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)

We have characterized a transcriptional enhancer of the human urokinase-type plasminogen activator (uPA) gene and found a regulatory element required for co-operation between a PEA3--AP-1 element and an AP-1 site in the enhancer. We designated this regulatory element co-operation mediator (COM). Both the PEA3--AP-1 element, the AP-1 site and the COM are required for efficient phorbol ester induction of transcription from the uPA promoter in the HepG2 hepatoma cell line. We show that the COM is also required for co-operation between the PEA3--AP-1 element and a glucocorticoid response element, both in the presence or absence of TPA, indicating that the COM is generally capable of mediating synergism between inducible enhancer elements. The COM contains multiple overlapping binding sites for nuclear proteins, designated uPA enhancer factors 1-4 (UEF-1-4). We have identified putative binding sites for UEF-1, -2 and -3. The UEF-1 and -3 sites in the uPA enhancer are highly conserved between species. We demonstrate the binding of UEF-3 to the NIP element, a previously characterized regulatory element in the human interleukin-3 and stromelysin promoters, suggesting that this factor plays a role in regulation of a variety of genes.
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PMID:A regulatory element that mediates co-operation between a PEA3-AP-1 element and an AP-1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells. 133 May 39

1. The induction of metallothionein (MT) protein by TPA (O-tetradecanoyl phorbol acetate), a protein kinase C activator, was demonstrated in vivo in rat liver and in vitro in rat hepatocytes in primary culture. In vivo half maximal induction at 25 hr was seen at 26 nmol TPA/kg body wt. Five- to seven-fold inductions were seen in vivo. De novo protein synthesis was required for this induction as demonstrated by cycloheximide inhibition of [35S]cysteine incorporation into MT protein. 2. TPA induction of MT protein in primary cultures of rat hepatocytes reached levels of 2.6-4.1-fold, as assessed by [35S]cysteine incorporation, 1.34-2.20-fold, as assessed by 109Cd binding in a metal displacement/HPLC assay, and 2.5-5-fold, as assessed by 109Cd binding in a metal displacement/Sephadex G-75 Superfine assay. 3. The induction of MT mRNA by TPA was demonstrated in vivo in rat liver and in vitro in 2 rat hepatoma cell lines, EC3 and 2M. MT mRNA was quantitated using dot blot and Northern gel assays. In vivo TPA induced hepatic MT mRNA 2.36-5.88-fold (dot blot) and 7.4-22-fold (Northern gels). In vitro TPA induced MT mRNA 1.71-15.26-fold in EC3 cells and 2.23-8.43-fold in 2M cells. MT mRNA was 0.54 kb, and alpha-tubulin mRNA was 1.62 kb in size on Northern gels. 4. TPA induction of MT protein and mRNA in vivo and in vitro is rapid and persistent and occurs at low concentrations. The 2 rat hepatoma cell lines provide a useful system in which to study MT induction in vitro without confounding secondary effects which can occur in vivo.
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PMID:Phorbol ester induction of rat hepatic metallothionein in vivo and in vitro. 139 94

O6-Methylguanine-DNA methyltransferase (MGMT) is decisively involved in protecting mammalian cells against genotoxic effects of alkylating carcinogens. We analysed regulation of MGMT expression after exposing rat hepatoma H4IIE cells to various 'stress' factors. Treatments that damage DNA such as alkylation, hydrogen peroxide, ultraviolet or X-ray exposure, as well as restriction enzymes introduced into cells by electroporation or arrest of replication by hydroxyurea significantly induced MGMT mRNA (2.5 to 5-fold). Slight induction (up to 2.5-fold) was observed after heat shock or cadmium/zinc treatment. No or only a very weak induction (less than 1.5-fold) was observed after treatment with 6-thioguanine, 5-azacytidine, transfection of methylated DNA, depletion of MGMT by feeding with O6-methylguanine or O6-benzylguanine, serum starvation and feeding of starved cells, cAMP, TPA and dexamethasone treatment. Inhibitors of protein kinases, H8 and H9, induced MGMT mRNA. On the other hand, an inhibitor of phosphatases (sodium vanadate) prevented induction of MGMT by N-methyl-N'-nitro-N-nitrosoguanidine. The data indicate that DNA breaks are an ultimate signal for MGMT mRNA induction and that protein phosphorylation is involved in regulating MGMT expression.
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PMID:Stress factors affecting expression of O6-methylguanine-DNA methyltransferase mRNA in rat hepatoma cells. 142 Mar 62

The calcium ionophore, A23187, can induce rat hepatic metallothionein (MT) when administered in vivo (5.8-fold, 5.0 microM, 11 h) and rat hepatocyte MT when administered in vitro (10.70-fold, 1.0 microM, 24 h). Several rat hepatoma cell lines (2M, 4.55-fold; JM2, 12.29-fold; EC3, 14.12-fold; HTC, 7.99-fold) and a normal rat liver cell line (Clone 9, 39.67-fold) were tested for their inducibility of MT mRNA by Cd2+ (10 microM, 8 h). Quantitatively, JM2 and 2M made the most MT mRNA, while HTC made the least. A23187 (0.1-7.0 microM) was studied as an inducer of MT mRNA in these cell lines (except for HTC) and in HeLa. A variety of responses and tolerances were seen with inductions ranging up to 32.11-fold. Quantitatively, the best responding cell lines were EC3 and 2M. A combination induction experiment, using TPA, a protein kinase C activator, and A23187 in EC3 cells revealed an additive effect of the two inducers on MT mRNA levels: TPA (10 nM), 11.71-fold; A23187 (3.0 microM), 6.71-fold; and TPA + A23187, 20.00-fold. These studies have implicated perturbations in cytosolic calcium ion concentrations, caused by the ionophore A23187, as being involved in the complicated signaling systems which can lead to induction of MT mRNA and protein.
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PMID:Induction of zinc metallothionein by calcium ionophore in vivo and in vitro. 154 93

The present study is based on the assay of four markers (AFP, CEA, TPA, Ca 19-9) using IRMA methods in 36 normal subjects, 44 cirrhosis and 66 HCC patients. Parametric and non parametric tests were used to test differences and correlations. ROC curves and discriminant functions were also elaborated. Normal 95% "cut-off" was determined by the "boostrap" method yielding: CEA 3.4 ng/ml; Ca 19-9 55 U/ml; TPA 58U/l and AFP 5.2 ng/ml. In HCC patients the values of the four markers were, on average, significantly different from those of normal subjects. However, only AFP and TPA exhibited high diagnostic accuracy (90%) for detection of the tumor. Higher than normal mean values for all markers were, also observed in cirrhotic patients. Only AFP yielded effective discrimination between HCC and cirrhosis. The positive prediction for the presence of the tumor on cirrhotic ground was 95% for AFP values higher than 18.5 ng/ml, with a 78% negative predictive value with a 6 ng/ml threshold. Association of AFP with TPA showed only a marginal diagnostic improvement. Results were not improved at all by combining CEA and Ca 19-9 with AFP and/or TPA. In conclusion, AFP is and remains the best marker for HCC and the only one effective in discriminating of HCC from cirrhosis. TPA may be considered a valid alternative if cirrhosis is not present. CEA and Ca19-9 are of no use.
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PMID:AFP, CEA, CA 19-9 and TPA in hepatocellular carcinoma. 170 5

The serum level of CA 19-9 elevated exponentially in gastrointestinal carcinoma and the specificity of CA 19-9 was extraordinarily high. The sensitivity of CA 19-9 to pancreas, bile duct, hepatocellular and metastatic liver carcinoma was 75%, 79%, 22%, and 82% each. TPA seems to be useful as a screening tumor maker of gastrointestinal carcinoma, because the sensitivity was very high (84%) in every gastrointestinal carcinoma. IAP increased in pancreas and bile duct carcinoma and reflected immunological status of tumor bearing host. 5'-NPD-V was useful tumor marker not only of hepatocellular carcinoma but also pancreas and bile duct carcinoma.
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PMID:[Clinical evaluation of CA 19-9, TPA, IAP and 5'-NPD-V as tumor markers of hepatocellular, bile duct and pancreas carcinoma]. 241 64

Twenty-two cases of primary hepatic tumors consisting of 11 hepatocellular carcinomas, 6 cholangiocarcinomas, 3 mixed hepatocellular and cholangiocellular carcinomas, and 2 biliary cystadenocarcinomas together with 8 cases of metastatic adenocarcinoma from various sites were studied by immunoperoxidase technic to demonstrate tissue polypeptide antigen. All of the tumors presumably derived from the epithelial lining of the bile duct, including cholangiocarcinoma, cholangiocarcinomatous portion of the mixed hepatocellular and cholangiocellular carcinoma, and biliary cystadenocarcinoma showed strong positive reaction. The hepatocellular carcinoma and the metastatic adenocarcinoma exhibited negative to weakly positive reactions. These results indicate that TPA can be of use in differentiating bile duct carcinomas from hepatocellular carcinoma and, to a lesser extent, from hepatic metastases of various adenocarcinomas.
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PMID:Tissue polypeptide antigen--a marker antigen differentiating cholangiolar tumors from other hepatic tumors. 302 21

The metabolism of the tumor promoters 120-O-[3H]tetradecanoylphorbol-13-acetate ([3H]TPA) and [3H]phorbol-12,13-didecanoate ([3H]PDD) was analyzed in several cell types in culture. In contrast to the rapid metabolism of [3H]TPA, [3H]PDD was degraded much more slowly in hamster, rat, chick, and mouse fibroblasts. Human fibroblasts did not significantly metabolize either phorbol diester over a three-day period. In hamster fibroblasts, addition of increasing amounts of nonradioactive TPA inhibited the metabolism of [3H]TPA, while a 100-fold excess of PDD had no effect on [3H]TPA metabolism. Primary cultures of hamster epidermal cells, a long-term epidermal cell line, and a hamster preadipose cell line rapidly metabolized [3H]TPA but only slowly metabolized [3H]PDD. In contrast to human fibroblasts, a human hepatoma cell line metabolized [3H]TPA, but these cells metabolized [3H]PDD much more slowly. The profile of metabolites produced from [3H]PDD was studied in two cell types. In hamster cells, the major metabolite produced was [3H]phorbol-12-decanoate while in BALB/c 3T3 cells, approximately equal amounts of [3H]phorbol-12-decanoate and [3H]phorbol-13-decanoate were produced. When tested for biological activity in cell culture, phorbol-13-decanoate was 17 to 40 times less active than PDD as measured by the induction of ornithine decarboxylase in hamster cells and the stimulation of 2-deoxyglucose uptake in BALB/c 3T3 cells. Phorbol-12-decanoate was virtually inactive in both assays.
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PMID:Differences in the metabolism of 12-O-[3H]tetradecanoylphorbol-13-acetate and [3H]phorbol-12,13-didecanoate by cells in culture. 743 74

The hepatic expression of the alpha-2u-globulin gene family is controlled by a variety of hormones including steroids, growth hormone and insulin. The mechanisms by which these hormones affect alpha 2u-globulin expression are only partially understood. Recently we isolated and characterized clone RAP 01, an alpha 2u-globulin gene expressed in the liver. In preliminary experiments we noted that partial hepatectomy, a procedure which results in a sharp rise in the level of the oncoproteins c-Fos and c-Jun, also causes a transient induction of the messenger RNA corresponding to clone RAP 01. Using the DNAseI footprinting technique we were able to show that this clone contains a TPA (phorbol 12-myristate 13-acetate)-responsive element (TRE) in its first intron. This element (denoted as element X) is identical to the consensus AP-1 binding site (TGACTCAG) and is protected by rat liver nuclear extracts as well as by purified c-Jun. Gel retardation experiments show that an oligonucleotide containing the TRE consensus sequence competes for binding of liver nuclear proteins to element X and that antibodies directed against the M2 peptide of the mouse Fos protein or the PEP-2 peptide of Jun prevent the formation of specific complexes with the same element. Moreover, element X functions as a TRE in transfected BWTG3 hepatoma cells treated with TPA. Co-transfection with fos and jun expression vectors mimics the effects of TPA suggesting that AP-1 is in fact the mediator of the observed response. It is concluded that the first intron of RAP 01 contains a functional Fos-Jun element.
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PMID:A Fos-Jun element in the first intron of an alpha 2u-globulin gene. 750 7

The effects of a phorbol ester (TPA) and of members of the Jun and Fos oncoprotein family on the activity of the rat alpha-fetoprotein (AFP) promoter were checked by using transient expression experiments in HepG2 hepatoma cells. TPA blocked the activity of the rat AFP promoter in a dose-dependent manner. Overexpression of c-Jun specifically repressed the rat AFP promoter but not the albumin promoter. JunB and JunD were poorer inhibitors. c-Fos expression did not potentiate the negative effect of Jun. The Jun-induced repression does not require binding of c-Jun to the AFP promoter. DNase 1 footprinting experiments did not display any high affinity binding site for Jun on the AFP promoter. Integrity of the c-Jun DNA binding domain is not required for the c-Jun protein to block the AFP promoter. The N-terminal part of Jun, which contains the activating domain, is responsible for the repression as shown by using Jun-Gal4 chimera. Jun likely exerts its negative control on the AFP promoter via protein-protein interactions with a not yet identified trans-activating factor within the -134 to +6 region or with a component of the general machinery of transcription. Jun proteins can thus be key intermediates in regulatory cascades which result in the differential modulation of the AFP and albumin gene expression in the course of liver development and carcinogenesis.
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PMID:The c-jun proto-oncogene down-regulates the rat alpha-fetoprotein promoter in HepG2 hepatoma cells without binding to DNA. 753 66


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