together these data suggested that glucocorticoids are required for the constitutive high level expression of this gene in normal adult rat livers. A series of 5' deletion constructs and linker scanning mutants of the promoter upstream region were produced and transfected into FAZA cells. A functional glucocorticoid response element was mapped between -168 and -151 base pairs 5' of the transcription start site. This element conforms with an inverted consensus glucocorticoid response element (GRE) but differs in two positions essential for protein DNA interaction between the GRE and the glucocorticoid receptor (GR). The induction of alpha 1 I3 gene promoter region constructs by dexamethasone was abolished by the receptor antagonist RU486, indicating that the GR participated in the activation of the alpha 1 I3 gene. In DNase I footprinting experiments with nuclear protein extracts from untreated and dexamethasone-treated FAZA cells, similar extents of alpha 1 I3 promoter upstream sequences were protected, indicating that proteins capable of binding in the glucocorticoid response-mediating element (GME) region were present before and after arrival of the hormonal signal. However, a purified recombinant fragment of the GR which contained essentially only its DNA binding domain was unable to bind at the GME although it interacted strongly with a consensus GRE sequence.
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PMID:Identification of a glucocorticoid response element contributing to the constitutive expression of the rat liver alpha 1-inhibitor III gene. 191 55

The male hybrid B6C3F1 mouse exhibits a 30% spontaneous hepatoma incidence, whereas the paternal C3H/He strain and the maternal C57BL/6 strain exhibit a 60% and a negligible incidence, respectively. In addition, both male and female B6C3F1 mice are extremely sensitive to chemical induction of hepatocarcinogenesis. The Ha-ras, Ki-ras, and myc oncogenes have been implicated in a variety of solid tumors. Specifically, Ha- and, less frequently, Ki-ras have been reported to be activated in B6C3F1 mouse liver tumors. The objective of this study was to examine a possible point of transcriptional control of Ha-ras, Ki-ras, and myc in all three mouse strains, our hypothesis being that these oncogenes may be primed for expression in the nascent liver of those strains exhibiting a high spontaneous hepatoma incidence. A positive correlation has been established between gene expression and the presence of DNase I hypersensitive sites. DNase I hypersensitive sites were observed in the Ha-ras and myc oncogenes in the three mouse strains. However, Ha-ras appears to possess an additional site in B6C3F1 and C3H/He as compared to C57BL/6. Similarly, the Ki-ras oncogene exhibited a DNase I hypersensitive site only in B6C3F1 and C3H/He mouse liver. These results indicate that the hepatoma-prone strains (B6C3F1 and C3H/He) may have a greater potential for Ha- and Ki-ras expression than does the non-hepatoma-prone strain (C57BL/6).
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PMID:Differential DNase I hypersensitivity of ras oncogenes in B6C3F1, C3H/He, and C57BL/6 mouse liver. 194 24

The P97 promoter upstream of the oncogenic early genes of human papillomavirus (HPV)-16 is active in keratinocytes and in cervical carcinoma cells due to a 5' keratinocyte-dependent cis enhancer. In this study, we have mapped the main enhancer activity to an 88-nucleotide (nt) fragment composed of multiple cis elements. A 63-nt promoter-proximal enhancer core was sufficient for P97 activation in a human keratinocytic cell line, HaCaT, and in cervical carcinoma cells. Although the enhancer functioned poorly in hepatoma cells or in fibroblasts, nuclear extracts from different cells protected similar cis elements from DNase I digestion. Two protected half-palindromic NF-I/CTF sites within the 63-nt core were necessary for its function; one represents a "cytokeratin element" (CK), a previously described 8-nt sequence shared with cytokeratin gene promoters. Both sites formed complexes of the same apparent size and relative binding affinity with NF-I/CTF-like factor(s) present in all cells tested. Although cell-dependent P97 activation could be determined by similar, yet distinct NF-I/CTF-like proteins, adjacent cis elements in the enhancer core were also required for function, and may thus interact with additional transcription factors. A 25-nt distal module with two AP-1 sites increased enhancer activity and cooperated with cis elements of the proximal core. Each AP-1 site as well as a third AP-1 site near the promoter bound c-Jun and Jun/Fos in vitro, and was activated by c-Jun and c-Fos in transfections. In addition to cell type-dependent activation, HPV-16 P97 transcription may therefore respond to growth factors and oncogene products via the AP-1 pathway.
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PMID:Transcriptional activation of the human papillomavirus-16 P97 promoter by an 88-nucleotide enhancer containing distinct cell-dependent and AP-1-responsive modules. 196 84

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