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)

Hemopexin (Hx) is an abundant acute-phase protein (APP) that binds heme with high affinity. In rat hepatic cells, the transcription rate of the Hx gene is increased by interleukin (IL)-1 and IL-6. To investigate the cis-acting regulatory elements (REs) responsive to these hormones, chloramphenicol acetyltransferase constructs of rat and human Hx gene sequences were tested in transiently transfected hepatoma cells. An IL-6-RE was identified in the promoter of both rat and human Hx genes, the function of which was dependent on the core sequence (CCGGGAA) common in other APP genes. The previously characterized Hx A element mediated a relatively minor cytokine response as compared with the Hx IL-6-RE. The human Hx A element, in contrast to the rat and human Hx IL-6-REs, was strongly trans-activated by cotransfected CAAT enhancer-binding proteins (C/EBP)-beta and -delta. The rat gene homolog of the human Hx A element was inactive as a cytokine RE and was minimally trans-activated by C/EBP isoforms. Results of electrophoretic mobility shift assays indicated that the Hx IL-6-RE is a binding site for the IL-6-inducible nuclear protein IL-6 RE-BP, which also binds to the conserved IL-6-REs of other APP genes and is distinct from C/EBP beta.
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PMID:The rat and human hemopexin genes contain an identical interleukin-6 response element that is not a target of CAAT enhancer-binding protein isoforms. 817 75

A patient with liver cirrhosis who progressed to hepatocellular carcinoma was found to develop novel antinuclear antibodies. The serum was used to isolate full-length cDNA clones encoding related proteins of 530 amino acids (representative clone HCC1.4) and 524 amino acids (representative clone HCC1.3). Affinity-purified antibodies eluted from recombinant proteins recognized a 64-kD nuclear protein in Western blotting and decorated the nucleoplasm in a speckled-network fashion in immunofluorescence, colocalizing with antibodies to pre-mRNA splicing factor SC35 and uridine-rich small nuclear RNAs. The deduced amino acid sequence contained an arginine/serine-rich (RS) domain and three-ribonucleoprotein consensus sequence domains, two classes of motifs present in several splicing factors. A repeating octapeptide of Arg-Ser-Arg-Ser-Arg(Lys)-Glu(Asp)-Arg-Lys(Arg) was present in RS region of HCC1. This octapeptide sequence called RS-ERK motif was also found in splicing factors U2AF 35- and 65-kD proteins and 70-kD U1 small nuclear ribonucleoprotein. The molecular features and immunolocalization data suggest that the HCC1 autoantigen may be associated with splicing activities and are consistent with observations that autoantibody responses frequently target molecules involved in important cellular biosynthetic functions.
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PMID:Novel nuclear autoantigen with splicing factor motifs identified with antibody from hepatocellular carcinoma. 822 58

Mannose-binding protein (MBP) is a plasma protein synthesized by hepatocytes. MBP, a structural analogue of the complement component C1q, can activate complement via the classical pathway and plays an important role in host defence. Expression of the human MBP gene was studied using the human hepatoma cell line HuH-7. RNA extracted from HuH-7 cells was reverse-transcribed to cDNA, amplified by the polymerase chain reaction and analysed by Southern blot hybridization. MBP mRNA expression in HuH-7 cells was increased by interleukin-6 (IL-6), dexamethasone and heat shock, decreased by interleukin 1 (IL-1), and unaffected by interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta). Gel shift assays demonstrated Sp-1 binding sites in the 5' region of the gene, and formation of specific complexes between DNA and nuclear protein extracted from HuH-7 cells treated with IL-1 or IL-6. Human MBP is an acute-phase protein, and transcription of its gene is enhanced by IL-6, dexamethasone and heat shock but inhibited by IL-1. The actions of the cytokines appear to be mediated by specific transcription factors.
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PMID:Human mannose-binding protein gene is regulated by interleukins, dexamethasone and heat shock. 825 72

The search for cancer specific nuclear proteins, stimulated by the supposition that transition from the normal to the neoplastic state resulting from disturbances in the control mechanisms of gene expression, indicated that non-histone protein of MW 48 kD is much more abundant in animal tumour cells than in normal liver (Krajewska et al., 1990). A non-histone component of MW 48 kD was assessed for changes during chemically induced carcinogenesis. Rats were treated with the hepatocarcinogen thioacetamide (TAA) and the expression of the polypeptide studied, in total nuclear protein and nonhistone protein fractions, was tested by Western blot technique in the presence of antibodies developed against a component of MW 48 kD from Kirkman-Robbins hepatoma. It was demonstrated that TAA-induced hepatocarcinogenesis was accompanied by the expression of non-histone protein of MW 48 kD at a significantly elevated level. A clear and distinct change in the expression of the component studied in the spleen of TAA-treated rats was also observed. These results support the suggestion that over-expression of non-histone protein of MW 48 kD could contribute to neoplastic transformation.
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PMID:Thioacetamide-stimulated expression of non-histone protein. 840 30

Patients with hepatocellular carcinoma (HCC) develop autoantibodies to nuclear and nucleolar antigens (ANAs) which can be readily detected by immunofluorescence on cell substrates. The frequency of ANAs in HCC is 31% (57/184). The identity of three autoantigens was established as: NOR-90, nucleolus organizer region (doublet) polypeptides involved in RNA polymerase I transcription; fibrillarin, a component of nucleolar U3 RNP involved in pre-ribosomal RNA processing, and nucleophosmin/protein B23, a nucleolar protein involved in ribosome maturation and cell proliferation. Changes in ANAs were observed in some patients during transition from chronic liver disease to HCC and were manifested as seroconversion from ANA-negative to ANA-positive status by an increase in titers and changes in ANA specificities. Serum from a patient during this transition period was used to isolate a cDNA clone encoding a novel nuclear protein with structural motifs characteristic of a family of splicing factors. These observations support the notion that ANA responses in HCC might be driven by intracellular events related to transformation from the stage of chronic injury to the stage of malignancy. Changes in ANA profiles which were observed to precede clinically diagnosed HCC in some patients might be early markers of transformation.
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PMID:Autoantibodies in viral hepatitis-related hepatocellular carcinoma. 840 52

Hepatitis B virus gene expression is to a large extent under the control of enhancer I (EnhI). The activity of EnhI is strictly dependent on the enhancer factor C (EF-C) site, an inverted repeat that is bound by a ubiquitous nuclear protein known as EF-C. Here we report the unexpected finding that EF-C is in fact identical to RFX1, a novel transcription factor previously cloned by virtue of its affinity for the HLA class II X-box promoter element. This finding has allowed us to provide direct evidence that RFX1 (EF-C) is crucial for EnhI function in HepG2 hepatoma cells; RFX1-specific antisense oligonucleotides appear to inhibit EnhI-driven expression of the hepatitis B virus major surface antigen gene, and in transfection assays, RFX1 behaves as a potent transactivator of EnhI. Interestingly, transactivation of EnhI by RFX1 (EF-C) is not observed in cell lines that are not of liver origin, suggesting that the ubiquitous RFX1 protein cooperates with liver-specific factors.
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PMID:RFX1 is identical to enhancer factor C and functions as a transactivator of the hepatitis B virus enhancer. 841 36

1. We have established a murine hybridoma (F86) that secretes a monoclonal antibody (MoAb) specific for a 120 kDa nuclear protein (p120). p120 is expressed in all human cell lines investigated, whether of tumor or normal cell origin. 2. However, expression of p120 is significantly higher in neoplastic cells than in normal cells. The amount of p120 is relatively constant through the cell cycle and does not appear to be modulated by 72 hr serum starvation. 3. These results suggest that p120 plays some role in nuclear events associated with neoplastic phenotypes rather than in cell proliferation. 4. In situ immunofluorescence analyses indicate that p120 is located exclusively in nuclei of interphase cells. It is not present in nucleoli. 5. During mitosis, p120 is distributed in the cytoplasm and is not associated with condensed chromosomes which, together with RNAse experiments, suggests that it may be associated with hnRNA or hnRNP particles. 6. Western blot analyses indicate that p120 consists of two molecular weight forms which differ by 2-3 kDa in reduced SDS-PAGE, and several isoelectric variants in the acidic range. 7. Fractionation studies indicate that p120 has accessible free sulfhydryl group(s) and can bind ssDNA and heparin. 8. A partial cDNA clone, encoding the carboxyl terminus of p120, was isolated from a lambda gt11 library which had been prepared from human hepatoma cells (KYN-1). 9. Sequence analysis of the open reading frame revealed two possible nuclear localization sequences and several clusters of acidic amino acid residues, including a continuous run of 11 glutamic acid residues. 10. Northern blot analyses of human hepatoma RNA revealed hybridization to three transcripts which are about 4.1, 3.6, and 0.6 kb in size. 11. Dot blot analyses show that these transcripts are about 10-fold more abundant in KYN-1 hepatoma cells than in normal liver cells.
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PMID:A tumor-associated 120 kDa nuclear protein: characterization using a monoclonal antibody and a partial cDNA clone. 844 14

The regulation of nuclear protein transport by phosphorylation plays a central role in gene expression in eukaryotic cells. We previously showed that nuclear import of SV40 large tumor antigen (T-ag) fusion proteins is regulated by the CcN motif, comprising phosphorylation sites for casein kinase II and the cyclin-dependent kinase cdc2, together with the nuclear localization signal. Regulation of nuclear uptake by CcN motif kinase sites also holds true for the yeast transcription factor SWI5 and the Xenopus nuclear phosphoprotein nucleoplasmin. To test directly whether a kinase site other than those of the CcN motif could regulate nuclear import of T-ag, the CcN motif casein kinase II site, which markedly increases the rate of T-ag nuclear import, was replaced by a consensus site for the cAMP-dependent protein kinase (PK-A) using site-directed mutagenesis. The resultant fusion protein could be specifically phosphorylated by PK-A in vitro and in cell extracts. Nuclear import of the fluorescently labeled protein was analyzed in the HTC rat hepatoma cell line both in vivo (microinjected cells) and in vitro (mechanically perforated cells) in the presence and the absence of cAMP and/or PK-A catalytic subunit using confocal laser scanning microscopy. In vitro PK-A-prephosphorylated protein was also tested. All results indicated that the rate of nuclear import was increased by phosphorylation at the PK-A site (2-5-fold), demonstrating that kinases other than those of the CcN motif can regulate nuclear import in response to stimulatory signals. The phosphorylation-regulated nuclear localization signal derived here represents an important first step toward developing a signal conferring inducible nuclear targeting of molecules of interest.
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PMID:A consensus cAMP-dependent protein kinase (PK-A) site in place of the CcN motif casein kinase II site simian virus 40 large T-antigen confers PK-A-mediated regulation of nuclear import. 862 46

Nuclear protein import is central to eukaryotic cell function. It is dependent on ATP, temperature and cytosolic factors, and requires specific targeting sequences called nuclear localization signals (NLSs). Nuclear import kinetics was studied in vitro using digitonin-permeabilized cells of the HTC rat hepatoma cell line and a fluorescently labelled beta-galactosidase fusion protein carrying amino acids 111-135 of the simian virus 40 large T-antigen (T-ag), including the NLS. Nuclear accumulation was rapid, reaching steady-state after about 80 min at 37 degrees C (t1/2 at about 17 min). Surprisingly, maximal nuclear concentration was found to be directly proportional to the concentration of the cytosolic extract and of cytoplasmic T-ag protein. Neither preincubation of cells for 1 h at 37 degrees C before the addition of T-ag protein nor the addition of fresh transport medium after 1 h and continuation of the incubation for another hour affected the maximal nuclear concentration. If cells were allowed to accumulate T-ag protein for 1 h before the addition of fresh transport medium containing different concentrations of T-ag protein and incubated for a further hour, the maximal nuclear concentration did not change unless the concentration of T-ag protein in the second transport mixture exceeded that in the first, in which case the nuclear concentration increased. Nuclear import of T-ag thus appeared (i) to be strictly unidirectional over 2 h at 37 degrees C and (ii) to be regulated by an inhibitory feedback loop, whereby the cytosolic concentration of protein appears to determine directly the precise end point of nuclear accumulation. This study represents the first characterization of this previously undescribed mechanism of regulation of nuclear protein import.
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PMID:Evidence for an inhibitory feedback loop regulating simian virus 40 large T-antigen fusion protein nuclear transport. 867 Jan 27

The gene for fatty acid synthase (FAS), which contains both GC-rich sequences and a TATA box in its promoter region, is expressed in a tissue-specific manner in response to developmental, nutritional and hormonal signals. Here we report the identification of sequence elements in the 5'-flanking region responsible for modulation of basal promoter activity. Transient transfection of H4IIE hepatoma cells and 3T3-30A5 preadipocytes with plasmids containing the chloroamphenicol acetyltransferase gene driven by FAS promoter sequences of different lengths revealed that two regions between nucleotides -249 and -30 contain elements capable of enhancing transcription. One of these positive regulatory elements was localized to nucleotides -241/-236 using DNase I footprinting, electrophoretic mobility-shift assays and mutagenesis. The sequence element is a typical GC box and the nuclear protein binding to this region appears immunochemically indistinguishable from Sp1. The second positive regulatory element, an inverted CCAAT box, was localized to nucleotides -98/-92 by electrophoretic mobility-shift assays and mutagenesis. A putative negative regulatory element, initially identified by reporter gene transfection experiments, was localized between nucleotides -319 and -301 by DNase I footprinting, electrophoretic mobility-shift assays and deletion mutagenesis; this region consists of 78% G residues. In conclusion, initiation of FAS transcription from a single start site is enhanced by the presence of an adjacent TATA motif, an inverted CCAAT box and an upstream binding site for the transcription factor Sp1; further modulation of transcription is achieved through complex interactions between these promoter elements and an upstream negative regulatory element.
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PMID:Transcriptional regulation of the rat fatty acid synthase gene: identification and functional analysis of positive and negative effectors of basal transcription. 869 72


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