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)

It has been proposed that hexokinase bound to mitochondria occupies a preferred site to which ATP from oxidative phosphorylation is channeled directly (Bessman, S. (1966) Am. J. Medicine 40, 740-749). We have investigated this problem in isolated Zajdela hepatoma mitochondria. Addition of ADP to well-coupled mitochondria in the presence of an oxidizable substrate initiates the synthesis of glucose 6-phosphate via bound hexokinase. This reaction is only partially inhibited by oligomycin, carboxyatractyloside, carbonyl cyanide m-chlorophenylhydrazone (CCCP) or any combination of these, suggesting a source of ATP in addition to oxidative phosPhorylation. This source appears to be adenylate kinase, since Ado2P5, an inhibitor of the enzyme, suppresses hexokinase activity by about 50% when added alone or suppresses activity completely when added together with any of the inhibitors of oxidative phosphorylation. Ado2P5 does not uncouple oxidative phosphorylation nor does it inhibit ADP transport (state 3 respiration) or hexokinase. The relative amount of ATP contributed by adenylate kinase is dependent upon the ADP concentration. At low ADP concentrations, glucose phosphorylation is supported by oxidative phosphorylation, but as the adenine nucleotide translocator becomes saturated the ATP contributed by adenylate kinase increases due to the higher apparent Km of the enzyme. Under conditions of our standard experiment ([ADP] = 0.5 mM), adenylate kinase provides about 50% of the ATP used by hexokinase in well-coupled mitochondria. In spite of this, externally added ATP supported higher initial rates of hexokinase activity than ADP. Our findings demonstrate that oxidative phosphorylation is not a specific or preferential source of ATP for hexokinase bound to hepatoma mitochondria. The apparent lack of a channeling mechanism for ATP to hexokinase in these mitochondria is discussed.
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PMID:Adenylate kinase is a source of ATP for tumor mitochondrial hexokinase. 299 May 72

The susceptibility of rat liver tissue to oxidative stress during its neoplastic transformation was analyzed by both qualitative and quantitative measurements of the carbonyl products of lipid peroxidation. Diethylnitrosamine was used as initiating agent of hepatocarcinogenesis and lipid peroxidation levels were monitored in the homogenates from normal liver, hyperplastic nodules and tumour, incubated in the presence or in the absence of ascorbate or adenosine diphosphate-iron complex. While the basal levels of lipid peroxidation in the three experimental conditions were found to be quite similar, in the presence of the pro-oxidant stimulus a remarkable reduction in aldehyde production was shown not only by the hepatoma tissue but also by the preneoplastic nodules.
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PMID:Resistance to oxidative stress by hyperplastic and neoplastic rat liver tissue monitored in terms of production of unpolar and medium polar carbonyls. 309 Oct 76

The endogenous poly(ADP-ribosyl)--nonhistone protein conjugates were isolated from dimethyl-sulfate-treated rat hepatoma AH 7974 cells using aminophenylboronic-acid--agarose chromatography. Seven major components could be discerned on dodecyl sulfate gels (molecular mass 43, 60, 66, 86, 100, 110 and 170 kDa) while control cells indicated only slight staining at above 200 kDa. The most abundant conjugate formed in response to alkylation damage was further purified using preparative gel electrophoresis and identified on the basis of its intrinsic enzymic activity as automodified poly(APD-ribose) synthase. In addition, topoisomerase I activity was found associated with a 60-kDa peptide. ADP-ribosylated endonuclease and actin were not detect-able. The purified conjugate fraction contained maximally 8.8 nmol/mg ADP-ribose and 7.9 nmol/mg oligo(ADP-ribose) with a mean chain length of 2.3 residues. The modifying (ADP-ribosyl)n groups were attached to its acceptors by a hydroxylamine-insensitive bond and had practically no effect on the DNA affinity of either poly(ADP-ribose) synthase or topoisomerase I.
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PMID:Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells. 312 14

Mitogens evoke many alterations in gene expression in eukaryotic cells. Genes which are activated rapidly and transiently, that are evolutionarily conserved and whose induction is shared by diverse cell types when exposed to different growth stimuli are likely to be of critical importance in transducing mitogenic signals and regulating cellular proliferation. c-myc and c-fos are the only known genes fulfilling these criteria. We report on the molecular cloning of a novel early growth response (egr) gene which also satisfies these conditions. In response to serum, its 3.7 kb mRNA is induced dramatically in mouse fibroblasts reaching a peak level at about 30 minutes that is ten times higher than the maximal value attained by c-fos mRNA. This transcript is induced by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate and is "superinduced" by serum and cycloheximide together. Importantly, the gene is highly induced by different mitogens in a wide array of cell types: insulin stimulated rat hepatoma cells, adenosine diphosphate treated monkey kidney epithelial cells, and phytohemagglutinin stimulated human peripheral blood lymphocytes. Given the many properties that this gene shares with c-myc and c-fos, it may play a key role in the control of cell growth and perhaps in oncogenesis.
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PMID:A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. 313 Jun 2

A model for studying the 31P NMR spectrum of rat skin without contribution from other tissue signals has been developed by creating a skin pedicle. 31P NMR spectra were obtained with a solenoidal coil, which was separated from the flank of the rat by a Faraday shield. Phosphomonoesters, inorganic phosphate (Pi) (1.63 +/- 0.12 mumols per g wet wt), phosphodiesters, phosphocreatine (PCr) (1.4 +/- 0.12 mumols per g wet wt) and ATP (1.35 +/- 0.22 mumols per g wet wt) were observed, superimposed on broader signals, probably due to phospholipids. Extracts of freeze-clamped pedicles contained concentrations of phosphorus metabolites similar to those seen by NMR. The exception was Pi which was twofold higher in the extract. The presence of the broader phospholipid contribution suggests that the signals did not arise solely from the panniculus carnosus muscle of rat skin, although this muscle was evident on histological examination of the pedicles. In extracts of normal rat skin levels of creatine, ATP, ADP and Pi were similar to those of pedicles, whereas PCr was about twofold higher. Signals from rat skin are likely to contribute to spectra of subcutaneous organs and tumours. Two kinds of rat hepatoma that contained no PCr frequently gave PCr signals from the overlying skin, whereas in three other subcutaneous tumours the contribution from skin was negligible.
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PMID:Phosphate metabolites in rat skin. 327 23

Lipoperoxidative damage caused by exposure of isolated hepatocytes or cultivated hepatoma cells to ADP-iron or to 4-hydroxynonenal induces the synthesis of some proteins which are different under these two conditions but are always a subset of the proteins induced in each type of cells upon heat-shock (heat-shock proteins). For at least one of these proteins (hsp 31), induced by 4-hydroxynonenal, the increase is dose-dependent and the effect of heat and the chemical seems to be additive. Lipoperoxidation may be implicated in the induction of some of the heat shock proteins, but reproduces only incompletely the response of protein synthesis typical of heat-shock conditions.
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PMID:Oxidative stress induces a subset of heat shock proteins in rat hepatocytes and MH1C1 cells. 337 79

Fundamental differences were previously discovered in the ADP-ribosylation of proteins from metaphase chromosomes and interphase nuclei of HeLa cells. The number of modified nonhistone species was found to be dramatically reduced for metaphase chromosomes. An investigation has therefore been made of factors which could influence, and therefore be responsible for, this change in ADP-ribosylation during the cell cycle. Modified proteins were detected by autoradiography of sodium dodecyl sulfate-polyacrylamide gels containing mitotic and interphase samples from permeabilized cells that had been incubated with [32P]NAD. Whole cells showed a difference between interphase and metaphase similar to that for isolated nuclei and chromosomes. Chromosome expansion, disruption of chromosomes or nuclei, DNA nicking, and cellular growth activity significantly changed the incorporation of 32P label. Inhibitors of protein, RNA, and DNA synthesis did not, however, greatly affect ADP-ribosylation. The pattern of labeled species was not altered by the presence of nonradioactive NAD, though the extent of labeling declined. The results were not artifactually due to the procedure used to arrest cells in mitosis. Similar results were found with Novikoff rat hepatoma cells, demonstrating that the difference between metaphase and interphase is not confined to HeLa cells.
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PMID:Factors influencing ADP-ribosylation differences between chromosomal proteins of interphase and metaphase HeLa cells. 349 64

A study was made of the effect of poly(ADP-ribosylation) of proteins on the formation and repair of single-strand DNA breaks in gamma-irradiated (50 Gy) permeable Zajdela ascites hepatoma cells permeabilized by the treatment with 0.05% triton X-100. Incubation of gamma-irradiated permeable cells in conditions promoting DNA synthesis and providing ADP-ribosylation (in the presence of 1 mM NAD) did not cause any substantial changes in the formation of single-strand DNA breaks and did not influence their repair.
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PMID:[Relation of the poly(ADP-ribosylation) of proteins to the formation and repair of DNA single-strand breaks in gamma-irradiated permeable Zajdela hepatoma cells]. 377 78

Starvation of the mouse hepatoma cell line Hepa for an essential amino acid (Trp, His, Leu, Ile or Phe) stimulated the incorporation of [3H]adenosine as ADP-ribose monomer into an 80,000-Mr protein, P80. Two-dimensional electrophoresis of Hepa proteins showed that P80 was the only protein labeled under starvation conditions. Time course experiments showed that the ADP-ribosylation of P80 was a consequence rather than the cause of reduced translational activity. Cycloheximide treatment and incubation at reduced temperatures also reduced the rate of protein synthesis and stimulated the ADP-ribosylation of P80. Starvation-dependent ADP-ribosylation of P80 was shown to occur in three other cell lines (Chang, Neuro-2a, and chick comb fibroblasts).
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PMID:Translational control of ADP-ribosylation in eucaryotic cells. 379 12

Lipid peroxidation has been found decreased in several hepatomas. The decline has been shown already at the level of preneoplastic nodules obtained after DEN treatment of rats. A substantial exception is represented by the hepatoma cell line MH1C1, deriving from a slightly deviated Morris tumor. Most of the described experiments estimated lipid peroxidation levels in terms of malonaldehyde production by the thiobarbituric acid test. It is now clear that this test does not account for several other aldehydes produced during lipid peroxidation. We now investigated by high performance liquid chromatography (HPLC) the whole range of non-polar aldehydes produced by tumor homogenates and by preneoplastic nodules both in basal conditions and after stimulation with ADP-iron or ascorbate. It was reduced in the preneoplastic nodules as well as in the DEN-induced hepatoma. The susceptibility to the prooxidant effect of ADP-iron or ascorbate was strongly decreased in all hepatomas as well as in preneoplastic nodules. It has been recently published that hepatoma cells are more susceptible than normal liver to the toxic action of aldehydes. This was attributed at least in part to the decreased activity of aldehyde dehydrogenases, as well as to their different distribution in tumor cells. A deeper study on aldehyde metabolism in hepatomas has shown that alcohol dehydrogenase and NADPH-aldehyde reductase also are markedly decreased in Yoshida hepatoma cells and the MH1C1 cell line. However, glutathione transferase, that can use hydroxynonenal as a substrate, is strongly decreased in Yoshida hepatoma cells but not in MH1C1 cells.
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PMID:New data on kinetics of lipid peroxidation in experimental hepatomas and preneoplastic nodules. 380 93


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