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)

Like such hepatic genes as those for albumin and aldolase B, the rat catalase gene shows markedly reduced expression in carcinogenesis of hepatocytes. Strong silencer activity has been widely observed in the 5'-flanking region of the gene, downstream from the G-rich sequence identified in a previous study. In this study, we identified and characterized multiple elements involved in negative regulation of catalase gene expression by reporter assay and gel shift assay. One of the silencer elements is located 3 kb upstream of the gene and has GATATCCCGATATC as core sequence. The observation that protein binding to the element is abundantly expressed in dedifferentiated hepatoma cell lines, but scarcely in well-differentiated cell lines suggests that this element is involved in negative regulation of the catalase gene expression in hepatocarcinogenesis. This element was targeted by a novel 20-kDa nuclear protein, which is designated HNRF (hepatocarcinogenesis-related negative regulatory factor).
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PMID:Multiple elements for negative regulation of the rat catalase gene expression in dedifferentiated hepatoma cells. 1109 46

The transcriptional mechanism of regucalcin gene expression was determined using gel mobility shift assay with TTGGC oligonucleotide (II-b) which is located between position -523 and -506 in the promoter region, containing a nuclear factor I (NF1) consensus motif TTGGC(N)(6)CC. The mutation analysis in this motif showed that TTGGC sequence was a specific binding region of the nuclear protein in rat liver and the cloned rat hepatoma cells (H4-II-E). When liver nuclei were incubated with ATP (1 mM), the nuclear protein binding to TTGGC sequence was increased. This binding was also increased in the nuclei of H4-II-E cells cultured with 10% FBS. Such an increase was also seen by culture with vanadate (100 microM), a potent inhibitor of protein tyrosine phosphatase. Serum-enhanced nuclear protein binding to TTGGC sequence was decreased in the presence of TFP (10 microM), staurosporine (100 nM), genistein (10 microM), PD98059 (10 microM), or wortmannin (10 nM), which are inhibitors of various protein kinases. Treatment of a monoclonal phosphotyrosine antibody (4G10) caused an alteration in the TTGGC oligonucleotide-nuclear protein complex formation, indicating that tyrosine phosphorylation of nuclear protein is partly involved in the binding to TTGGC sequence. Moreover, when H4-II-E cells were cultured with FBS (10%), Bay K 8644 (5 microM), PMA (1 microM), or insulin (20 nM), the protein binding to TTGGC sequence in the nuclei was increased, while it was reduced in the cytoplasm, indicating a nuclear localization of the TTGGC sequence-binding protein. This study demonstrates that hepatic nuclear protein can specifically bind to the TTGGC sequence in rat regucalcin gene promoter region, and that this binding is enhanced by intracellular signaling factors which are partly mediated through protein phosphorylation.
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PMID:Intracellular signaling factors--enhanced hepatic nuclear protein binding to TTGGC sequence in the rat regucalcin gene promoter: involvement of protein phosphorylation. 1111 52

The liver is a major target organ of insulin and is important for glucose homeostasis. We analyzed the tissue specific regulation of the insulin receptor gene in the liver by studying the cis-acting element and trans-acting factor of the human insulin receptor gene in human hepatoma cell line, HepG2 cells. In the chloramphenicol acetyl transferase (CAT) assay with chimeric plasmids containing various deletions and insertions of the human insulin receptor promoter/CAT gene, a HepG2 cell specific cis-acting element was identified between nt -592 to -577 of the promoter. In electrophoretic mobility shift assay and UV cross-link analysis, a 35-kDa nuclear protein that bound to 5'-TCCCTCCC-3' (nt -588 to -581) sequence was identified in HepG2 cells as well as in rat hepatocytes. This nuclear protein, designated as hepatocyte-specific transcription factor of the insulin receptor gene (HTFIR), might play an important role in tissue-specific expression of the insulin receptor gene in the liver.
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PMID:Identification of a cis-acting element and a novel trans-acting factor of the human insulin receptor gene in HepG2 and rat liver cells. 1116 34

A negative regulatory element (NRE) is located immediately upstream of the upstream regulatory sequence of core promoter and second enhancer of human hepatitis B virus (HBV). NRE represses the transcription activation function of the upstream regulatory sequence of core promoter and the second enhancer. In this study, we described the cloning and characterization of an NRE-binding protein (NREBP) through expression cloning. NREBP cDNA is 8266 nucleotides in size and encodes a protein of 2386 amino acids with a predicted molecular mass of 262 kDa. Three previously described cDNAs, DBP-5, SONB, and SONA, are partial sequence and/or alternatively spliced forms of NREBP. The genomic locus of the NREBP/SON gene is composed of 13 exons and 12 introns. The endogenous NREBP protein is localized in the nucleus of human hepatoma HuH-7 cells. Antibody against NREBP protein can specifically block the NRE binding activity present in fractionated nuclear extracts in gel shifting assays, indicating that NREBP is the endogenous nuclear protein that binds to NRE sequence. By polymerase chain reaction-assisted binding site selection assay, we determined that the consensus sequence for NREBP binding is GA(G/T)AN(C/G)(A/G)CC. Overexpression of NREBP enhances the repression of the HBV core promoter activity via NRE. Overexpression of NREBP can also repress the transcription of HBV genes and the production of HBV virions in a transient transfection system that mimics the viral infection in vivo.
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PMID:Transcription repression of human hepatitis B virus genes by negative regulatory element-binding protein/SON. 1130 77

Peroxisome proliferators (PPs) are nongenotoxic compounds causing the emergence of hepatocellular carcinoma in rodents, but the mechanisms of the hepatocarcinogenesis have been unclear. The authors examined the changes in phosphorylation of nuclear proteins after treatment with (4-chloro-6-[2,3-xylidino]-2-pyrimidinylthio) acetic acid (Wy-14,643). Wy-14,643 (0.1% w/w in diet) was given orally to male F-344 rats for up to 80 wk. In the hepatocarcinomas induced by Wy-14,643, phosphorylation of 13 kDa nuclear protein (NP 13), which was resistant to alkaline treatment, was significantly increased. NP 13 phosphorylation gradually increased, dependent on treatment period. Furthermore, in the hepatocarcinomas induced by other PP, di(2-ethylhexyl)phthalate, increase in NP13-phosphorylation was also observed. Therefore, NP 13-phosphorylation may relate to development of preneoplastic or neoplastic lesions induced by PPs.
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PMID:Phosphorylation of 13 kDa nuclear protein in hepatocarcinomas induced by peroxisome proliferators. 1133 66

The polypeptide ligand angiogenin, a potent inducer of angiogenesis, localizes in the nucleus/nucleolus subsequent to endocytosis by relevant cell types. This study examines the kinetic properties of the nucleolar targeting signal (NTS) of angiogenin (IMRRRGL(35)) at the single cell level. We show that the NTS is sufficient to target green fluorescent protein (GFP), but not beta-galactosidase, to the nucleolus of rat hepatoma cells. Mutation of Arg(33) to Ala within the NTS abolishes targeting activity. Nuclear/nucleolar import conferred by the NTS of angiogenin is reduced by cytosolic factors as well as ATP and is independent of importins and Ran. The NTS also confers the ability to bind to nuclear/nucleolar components which is inhibited by ATP hydrolysis; nonhydrolysable GTP analogs prevent nuclear accumulation in the absence of an intact nuclear envelope through an apparent cytoplasmic retention mechanism. Since the lectin wheat germ agglutinin does not inhibit transport, we postulate a mechanism for angiogenin nuclear/nucleolar import involving passive diffusion of angiogenin through the nuclear pore and NTS-mediated nuclear/nucleolar retention, and with cytoplasmic retention modulating the process. This pathway is clearly distinct from that of conventional signal-mediated nuclear protein import.
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PMID:Novel properties of the nucleolar targeting signal of human angiogenin. 1137 89

A feature of hepatocellular carcinoma (HCC) is that antecedent liver cirrhosis and chronic hepatitis are common precursor conditions and during transition to malignancy some patients develop autoantibodies which were not present during the preceding chronic liver disease phase. Serum samples from such patients can be used to immunoscreen cDNA expression libraries to identify genes encoding the new autoantigens. We demonstrate here the de novo appearance of antibodies to p62, a cytoplasmic protein which has been shown to bind to a developmentally regulated fetal species of insulin-like growth factor II (IGF-II) mRNA. Another antibody appearing during the transition period was against CENP-F, a cell cycle-related nuclear protein with maximum expression in the G2 and M phases of the cell cycle and previously shown to have a high association with malignancy. In three additional patients in whom serial serum samples were examined, new appearance of anti-p62 was detected in two patients and anti-CENP-F in one patient. This study demonstrates that transition to malignancy can be associated with autoantibody responses to certain cellular proteins which might have some role in tumorigenesis.
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PMID:De-novo humoral immune responses to cancer-associated autoantigens during transition from chronic liver disease to hepatocellular carcinoma. 1147 19

Hepatitis B virus (HBV) gene expression is mainly regulated at the transcription initiation level. The viral X protein (pX) is a transcription coactivator/mediator targeting TFIIB for the recruitment of RNA polymerase II. Here we report a novel pX nuclear target designated HBXAP (hepatitis B virus X-associated protein). HBXAP is a novel cellular nuclear protein containing a PHD (plant homology domain) finger, a domain shared by many proteins that play roles in chromatin remodeling, transcription coactivation, and oncogenesis. pX physically interacts with HBXAP in vitro and in vivo via the HBXAP region containing the PHD finger. At the functional level HBXAP increases HBV transcription in a pX-dependent manner suggesting a role for this interaction in the virus life cycle. Interestingly, HBXAP collaborates with pX in coactivating the transcriptional activator NF-kappaB. Coactivation of NF-kappaB was also observed in tumor necrosis factor alpha-treated cells suggesting that pX-HBXAP functional collaboration localized downstream to the NF-kappaB nuclear import. Collectively our data suggest that pX recruits and potentiates a novel putative transcription coactivator to regulate NF-kappaB. The implication of pX-HBXAP interaction in the development of hepatocellular carcinoma is discussed.
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PMID:Hepatitis B virus pX interacts with HBXAP, a PHD finger protein to coactivate transcription. 1178 98

Expression of glucose-6-phosphatase (G6Pase), one of the rate-limiting enzymes of hepatic gluconeogenesis, has recently been shown to be transactivated by the transcription factor FKHR. One of the proteins known to directly interact with FKHR is the nuclear protein kinase DYRK1A. In order to study the effects of DYRK1A on G6Pase gene expression, we generated a H4IIEC3 rat hepatoma cell line stably expressing DYRK1A by retroviral infection. Overexpression of DYRK1A increased the expression of G6Pase about threefold, as determined by Northern blotting. In transiently transfected HepG2 cells, co-expression of DYRK1A and a G6Pase promoter construct increased G6Pase promoter activity about twofold. This effect of DYRK1A was independent of its kinase activity, since a kinase-dead DYRK1A mutant as well as a point mutant of the phosphorylation site of DYRK1A in FKHR (Ser329Ala) failed to affect the effect of DYRK1A on the G6Pase expression. The effect of DYRK on the G6Pase promoter activity was produced by the isoforms DYRK1A and DYRK1B, which are localized in the nucleus, but not by DYRK2. Mutations of the FKHR-binding sites in the G6Pase promoter markedly reduced the effect of DYRK1 on the G6Pase promoter activity. In summary, the data suggest that DYRK1 is a specific co-activator of FKHR, independent of its kinase activity.
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PMID:DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. 1250 16

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an important physiological role by contributing to the metabolism of endogenous substances such as bilirubin in addition to xenobiotics and drugs. The UGT1A1 gene has been shown to be inducible by nuclear receptors steroid xenobiotic receptor (SXR) and the constitutive active receptor, CAR. In this report, we show that in human hepatoma HepG2 cells the UGT1A1 gene is also inducible with aryl hydrocarbon receptor (Ah receptor) ligands such as 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD), beta-naphthoflavone, and benzo[a]pyrene metabolites. Induction was monitored by increases in protein and catalytic activity as well as UGT1A1 mRNA. To examine the molecular interactions that control UGT1A1 expression, the gene was characterized and induction by Ah receptor ligands was regionalized to bases -3338 to -3287. Nucleotide sequence analysis of this UGT1A1 enhancer region revealed a xenobiotic response element (XRE) at -3381/-3299. The dependence of the XRE on UGT1A1-luciferase activity was demonstrated by a loss of Ah receptor ligand inducibility when the XRE core region (CACGCA) was deleted or mutated. Gel mobility shift analysis confirmed that TCDD induction of nuclear proteins specifically bound to the UGT1A1-XRE, and competition experiments with Ah receptor and Arnt antibodies demonstrated that the nuclear protein was the Ah receptor. These observations reveal that the Ah receptor is involved in human UGT1A1 induction.
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PMID:Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. 1256 46


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