UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase; EC 2.7.1.68), the second ATP-utilizing enzyme of 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in the rat in a spectrum of transplantable solid hepatomas of different growth rates and in normal tissues of high and low cell renewal rates. In a standard isotopic method developed for the assay, the enzyme activity was linear with time for 4 min and proportional with protein concentration over a range of 0.05 to 1 mg per 0.135-ml reaction mixture. The apparent Km for the substrate PIP (phosphatidylinositol 4-phosphate) and for ATP and Mg2+ in normal liver were 0.06, 0.5, and 4.2 mM, respectively, and in rapidly growing hepatoma 3924A, 0.08, 0.7, and 7.1 mM. The kinase activity in adult Wistar rat liver was 0.046 +/- 0.003 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, PIP kinase activity increased 3.3-9.7-fold, and in hepatoma 3924A, it was elevated 45-fold over that of normal liver. When hepatoma 3924A cells were plated and expressed their proliferative program, enzyme activity increased 4.3-fold in mid-log phase. To further clarify the linkage between PIP kinase activity and proliferation, enzyme activity was determined in rat organs of high and low cell renewal capacity. The PIP kinase activity in rat thymus, bone marrow, spleen, and testes was 5.4-, 6.3-, 4.8- and 4.3-fold higher, respectively, than in normal rat liver; in lung, brain, skeletal muscle, renal cortex, and heart, the activities were low. In all tissues examined, the activity of PIP kinase was 4.6 to 18% of that of phosphatidylinositol kinase. Since enzymes of crucial significance frequently have short half-lives, the decay rates of PIP kinase were examined in liver, bone marrow, and hepatoma 3924A in rats injected with cycloheximide, which inhibits protein biosynthesis. In cycloheximide-treated animals, PIP kinase had the shortest decay rate (t1/2 = 0.12 h) in comparison with eight enzymes of purine and pyrimidine biosynthesis of rat bone marrow (t1/2 = 0.6 to 4.3 h). In liver and solid hepatoma 3924A, the activity of PIP kinase was degraded less rapidly (t1/2 = 5 h). The relationship of PIP kinase activity with proliferation and transformation is apparent in the high activity in thymus, bone marrow, spleen, and testes and in the increased activities in the rat hepatomas of different growth rates. The coordinate increases in phosphatidylinositol and PIP kinase activities suggest that the capacity for signal transduction is heightened in cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): a proliferation- and malignancy-linked signal transduction enzyme. 792 99

We have previously demonstrated (M. Stubbs, Z. M. Bhujwalla, G. M. Tozer, L. M. Rodrigues, R. J. Maxwell, R. Morgan, F. A. Howe, and J. R. Griffiths, NMR Biomed., 5: 351, 1992) that the intracellular pH (pHi) of several rat tumors is higher (> pH 7.0) than that of the tumor extracellular fluid (pHe), in contrast to normal tissues (e.g., liver) in which pHi is lower than pHe. In this paper we confirm a pHe of 6.8 +/- 0.07 (SEM) in Morris hepatoma 9618a by an independent method and report the tissue content of other ions by both 31P magnetic resonance spectroscopy and by conventional analysis in hepatomas and livers in rats. Compared with liver, tissue Na+ was 2-fold higher and tissue K+ was lower. Tissue Ca2+ was 8-fold higher (7.4 +/- 4.3 mumol/g wet weight) and tissue Pi was 2-fold higher (8.5 +/- 1.3 mumol/g wet weight) suggesting the presence of insoluble calcium phosphate. Cl- was unchanged (approximately 40 mumol/g wet weight), whereas HCO3- was lower in the hepatoma (12.4 +/- 0.83 compared to 15.5 +/- 0.76 mumol/g wet weight). Total tissue Mg2+ was similar in both tissues, but free [Mg2+] (calculated by two different methods) was approximately 5-fold lower in the hepatoma. The ATP values were 3.5-fold and [NAD]/[NADH] 9-fold lower in the hepatoma. The results are compatible with the hypothesis that the chronic partial hypoxia of tumor tissue involves changes in the linked equilibria of many ions and metabolites and may help explain such pathologies as calcification.
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PMID:Metabolic consequences of a reversed pH gradient in rat tumors. 803 32

1. The distribution of control of the rate of state 3 respiration of AS-30D hepatoma mitochondria was determined. 2. The ATP/ADP carrier (flux control coefficient, Ci = 0.70) and the ATP synthase (Ci = 0.19-0.32) were the only steps that exerted significant control on the phosphorylating flux supported by either glutamate+malate, pyruvate+malate, or succinate+rotenone. This is in contrast to liver mitochondria where the control is distributed between several steps. 3. It is suggested that this pattern of control of phosphorylation in hepatoma mitochondria is a consequence of a lower content of adenine nucleotides or a higher content of Mg2+.
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PMID:Control of oxidative phosphorylation in AS-30D hepatoma mitochondria. 809 69

The activity of 1-phosphatidylinositol 4-kinase (EC 2.7.1.67), the first committed ATP-utilizing enzyme of inositol 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in a spectrum of rat hepatomas of different growth rates, in sarcoma, and in normal tissues of high cell renewal rates which include differentiating and regenerating liver. A standard isotopic method was developed to measure the enzymic activity in crude particulate extracts. In this assay, the enzyme activity was linear with time for 2 min and proportional with protein concentrations over a range of 0.1 to 1.0 mg per 0.1 ml reaction mixture. The optimum pH for both liver and hepatoma enzyme was 7.4. The apparent Km values of the kinase for ATP, Mg2+, and the substrate phosphatidylinositol in normal liver were 0.03, 10, and 0.2 mM, respectively, and in rapidly growing hepatoma 3924A 0.01, 0.1, and 5.3 mM. The kinase activity in adult rat livers was 0.3 to 0.5 +/- 0.01 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, kinase activity increased 5.3- to 7.6-fold, and in rapidly proliferating hepatoma 3924A, it was elevated 28.5-fold over that of normal liver. In rat sarcoma, kinase activity was 13.2-fold higher than in normal muscle. To clarify further the linkage between kinase activity and proliferation, enzymic activity was determined in rapidly growing rat tissues. The kinase activity in rat thymus, bone marrow, spleen, and testis increased 8.4-, 7.6-, 5.6- and 5.6-fold, respectively, over the values of normal rat liver; by contrast, in skeletal muscle, liver, heart, and renal cortex, the activities were low. In the rapidly growing neonatal rat liver and in 24-h regenerating liver, activities were 3.4- and 3.0-fold higher than in the adult resting liver. From this study, the relationship of 1-phosphatidylinositol 4-kinase activity with transformation and cell proliferation is clearly apparent in the markedly increased activity in transplantable hepatomas of different growth rates and in sarcoma and is further emphasized by the high activity observed in newborn and regenerating liver and in thymus, bone marrow, spleen, and testis. Since the kinase activity is linked with proliferation and malignancy, it may well be a sensitive target for chemotherapy.
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PMID:1-Phosphatidylinositol 4-kinase: an enzyme linked with proliferation and malignancy. 816 87

The hepatocyte has an organic anion transport system that recognizes compounds such as bilirubin and sulfobromophthalein. These anions circulate bound tightly to albumin from which they are extracted rapidly by hepatocytes by an electroneutral process that requires extracellular inorganic anions such as Cl- for activity. Transport activity is reduced by depletion of intracellular ATP, but whether ATP interacts directly with this transporter is not known. In this study, the influence of extracellular ATP on the hepatocyte organic anion transport mechanism has been characterized. In the presence of 2.5 mM Ca2+ and 2 mM Mg2+, initial uptake of [35S]sulfobromophthalein was reduced by 50% at 1 mM ATP. In the absence of divalent cations sensitivity to ATP was 10-fold greater. Other nucleotides including UTP, CTP, GTP, ADP, AMP, and AMP-PCP (adenosine 5'-(beta,gamma-methylene)triphosphate) were inactive. Decreased transport activity was rapidly reversible, was non-competitive with respect to ATP, did not require ATP hydrolysis, and did not correlate with P2y purinergic receptor activity. Differential activity of ATP on sulfobromophthalein transport in the presence and absence of divalent cations was not due to ecto-ATPase activity but rather to alteration in [ATP4-]. Although an ATP4- receptor in macrophages mediates increased cellular permeability, reduced organic anion permeability is seen in hepatocytes. This effect is not seen in the hepatoma cell line HepG2. Modulation of activity of the organic anion transporter by extracellular ATP may have important pathophysiological consequences in conditions resulting in liver cell injury.
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PMID:Extracellular ATP4- modulates organic anion transport by rat hepatocytes. 834 Mar 70

We previously reported the detection of novel O-linked sugar chains classified as being of the glucosyl-O-serine type [Hase et al. (1988) J. Biochem. 104, 867-868]. The sugar chains are a disaccharide (Xyl alpha 1-3Glc) and a trisaccharide (Xyl alpha 1-3Xyl alpha 1-3 Glc) linked to serine residues in epidermal growth factor-like domains of human and bovine blood coagulation factors. The structures of these sugar chains suggested the presence of an alpha 1-->3xylosyltransferase for their biosynthesis. We report here on the detection of alpha 1-->3xylosyltransferase activity which catalyzes the transfer of xylose to Xyl alpha 1-3Glc in the human hepatoma cell line HepG2. We employed pyridylaminated Xyl alpha 1-3Glc as a fluorescent acceptor and UDP-D-Xyl as a donor. The reaction product was purified by reversed-phase HPLC, and the structure of the transfer product isolated was confirmed to be pyridylaminated Xyl alpha 1-3Xyl alpha 1-3Glc by Smith degradation, mass spectrometry, and alpha- and beta-xylosidase digestions. The apparent K(m) value for pyridylaminated Xyl alpha 1-3Glc was 52 mM and for UDP-D-Xyl 0.28 mM. Optimum pH was 7.2. The enzyme was inactivated by addition of EDTA, and its activity was restored by addition of Mn2+ and Mg2+. These results indicate the presence of a novel enzyme which is able to transfer xylose to Xyl alpha 1-3Glc, forming Xyl alpha 1-3Xyl alpha 1-3Glc in human cells.
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PMID:Detection of UDP-D-xylose: alpha-D-xyloside alpha 1-->3xylosyltransferase activity in human hepatoma cell line HepG2. 898 69

NS5A derived from a hepatitis C virus (HCV) genotype 1b isolate has previously been shown to undergo phosphorylation on serine residues (T. Kaneko, Y. Tanji, S. Satoh, M. Hijikata, S. Asabe, K. Kimura, and K. Shimotohno, Biochem. Biophys. Res. Commun. 205:320-326, 1994). In this report, phosphorylation of NS5A derived from HCV isolates of the 1a and distantly related 2a genotypes is demonstrated. Phosphoamino acid analysis of NS5A from the 1a isolate indicated that phosphorylation occurs predominantly on serine, with a minor fraction of threonine residues also being phosphorylated. NS5A phosphorylation was observed in diverse cell types, including COS-1, BHK-21, HeLa, and the hepatoma cell line HuH-7. Phosphorylation of a glutathione S-transferase (GST)/HCV-H NS5A fusion protein was also demonstrated in an in vitro kinase assay. This activity seemed to be highest when the pH of the reaction was neutral or slightly alkaline and displayed a preference for Mn2+ over Mg2+, with an optimum concentration of approximately 10 mM Mn2+. Somewhat surprisingly, in vitro phosphorylation of NS5A was inhibited by the addition of > or = 0.25 mM Ca2+ to reaction buffer containing Mn2+ and/or Mg2+. Comparison of phosphopeptide maps of NS5A phosphorylated in vitro and in cultured cells showed that most of the phosphopeptides comigrated, suggesting that one or more kinases involved in NS5A phosphorylation in vivo and in vitro are the same. The effects of various kinase inhibitors on NS5A phosphorylation were consistent with a kinase activity belonging to the CMGC group of serine-threonine kinases. The development of an in vitro kinase assay for NS5A phosphorylation should facilitate identification of kinase(s) responsible for its phosphorylation and of phosphorylation sites which may influence the function of NS5A in HCV propagation.
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PMID:Phosphorylation of the hepatitis C virus NS5A protein in vitro and in vivo: properties of the NS5A-associated kinase. 931 91

Direct exposure of human hepatoma cell line SMMC-7721 to hydrogen peroxide (H2O2) can induce apoptosis. Apoptosis induced by H2O2 was inhibited by cycloheximide, actinomycin D, 3-aminobenzamide, EGTA or Zn2+. H2O2 can increase the level of intracellular Ca2+, downregulate GSH levels, slightly induce lipid peroxidation, and lead to change in the ratio of reduced ion components to oxidized ion components of cells. Analysis of flow cytometry indicates that H2O2 decreases the level of Bcl-2. The data indicate that H2O2-induced apoptosis requires new mRNA and protein syntheses; H2O2 can activate Ca2+/Mg2+-dependent endonuclease leading to internucleosomal DNA fragmentation and activation of poly (ADP-ribose) polymerase interfering with the energy metabolism of the cell. The H2O2 downregulation of GSH may be more important for apoptosis than H2O2 induction of lipid peroxidation, and the H2O2 induced changes in redox status of the cell may be among the original events which lead up to other biochemical changes.
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PMID:Hydrogen peroxide induces apoptosis in human hepatoma cells and alters cell redox status. 1082 69

AS-30D hepatoma cells, a highly oxidative and fast-growing tumor line, showed glucose-induced and fructose-induced inhibition of oxidative phosphorylation (the Crabtree effect) of 54% and 34%, respectively. To advance the understanding of the underlying mechanism of this process, the effect of 5 mM glucose or 10 mM fructose on the intracellular concentration of several metabolites was determined. The addition of glucose or fructose lowered intracellular Pi (40%), and ATP (53%) concentrations, and decreased cytosolic pH (from 7.2 to 6.8). Glucose and fructose increased the content of AMP (30%), glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-bisphosphate (15, 13 and 50 times, respectively). The cytosolic concentrations of Ca2+ and Mg2+ were not modified. The addition of galactose or glycerol did not modify the concentrations of the metabolites. Mitochondria isolated from AS-30D cells, incubated in media with low Pi (0.6 mM) at pH 6.8, exhibited a 40% inhibition of oxidative phosphorylation. The data suggest that the Crabtree effect is the result of several small metabolic changes promoted by addition of exogenous glucose or fructose.
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PMID:Multisite control of the Crabtree effect in ascites hepatoma cells. 1129 71

Mitochondrial ADP-ribosylation leads to modification of two proteins of approximately 26 and 53 kDA: The nature of these proteins and, hence, the physiological consequences of their modification have remained unknown. Here, a 55 kDa protein, glutamate dehydrogenase (GDH), was established as a specific acceptor for enzymatic, cysteine-specific ADP-ribosylation in mitochondria. The modified protein was isolated from the mitochondrial preparation and identified as GDH by N-terminal sequencing and mass spectrometric analyses of tryptic digests. Incubation of human hepatoma cells with [14C]adenine demonstrated the occurrence of the modification in vivo. Purified GDH was ADP-ribosylated in a cysteine residue in the presence of the mitochondrial activity that transferred the ADP-ribose from NAD+ onto the acceptor site. ADP- ribosylation of GDH led to substantial inhibition of its catalytic activity. The stoichiometry between incorporated ADP-ribose and GDH subunits suggests that modification of one subunit per catalytically active homohexamer causes the inactivation of the enzyme. Isolated, ADP-ribosylated GDH was reactivated by an Mg2+-dependent mitochondrial ADP-ribosylcysteine hydrolase. GDH, a highly regulated enzyme, is the first mitochondrial protein identified whose activity may be modulated by ADP-ribosylation.
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PMID:Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in mitochondria. 1135 Sep 29

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