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)

In a prior report (Pike, L.M., Khym, J.X., Jones, M.H., Lee, W.H., and Volkin, E. (1980) J. Biol. Chem. 255, 3340-3347), it was observed that CTP synthesis and concomitant incorporation of CMP into RNA and dCMP into DNA were markedly reduced in cells cultured in the presence of cycloheximide and puromycin. Experiments described here with Novikoff hepatoma cells reveal that the purine biosynthetic pathway is similarly affected. When the cells are subjected to cycloheximide (30 or 60 microgram/ml) or puromycin (100 microgram/ml), there is a substantial reduction in the bioconversion of hypoxanthine, adenosine, and deoxyadenosine into guanylate compared to untreated cultures. Whereas synthesis (counts per min/nmol) of pool ATP was 70 to 100% of controls, that of pool GTP was 20 to 35% of controls. Incorporation of AMP into RNA was 40 to 60% of controls, but that of GMP was only 10 to 25% of controls. Incorporation of dAMP into DNA averaged 10% of controls, but that of dGMP was only 4% of controls. Synthesis of guanylates from formate by the de novo pathway was similarly reduced, but incorporation of guanosine, which enters via kinase action alone, was not disproportionately lowered. These results suggest that protein synthesis inhibitors cause a severely reduced availability of newly synthesized GTP and CTP as well as their deoxy counterparts, dGTP and dCTP, the proximal precursors for the synthesis of RNA and DNA. However, the nanomolar levels of all nucleoside triphosphates remain high, probably as a result of recycling of nucleic acid breakdown products. Thus, reduced synthesis of these compounds may restrict nucleic acid synthesis only if some sort of compartmentation leads to a limitation of these precursors at the site(s) of nucleic acid synthesis.
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PMID:Suppression of the biosynthesis of guanosine triphosphate by protein synthesis inhibitors. 741 Apr 14

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

The role of the GTP-binding regulatory protein (G-protein) Gi alpha 2 in vivo was explored using transgenic mice in which the alpha-subunit of Gi alpha 2 was suppressed by antisense RNA. Rat hepatoma FTO-2B cells provide an ideal test system for constructs employing the expression vector pPCK-AS, designed to express antisense RNA at birth under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. Cells transfected with the expression vector containing a sequence antisense to Gi alpha 2 (pPCK-ASGi alpha 2) displayed expression of RNA antisense to Gi alpha 2 that, like transcription of the PEPCK gene, was inducible by cyclic AMP. Expression of RNA antisense to Gi alpha 2 and suppression of the expression of Gi alpha 2, but not Gsa and Gi alpha 3, was observed in the transfected FTO-2B cells. BDF1 mice carrying the transgene displayed suppression of Gi alpha 2 in liver and fat, two targets for tissue-specific expression of the PEPCK gene. The loss of Gi alpha 2 in white adipocytes of transgenic mice resulted in 3.1-fold elevation of basal cyclic AMP accumulation. Cyclic AMP accumulation in response to stimulation by epinephrine (10 microM) was normal in adipocytes of transgenic mice, demonstrating no alteration in the stimulatory adenylylcyclase capacity in the Gi alpha 2-deficient cells. The inhibitory adenylylcyclase pathway, in sharp contrast, was severely blunted in response to challenge by the inhibitory A1-purinergic agonist, (-)R-N6-phenylisopropyladenosine. These studies illuminate a critical role of Gi alpha 2 in the inhibitory adenylylcyclase signaling pathway in vivo.
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PMID:Gi alpha 2 mediates the inhibitory regulation of adenylylcyclase in vivo: analysis in transgenic mice with Gi alpha 2 suppressed by inducible antisense RNA. 769 86

Epidermal growth factor (EGF) decreased the basal, and blocked the dibutyryl cyclic AMP (Bt2cAMP)-induced, expression of P-enolpyruvate carboxykinase (GTP) (PEPCK) and tyrosine aminotransferase (TAT) genes in both rat hepatocytes in primary culture and the FTO-2B hepatoma cell line. Treatment of hepatocytes with EGF in combination with phorbol ester (TPA) resulted in an additive decrease of PEPCK mRNA levels. Overnight pretreatment of hepatocytes with TPA, which is known to downregulate protein kinase C, abolished the TPA and reduced the EGF-mediated inhibition of PEPCK gene expression. These results suggested that EGF caused its effect, at least in part, through protein kinase C.
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PMID:Epidermal growth factor inhibits phosphoenolpyruvate carboxykinase gene expression in rat hepatocytes in primary culture. 809 29

Four full-length cDNA clones coding for preprocathepsin B were isolated from a human gastric adenocarcinoma cDNA library (AGS 1-6-30-1) and analyzed for possible sequence modifications that might be linked to altered intracellular trafficking and secretion of cathepsin B (CTSB) in malignant tumors. Comparison of AGS 1-6-30-1 cDNAs with human kidney/hepatoma cDNAs revealed: (1) three potential N-glycosylation sites instead of two, (2) a nucleotide (nt) substitution in the coding region for the propeptide from GTG to CTG which would result in a Val26-->Leu change, (3) three silent nt replacements in the coding region for the mature protein, (4) five single-nt differences in the 5'- and 3'-UTR (untranslated regions), (5) heterogeneity in the 5'-UTR, and (6) a 10-bp insertion in the 3'-UTR. The 10-bp insertion in the 3'-UTR may alter the stability of CTSB mRNA transcripts and thereby the expression of CTSB. These clones should be useful for expressing human tumor CTSB and analyzing the function of this enzyme in malignant progression. Two restriction-fragment length polymorphisms (RFLPs), EcoRI and TaqI, were detected by Southern blot analysis of genomic DNA from 36 unrelated Caucasians. Inheritance and distribution of the EcoRI alleles (13.0 and 11.0 kb) and the TaqI alleles (5.7 and 4.6 kb) indicated they were independent polymorphisms. In contrast to the EcoRI alleles of 13.0 and 11.0 kb observed in the population survey, genomic DNA from two AGS gastric adenocarcinoma subclones revealed two EcoRI alleles of 13.0 and 7.8 kb.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene. 811

Quinones are widely distributed substances of often potential toxicological significance. On the other hand, cyclic AMP is known to promote a cell-survival response and to retard apoptosis [Berridge, Tan and Hilton (1993) Exp. Hematol. 21, 269-276]. Therefore the effects of quinones on adenylate cyclase were tested. Adenylate cyclase is rapidly inhibited by quinones, with IC50 values of 40-45 microM for p-benzoquinone (BQ) or 200 microM for dichlorophenol-indophenol (DCIP), with 2-substituted quinones being inactive. Membrane solubilization decreases the IC50 values for BQ and DCIP to 18 microM and 40 microM respectively. The inhibition is not affected by GTP, GDP or analogues, or by cholera and pertussis toxins; therefore it is not mediated by a G-protein or the activation of a defined receptor. Further, the inhibition stoichiometrically competes with forskolin activation of adenylate cyclase, equimolar concentrations of quinone and forskolin restoring the enzyme activity to its basal value. Reduction of BQ with sodium dithionite stoichiometrically prevents the inhibition of adenylate cyclase; in turn, oxidation of hydroquinone with ferricyanide fully restores it, indicating that the oxidized state of the quinone is required for inhibition. In addition, BQ is cytotoxic in vivo on HepG2, a human hepatocellular carcinoma cell line, but the effect can be prevented with forskolin. In plasma membranes, BQ tightly binds only one major and two minor proteins; these BQ-binding proteins were purified by means of labelling with [14C]BQ followed by PAGE under native conditions. Together these observations indicate that the action of quinone can be traced to targeting a limited number of proteins at the plasma membrane in a highly selective way and to affecting key enzymes such as adenylate cyclase.
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PMID:Selective inhibition of adenylate cyclase in bovine cortex by quinones: a novel cellular substrate for quinone cytotoxicity. 819 59

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

Glucocorticoids coincidentally regulate the localization of mouse mammary tumor virus (MMTV) glycoproteins and maturation of viral phosphoproteins in viral infected rat hepatoma cells. To test for a functional interaction between MMTV transmembrane glycoproteins and cytoplasmic phosphoproteins, the bacterial cytolysin streptolysin-O was utilized to selectively permeabilize the plasma membrane and reconstitute exocytic trafficking. Streptolysin-O-permeabilized M1.54 cells pretreated with glucocorticoids retained the capability for proteolytic processing, cell surface delivery, and externalization of MMTV glycoproteins as determined by immunoprecipitation and immunofluorescence microscopy. The efficient maturation of MMTV phosphoproteins indicated that these viral proteins are properly transported near or to the plasma membrane in permeabilized cells. These maturation events in semi-intact cells were dependent on the addition of cell cytosol and were specifically inhibited by the membrane impermeant GTP analog guanosine 5'3-O-(thio)triphosphate, an agent known to impede vesicular transport of membrane proteins, but which has not previously been shown to alter cytoplasmic protein maturation or transport. The addition of anti-MMTV antibodies directed against the cytoplasmic domain of the glycoprotein precursor to transport competent semi-intact M1.54 cells resulted in the dramatic inhibition of both MMTV glycoprotein and phosphoprotein maturation. These results were not obtained using either preimmune sera or antiserum specific for the luminal portion of the glycoprotein precursor. Our findings suggest that the functional interaction of cytosolic MMTV phosphoproteins with the cytoplasmic domain of the viral membrane glycoprotein is required for the efficient transport and processing of each class of proteins in glucocorticoid-treated cells and provides the first evidence for the involvement of vesicular transport in the delivery and maturation of cytoplasmic viral proteins at the plasma membrane or the pericellular region.
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PMID:Glucocorticoid-regulated trafficking of mouse mammary tumor virus proteins in permeabilized hepatoma cells. Requirements of intracellular membrane transport for maturation of the cytoplasmic phosphorylated polyprotein. 839 42

Plasma membranes from liver of control rats or from chemical-induced hepatoma were prepared. The basal activity of adenylate cyclase was increased significantly in the rat plasma membranes of DEN-induced hepatoma compared to normal tissue. The glucagon-induced response on the cellular effector systems via guanine nucleotide-binding regulatory proteins (G proteins) was inhibited in hepatoma plasma membranes. These findings suggest that in hepatoma membranes, unlike normal hepatic membranes, the response to hormonal stimuli through regulatory G proteins results in a loss of response to glucagon, as well as to GTP plus glucagon or to GTP gamma S. However, the activating effects of forskolin, which catalyses the formation of cyclic AMP from ATP acting on the catalytic subunit, were to some extent retained. The methyltransferase-I behaved in the opposite direction to the adenylate cyclase, showing a decreased activity in hepatoma plasma membranes compared to control membranes. In contrast, the activity of the ecto-5'-nucleotidase was significantly increased in hepatoma. These enzymatic changes have been found to influence the membrane fluidity and to be responsible for the ultrastructural modifications of hepatoma plasma membranes which are induced by chemical carcinogens.
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PMID:Enzymatic, biophysical and ultrastructural changes of plasma membranes in chemical-induced rat hepatoma. 856 46

ATP citrate lyase (EC 4.3.1.8.) was shown to be a major phosphorylation protein of a fraction derived from Zajdela rat hepatoma by chromatography on heparin-Ultrogel, after the incubation with [gamma-32P]ATP or [gamma-32P]GTP. Histidine was the only amino acid in the purified enzyme phosphorylated by [gamma-32P]ATP or [gamma-32P]GTP in the autocatalytic reaction which occurred apparently through an intramolecular mechanism regardless of a donor of phosphate. GTP inhibits the ATP-dependent autophosphorylation competitively despite its failure to replace ATP in the formation of acetyl-CoA catalyzed by this enzyme.
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PMID:GTP, a nonsubstrate of ATP citrate lyase, is a phosphodonor for the enzyme histidine autophosphorylation. 857 77


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