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)

Partial purification of DNA methylase from Novikoff rat hepatoma cells is described. Contamination with other proteins persists although the enzyme preparation has a high specific activity and is purified 980-fold over homogenate activity. Evidence suggests, but does not prove, that there may be more than one species of DNA methylase in these cells. The enzyme has two broad pH optima at pH 7.0 and 7.5 and most readily methylates heterologous denatured DNAs although complex reaction kinetics indicate that native DNAs may eventually be methylated to an equal or greater level. The preparation of undermethylated DNA from Novikoff cells is also described. Undermethylated homologous DNA is an 85-fold greater acceptor of methyl groups than fully methylated Novikoff cell DNA. In contrast to other DNA substrates, the enzyme preparation methylates native undermethylated homologous DNA at a 3.5-fold greater than denatured undermethylated homologous DNA.
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PMID:S-adenosylmethionine: DNA-cytosine 5-methyltransferase from a Novikoff rat hepatoma cell line. 17 25

The possibility that carcinogens may affect methylase-mediated methylation of replicating DNA was investigated. A system eminently suitable for this purpose is liver regenerating after partial hepatectomy, as one injection of dimethylnitrosamine (DMN) given during the ensuing period of increased DNA synthesis induces hepatocellular carcinoma. Methylation of DNA by DNA methylase normally occurs only in proportion to DNA synthesis. Therefore simultaneous measurements were made of synthesis (incorporation of [14C]adenine into DNA adenine, or of d[5-3H]cytidine into DNA cytosine), and of methylation (incorporation of [methyl-3H]methionine into 5-methylcytosine of DNA) in liver regenerating after partial hepatectomy. After treatment with DMN, the ratio of methylation: synthesis remained within the normal range. Methyl methanesulphonate (MMS), a compound which damages DNA in regenerating liver in a similar but not identical way to DMN and which does not induce tumors in liver even when given after partial hepatectomy, caused an increase in methylation in relation to synthesis. These experiments therefore do not support the view that altered DNA methylase activity is involved in carcinogenesis.
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PMID:Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine and methyl methanesulphonate on liver regenerating after partial hepatectomy. IV. Effect on methylase-mediated methylation of DNA. 47 54

O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which plays an important role in chemotherapy, mutagenesis, and carcinogenesis. The specific activity of MGMT in female rat liver can be induced by approximately 20-fold by treatment of the rats with gamma-irradiation. Maximum response occurred 48 h after 15 Gy irradiation. MGMT levels in male rats were induced by only 3-fold. MGMT activity was also induced by irradiation of rat hepatoma H4IIE cells with a 3-fold increase noted after treatment with 3 Gy. Northern analysis and nuclear run-on assays indicated that the induction of MGMT was regulated at the transcriptional level. The radiation-mediated increase in MGMT was blocked by H7, a protein kinase inhibitor, but not by H89, an inhibitor of protein kinase A. Hydroxyl radicals may play a role in the induction mechanism since dimethyl sulfoxide, a radical scavenger, blocked the radiation-mediated increase in MGMT. MGMT activity was also increased by treatment of the cells with H2O2, in accordance with the involvement of activated oxygen species in the induction of MGMT. Finally, the addition of cycloheximide, an inhibitor of protein synthesis, prior to but not after irradiation, abolished the increase in MGMT activity.
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PMID:Irradiation-induced expression of O6-methylguanine-DNA methyltransferase in mammalian cells. 137 30

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

Activity of DNA methylase and DNA methylation level were measured from normal mouse liver, mouse liver charged with H22a ascitic hepatoma and H22a ascitic hepatoma cell by measuring incorporation of H3-methyl. S-Adenosyl-3H-methyl-methionine (3H-SAM) was used as methyl donor. DNA methylation level of different cells were measured by HP-LC. DNA methylase activity and DNA methylation level of H22a ascitic hepatoma, mouse liver charged with H22a ascitic hepatoma are lower than normal mouse liver. Treatments of antitumor drugs lead to a rising of DNA methylase activity of tumor cell, however, the DNA methylation level of tumor cell has not rised after such treatments.
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PMID:[Studies on DNA methylation in transformed mouse liver cells]. 262 95

We have characterized in the accompanying paper (P. Herbomel, A. Rollier, F. Tronche, M.-O. Ott, M. Yaniv, and M. C. Weiss, Mol. Cell. Biol. 9:4750-4758, 1989) six different elements in the albumin promoter. One of them, the proximal element (PE), is the binding site for a strictly liver specific factor, APF/HNF1. This binding site contains a bacterial DAM DNA methylase methylation target sequence which, when methylated, decreases the affinity of the protein for this element. When the different albumin promoter constructions were prepared in an Escherichia coli deoxyadenosine methylase-negative strain, the respective contributions of the elements to the overall promoter activity were strikingly different. An intact proximal element plus the TATA box gave almost full transcriptional activity in transient transfection experiments and only in differentiated hepatoma cells of line H4II, whereas the distal elements (distal element III [DEIII], the NF1-binding site DEII, and the E/CBP-binding site DEI) had become essentially dispensable. Mutations affecting the CCAAT box showed only a two- to threefold decrease. When PE was methylated, mutated, or replaced by the homologous element from the alpha-fetoprotein gene, activity in the context of the short promoter (PE plus the TATA box) was abolished. However, activity was restored in the presence of the upstream elements, showing that cooperation with factors binding to the CCAAT box and distal elements favors the functional interaction of the liver-specific APF/HNF1 factor with lower-affinity binding sites.
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PMID:The rat albumin promoter: cooperation with upstream elements is required when binding of APF/HNF1 to the proximal element is partially impaired by mutation or bacterial methylation. 268 64

DNA methylation in eukaryotic cells is a post-replicative process involving the transfer of methyl groups from S-adenosyl-L-methionine to the 5 position of cytosine residues through the action of DNA (cytosine-5-)-methyltransferase (DNA-methylase). There are two types of methylation within the cell: a maintenance methylation and a de novo methylation. Its major function is the maintenance methylation of hemimethylated sites after replication in order to preserve the pattern from one generation to the next. Nevertheless DNA-methylase is also able to transfer methyl groups to unmethylated sites in various substrates in a de novo reaction. Male Sprague-Dawley rats have a low specific activity of liver maintenance DNA-methylase and are sensitive to the toxic and carcinogenic effects of N-hydroxy-N-acetylaminofluorene (N-OH-AAF). Female Sprague-Dawley rats, on the contrary, have a 4-5 times higher maintenance DNA-methylase activity and are 6-7 times less sensitive to this carcinogenic effect. Their de novo DNA-methylase activity is the same. When female Sprague-Dawley rats are treated with N-OH-AAF their total DNA-methylase activity diminishes. On the contrary, the maintenance DNA-methylase activity of male Sprague-Dawley rats increases, whereas the de novo activity remains constant. In the spleen, which is not a target organ, the total DNA-methylase activity decreases after injection of N-OH-AAF. These variations of DNA-methylase activity are due to a variation of extractable nuclear DNA-methylase. When Swiss mice, which are not sensitive to the carcinogenic effect, are treated with N-OH-AAF, their total DNA-methylase activity decreases. A decrease of DNA-methylase activity in response to this carcinogen seems to be correlated to the resistance of the animals in developing a hepatocarcinoma.
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PMID:Variations of DNA-(cytosine-5-)-methyltransferase activities after administration of N-hydroxy-N-aminofluorene to Sprague-Dawley rats. 318 39

DNA methyltransferase (DMase) was purified 700- and 1002-fold from normal rat liver and transplantable hepatocellular carcinoma 252 (THC 252) nuclei, respectively, using a four-step procedure that included chromatography on phosphocellulose, hydroxylapatite, DEAE-Sephacel and gel filtration on AcA 34. The enzymes had identical characteristics: pI = 7.4-7.6; Mr = 280 000 by gel filtration; preference for methylating double-stranded over single-stranded DNA and hemimethylated over unmethylated DNA templates; and apparent km of 10 microM for dinucleotide units in poly(dC-dG) and 0.5 microM for S-adenosylmethionine (SAM). Thermal inactivation profiles and sulfhydryl group alkylation inhibition curves for fraction III produced very similar single-transition curves, suggesting the presence of a single-functional enzyme species that is indistinguishable between normal and tumor tissue. Single-value Michaelis-Menten kinetics were obtained for fraction IV enzymes with respect to the concentration of SAM and dinucleotide units in poly(dC-dG), suggesting the absence of isozymic or multiple forms of DMase in normal and malignant liver tissues.
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PMID:Indistinguishable physical and catalytic properties of DNA methyltransferase from normal rat liver and a transplantable rat hepatocellular carcinoma. 400 74

The status of DNA methylation, as measured by the 5-methylcytosine content of nuclear DNA, was examined in normal livers and in chemically induced or spontaneous primary hepatocellular carcinoma (PHC) arising in three strains of mice. The DNA from spontaneous tumors of genetic origin in C3H mice and also from acetylaminofluorene, chlordane, or 3'-methyl-4-dimethylaminoazobenzene-induced tumors in C57Bl and B6C3 mice was undermethylated compared to the levels in background and normal liver samples. The DNA methylase activities from normal liver, background liver, and PHC were assayed in C3H mice to determine whether the observed genomic undermethylation is related to a dysfunction of this enzyme and were compared to the rates of DNA synthesis in these tissues. Since DNA methylase levels from tumor nuclei were elevated compared to background, it is concluded that the undermethylation found in the tumor genomes of this system is not due to inactivation nor a significant deficiency of the activity of this enzyme relative to the demand in tumors for methylation of de novo synthesized DNA.
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PMID:DNA methylation and methylase levels in normal and malignant mouse hepatic tissues. 627 14

O6-Methylguanine-DNA methyltransferase activity, i.e., the capacity of cells to transfer the methyl group from O6-methylguanine in DNA to protein, was determined in 10 hepatoma cell lines, all derived from Reuber H35 hepatoma but differing in their status of differentiation. Methyltransferase activity of the six differentiated lines tested was at least 4-5 times higher than that of two dedifferentiated lines. The activity of the two poorly differentiated lines examined was low to intermediate. Some of the differentiated lines possessed methyltransferase activities comparable to those in hepatocytes freshly isolated from adult rat. The results suggest that certain differentiated hepatoma lines are capable of mimicking liver in the capacity for repair of O6-methylguanine lesions and in this respect may be useful as model systems for studying liver-specific effects of monofunctional alkylating agents.
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PMID:The capacity of rat hepatoma cell lines for O6-methylguanine-DNA repair correlates with their status of differentiation. 673 58


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