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 studied the pattern of histone acetylation in intact rat hepatoma tissue culture (HTC) cells, in isolated HTC nuclei, and in chromatin prepared from these cells. The results have been compared with the histone acetylation observed in a reconstituted in vitro system consisting of a variety of purified soluble nucleosomal substrates, [3H]acetyl-CoA, and one of two different purified histone N-acetyltransferases. Acetylase A, a highly purified nuclear enzyme, catalyzed the acetylation of 1) nucleosomally bound histones in the order H4 > H2a = H2b > H3, and 2) free histones in the order H4 > H3 > H2b > H2a. Acetylase B, a cytoplasmic enzyme, modified only free histone H4, and it failed to acetylate histones in nucleosomes. The pattern of histone acetylation obtained by in vitro reaction of purified nucleosomes with the purified nuclear acetylase A differed considerably from the corresponding patterns obtained either by acetate labeling of intact cells, or by the acetyl-CoA labeling of nuclei and crude preparations of nucleosomes, as catalyzed by endogenous chromatin-bound acetylase(s). The most striking difference was in the relative preference for acetylation of histone H4 versus acetylation of histone H3: with the purified acetylase, histone H4 in nucleosomes was acetylated to a much greater extent than was histone H3, whereas the reverse preference was found with the endogenous acetylase(s). This result suggests that either a second nuclear acetylase enzyme, or a separate cofactor for acetylase A, is required for histone H3 acetylation in vivo. In support of this view, we find that the acetylation of histones H4, H2a, and H2b in nuclei is inhibited by urea, salt, or N-ethylmaleimide treatments to a very different extent than is the acetylation of histone H3. By comparing n-butyrate-treated HTC cells with untreated cells, classes of nucleosomes specially accessible and inaccessible to acetylation can be distinguished (Cousens, L. S., Gallwitz, D., and Alberts, B. M. (1979) J. Biol. Chem. 254, 1716-1723). Both types of special nucleosomal reactivities were present in isolated nuclei, but were lost as nucleosomes were purified from these cells. OUr data thus suggest the existence of labile specificity factors or structures, which guide the acetylase(s) to restricted groups of otherwise similar nucleosomes in vivo.
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PMID:Comparative studies of histone acetylation in nucleosomes, nuclei, and intact cells. Evidence for special factors which modify acetylase action. 744 May 48

The basic nonhistone phosphoprotein 110/8.4 (M.W. X 10(-3)/pI) was found in 0.35 M NaCl nuclear extracts of four tumor tissues, i.e., fast-growing Novikoff hepatoma, Morris hepatoma 3924A, HeLa cells, and Namalwa cells; it was also found in fetal rat liver. This protein was not detected in normal or regenerating liver and thus may represent an "oncofetal" protein of potential interest as a cancer "marker." Protein 110/8.4 was purified approximately 4000- to 5000-fold under nondenaturing condition from 0.35 M NaCl nuclear extracts of Novikoff hepatoma cells or Namalwa cells by ammonium sulfate fractionation, calcium phosphate gel treatment, and phosphocellulose chromatography. Sodium dodecyl sulfate:polyacrylamide gel electrophoresis of the purified native protein revealed a single polypeptide chain with a molecular weight of approximately 110,000. The pI of the protein was estimated to be 8.4 by nonequilibrium pH gradient electrophoresis in 9 M urea; accordingly, this protein was designated 110/8.4. Amino acid analysis showed that Protein 110/8.4 had an acidic:basic amino acid ratio of 1.25 and a high lysine and serine content; approximately 20% of the serine residues were found to be phosphorylated. Hydrazinolysis indicated that the carboxyl-terminal amino acid was serine; the amino terminus appeared to be blocked. Binding of Protein 110/8.4 to DNA was studied by the nitrocellulose filter assay. High-affinity binding occurred at ionic strength equal to or below 0.15 M.
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PMID:Purification and characterization of a nuclear DNA-binding phosphoprotein in fetal and tumor tissues. 744 1

We have isolated a population of post-TGN secretory vesicles from hepatocytes. These vesicles of 100-150 nm diameter carry heparan sulfate proteoglycans. Secretory proteins (albumin, apo-lipoprotein E, fibrinogen) are sorted into different post-TGN secretory vesicles. A member of the ARF family of small GTP-binding proteins is associated with these vesicles. A unique peripheral membrane protein of these vesicles (VAPP14) was shown to exist also on the TGN. Brefeldin A leads to a dissociation of VAPP14 from the TGN. Antibodies against VAPP14 inhibit budding of proteoglycan containing vesicles from the TGN in a cell-free system. Inhibition occurred also in the presence of GTP-gamma-S. The same type of vesicles exists in H35 Reuber hepatoma cells.
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PMID:Sorting and budding of constitutive secretory vesicles in hepatocytes and hepatoma cells. 757 49

Two kinds of arginine deiminase (AD, EC 3.5.3.6) were purified from cell extracts of Mycoplasma arginini (a-AD) and Mycoplasma hominis (h-AD), and their enzymic properties and anti-tumor activities were compared. The a-AD enzyme strongly inhibited the growth of mouse hepatoma cell line MH134 in vitro, and its concentration required for 50% growth inhibition (IC50) was estimated to be about 10 ng/ml. The IC50 value of h-AD against the same cell line was estimated to be about 100 ng/ml, due to its low enzyme activity under the physiological pH condition, i.e., pH 7.4. These results show that the reaction pH profile of the a-AD was superior to that of the h-AD as an anti-tumor enzyme. Moreover, the effects of L-arginine metabolism-related substances on the anti-tumor activity of the a-AD were examined to study the growth-inhibitory mechanism of this enzyme. The addition of 2 or 4 mM L-arginine restored, in a dose-dependent manner, the growth of mouse MH134 hepatoma and Meth A fibrosarcoma cell lines that had been inhibited by 20 ng/ml of the a-AD. The addition of 2 or 4 mM L-ornithine, which is biosynthesized from L-arginine in the urea cycle and is the starting material in the polyamine-biosynthesis pathway, also partially restored it in a dose-dependent manner. These results indicate that the tumor cell growth inhibition caused by a-AD originates from the depletion of the essential nutrient L-arginine, and that the resulting block of the polyamine-biosynthesis pathway is involved in part in the inhibitory mechanism.
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PMID:Anti-tumor activity of arginine deiminase from Mycoplasma argini and its growth-inhibitory mechanism. 759 61

Effects of TMP-153, N-[4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl]-N'-(2,4-difluorophe nyl)urea, on intestinal and hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activities, cholesterol absorption and plasma cholesterol level in rats and hamsters were studied. TMP-153 has IC50 values of around 5-10 nM for the hepatic and intestinal ACAT from various animals. The most potent inhibition was observed in the intestinal ACAT from Golden hamsters (IC50 = 2.3 nM). The inhibition mode of TMP-153 was non-competitive for rat intestinal ACAT. TMP-153 inhibited cholesterol esterification both in human colonic adenocarcinoma cells, LS180, and in human hepatoma cells, HepG2 (IC50 = 150 nM and 330 nM, respectively). [14C]cholesterol and cold cholesterol absorption from the small intestine was markedly inhibited by oral administration of TMP-153 (1 mg/kg) without affecting lymph flow and triglyceride absorption. When the compound was given as a dietary admixture, plasma cholesterol was reduced in rats fed a cholesterol diet (ED50 = 0.25 mg/kg/day), but not in those fed a stock diet. On the other hand, TMP-153 showed more prominent hypocholesterolemic effect in Golden hamsters fed the stock diet (ED50 = 0.81 mg/kg/day) than in those fed the cholesterol diet (ED50 = 8.01 mg/kg/day). In hamsters fed the stock diet, TMP-153 markedly decreased the hepatic unesterified cholesterol in addition to esterified cholesterol content, but did not affect bile flow and the biliary secretion of bile acid and lipids. Different mechanisms for plasma cholesterol lowering by TMP-153 between rats and hamsters was discussed.
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PMID:TMP-153, a novel ACAT inhibitor, inhibits cholesterol absorption and lowers plasma cholesterol in rats and hamsters. 775 57

Functional and DNA binding analyses were used to investigate transcriptional regulation of liver arginase, a mammalian urea cycle enzyme with marked tissue specificity. Reporter constructs containing the proximal 111 bp of the gene from man and Macaca fascicularis showed over sixfold background activity in HepG2 hepatoma cells, which express significant levels of liver arginase, and 12-fold background activity in minimally expressing HEK cells. Longer constructs, active in both cell lines, showed greater activity in the liver cell line. The constructs showed no activity in arginase-negative NIH 3T3 fibroblasts. A 54-bp dyad insert present in the human sequence and absent in M. fascicularis did not affect function. DNA binding analyses localized multiple liver-specific complexes as well as complexes shared among cell types. Little binding was evident in fibroblast extracts. Despite liver-specific binding, there was no evidence of a strong liver-specific enhancer. HEK and NIH 3T3 nuclear extracts showed strikingly different patterns of DNA binding. These studies demonstrate that molecular regulation of liver arginase transcription is complex and that control mechanisms differ among tissue types.
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PMID:Functional and molecular analysis of liver arginase promoter sequences from man and Macaca fascicularis. 797 6

Liver-selective transcription of the gene for rat arginase, an ornithine cycle (urea cycle) enzyme, is induced by glucocorticoids in a delayed secondary manner; the mRNA induction by the hormones requires de novo protein synthesis, and is preceded by a time lag of several hours. We searched for a DNA element mediating the glucocorticoid induction of the arginase gene with a transient transfection system using hepatoma cell lines. Within the 233-base pair region that is located 11 kilobases downstream from the transcription start site and that spans the junction of intron 7 and exon 8, we detected an enhancer element that is glucocorticoid-responsive and hepatoma cell-selective. The time course of the glucocorticoid induction through this enhancer element was delayed compared to that through the primary glucocorticoid-responsive mouse mammary tumor virus promoter. Footprint analysis revealed four protein-binding sites in this enhancer region. In gel retardation analysis, each site exhibited a complicated profile characterized by a number of shifted bands, some of which were tissue-selective and others ubiquitous. Gel shift competition and antibody supershift/inhibition analysis demonstrated that two of the four sites are recognized by members of the CCAAT/enhancer binding protein (C/EBP) family, some of which are liver-enriched.
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PMID:The delayed glucocorticoid-responsive and hepatoma cell-selective enhancer of the rat arginase gene is located around intron 7. 858 32

Carcinogenesis is a multistage process consisting of the three distinct stages: initiation, promotion, and progression. The initiation-promotion-progression (IPP) protocol models these stages and establishes a method whereby agents that possess a carcinogenic risk can be classified as acting primarily at any one or combination of these stages. In one hepatocarcinogenesis IPP protocol, rats were initiated with 10 mg of diethylnitrosamine/kg body wt at 5 days of age, started on the promoting agent phenobarbital at weaning, subjected to a 70% partial hepatectomy at 6 months, and, at the peak of proliferation, given a putative progressor agent, ethylnitrosourea ([ENU] 100 mg/kg, ip) or hydroxy-urea ([HU] 3 x 150 mg/kg, ip). Administration of the promoting agent was discontinued after the progressor agent was given, and the rats were sacrificed 6 months later. The number and volume fraction of promoter-independent (growth in the absence of the promoting agent) altered hepatic foci (AHF) were then determined by quantitative stereology. The number of such AHF increased with either ENU or HU treatment compared with animals not given a progressor agent. In addition, hepatocytes isolated from animals subjected to an IPP regimen with ENU as the progressor agent exhibited a greater degree of chromosomal breakage and aneuploidy than animals not given a second initiator. A variation of this model, in which the promoting agent was maintained after administration of the progressor agent, was examined. In this IPP model, the number of heterogeneous AHF (foci-in-foci) increased after application of the progressor agent (ENU or HU). An increased incidence of hepatocellular carcinoma was also observed in animals subjected to the IPP protocol when promotion was maintained until sacrifice. Thus, the characteristics of progression--increased chromosomal damage, aneuploidy, growth of AHF in the absence of continued tumor promotion, the presence of foci-in-foci, and an increased incidence of malignant neoplasia--have been used as end points for the demonstration of progressor activity by ENU. In addition, the potential progressor activity of HU and benzene has been demonstrated with the IPP model of rat hepatocarcinogenesis.
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PMID:The initiation-promotion-progression model of rat hepatocarcinogenesis. 809 13

The infectibility of the regenerating rat liver by ecotropic retroviruses was studied relative to the expression of the gene coding for the ecotropic retrovirus receptor (Ecor) that functions as a cationic amino acid transporter. It is known that the gene for the receptor is expressed in primary hepatocytes and hepatoma cells but is absent in adult liver cells. Isolation of a 2.85-kb cDNA for the rat Ecor suggested that the rat viral receptor is 97% homologous to the mouse viral receptor and that it contains the envelope-binding domain that determines the host range of ecotropic murine retroviruses. This explains the efficient infection of rat cells by ecotropic retroviruses. Since cell division is required for liver cells to be infected, we determined the susceptibility of the regenerating rat liver to infection at different time points after partial hepatectomy (0 to 24 h) in relation to the presence of receptor mRNA. Infection of the liver occurred only when the liver was exposed to virus 4 h after partial hepatectomy. This time course of infection paralleled expression of the gene for the Ecor, which was rapidly induced between 2 and 6 h during liver regeneration. However, expression of the dormant receptor gene in quiescent liver cells can be induced by insulin, dexamethasone, and arginine, indicating that cell division is not required for expression of the receptor gene in liver cells. A diet high in carbohydrate (low in protein) significantly increased the concentration of receptor mRNA in liver cells, indicating that hormones play a role in the regulation of expression of this gene in vivo. We conclude that the gene for the viral receptor is expressed in the regenerating and quiescent liver when the urea cycle enzymes are down regulated. The infection of the regenerating rat liver by ecotropic retroviruses at the time point of expression of the receptor gene supports the requirement of expression of this transporter for infection.
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PMID:Hormonal regulation of the gene for the type C ecotropic retrovirus receptor in rat liver cells. 810 22

The most early cirrhosis is observed in newborns with neonatal hemachromatosis. Early cirrhosis occurs in hereditary tyrosinemia type I, peroxisomal diseases and glycogen storage disease (type IV). In Wilson's disease, a case complicated with cirrhosis was reported in a 4-year-old patient. Slowly progressive cirrhosis is seen in patients with familial progressive intrahepatic cholestasis. Focal biliary cirrhosis is found in cystic fibrosis of the pancreas. Moreover, many other metabolic disorders, except for urea cycle disorders, are occasionally or rarely complicated with cirrhosis. Early diagnosis and proper management could prevent the development of cirrhosis in patients with galactosemia, hereditary fructose intolerance, etc. The occurrence of hepatoma must be monitored in these patients. Liver transplantation is indicated in a part of the patients with cirrhosis.
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PMID:[Liver cirrhosis in metabolic disorders]. 811 97


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