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 investigated the ability of intracellular ornithine to alter both the biosynthesis of putrescine and the activity of ornithine decarboxylase in Reuber H35 hepatoma cells in culture incubated with 12-O- tetrade - canoylphorbol 13-acetate (TPA). In confluent cultures of H35 cells, the addition of TPA (1.6 microM) caused the activity of ornithine decarboxylase to increase by more than 100-fold within 4 h. When exogenous ornithine (0.1-1.0 mM) was added to the culture medium with TPA, a marked dose-dependent increase in the production of putrescine was observed. The activity of ornithine decarboxylase in the same cultures incubated with ornithine decreased in a similar dose-dependent manner. The addition of arginine (0.1-1.0 mM) (but not lysine or histidine) to the H35 cells in culture concomitant with TPA also led to a relative increase in putrescine biosynthesis and a decrease in ornithine decarboxylase activity compared to cultures not receiving the amino acids. A similar response to exogenous ornithine and TPA was observed in a series of less confluent rapidly growing cultures which were in culture for a shorter period of time. The confluent cultures possessed a basal level of arginase (55 units/mg protein) which increased approx. 2-fold upon treatment with TPA. The intracellular concentration of ornithine in the unstimulated cells was in the order of 0.02-0.03 mM. Upon incubation of the cells with exogenous ornithine or arginine, the intracellular pools of these amino acids increased 4- to 8-fold.
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PMID:A role for ornithine in the regulation of putrescine accumulation and ornithine decarboxylase activity in Reuber H35 hepatoma cells. 653 29

Derivatives of methotrexate (MTX) in which the gamma-carboxyl group is joined to the epsilon-amino group of L-lysine, L-lysyl-L-lysine, or L-lysyl-L-lysyl-L-lysine, respectively, were prepared for evaluation of their dihydrofolate reductase (DHFR) affinity, their ability to retard cell growth in culture, and their antitumor activity in vivo. These small lysine derivatives of MTX are of interest as putative breakdown products of MTX-poly(L-lysine). Inhibition of DHFR in a cell-free assay was decreased only 3-fold relative to MTX, indicating that gamma-substitution by up to three lysines is well tolerated for binding. On the other hand, toxicity toward L1210 murine leukemia cells in culture decreased up to 120-fold relative to MTX as the lysines increased in number from one to three, suggesting that uptake across the cell membrane becomes difficult when positively charged lysines are at the gamma-position. Growth inhibition of H35 rat hepatoma cells was decreased 40- to 60-fold relative to MTX, but in H35R0.3 cells, which have normal DHFR content but are 180-fold MTX resistant by virtue of a transport defect, the lysine derivatives were only 3- to 7-fold less toxic than MTX. When the adducts were given to L1210 leukemic mice by twice-daily injection for 10 days, an increase in life span (ILS) of 80-100% was observed at 40 mg/kg (equivalent to 20-30 mg/kg of MTX). MTX itself, on the same schedule, gave a 100% ILS at 0.5 mg/kg. The low in vivo activity of the mono-, di-, and trilysine adducts suggests minimal systemic hydrolysis to free MTX.
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PMID:Methotrexate analogues. 23. Synthesis, dihydrofolate reductase affinity, cytotoxicity, and in vivo antitumor activity of some putative degradation products of methotrexate-poly(L-lysine) conjugates. 673 32

Polyamine-responsive protein kinase, a cyclic nucleotide-independent protein kinase from the cytosol of Morris hepatoma 3924A, was stimulated 8-9 fold by several different polymers of polylysine, polyornithine and random copolymers of lysine-alanine; spermidine, spermine, and mixtures of spermine and spermidine stimulated 2, 3, and 5 fold, respectively. The protein kinase was not stimulated by poly-carboxybenzyl-lysine, random copolymer of lysine-tyrosine, polyhistidine, polymethionine, polyglutamic acid, polyaspartic acid, dipeptide (Lys-Lys), lysine, ornithine, and putresine. The polyamine stimulation of the protein kinase was prevented by certain specific charged carbohydrates: heparin, chondroitin sulfates A, B, and C, dextran sulfate and hyaluronic acid. It was not prevented by noncharged carbohydrates: dextran, glycogen, starch, sucrose, etc; or by sulfate salts: ammonium sulfate, potassium sulfate, sodium thiosulfate, etc. The inhibition was reversed by increased polylysine. Heparin was non-competitive inhibitor of Mg2+-ATP. It would appear that this enzyme is regulated by certain highly specific molecules with certain sizes and charges; plus charge is stimulatory, negative charge prevents the stimulation.
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PMID:Regulation of polyamine-responsive protein kinase by certain highly specific polyamines and charged carbohydrates. 682 33

A protease active with N-alpha-benzoyl-DL-arginine-p-nitroanilide with an optimum pH of 7.3 has been found in the cytosol of rat liver. The activity of this protease increased in N-2-fluorenylacetamide-induced hepatoma as well as in fetal liver. It has been purified from normal liver and hepatoma about 200-fold. Its molecular weight is estimated by gel filtration to be about 200,000 in each tissue. The protease activity is unaffected by chymostatin, pepstatin, soybean trypsin inhibitor, and p-chloromercuribenzoate. Antipain, leupeptin, tosyl-L-lysine chloromethyl ketone, and phenylmethylsulfonyl fluoride inhibit the protease activity. This protease appears to be a serine protease.
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PMID:Increased activity of a neutral protease in cytosol from rat hepatoma induced by N-2-fluorenylacetamide. 703 Apr 84

Pulse-chase experiments with [3H]lysine-labeled tissue culture cells reveal that newly synthesized nucleosomal histones H2B, H3, H4 (and possibly H2A) in chromatin are more accessible to histone acetylase in vivo than are older, pre-existing histones. Thus, when rat hepatoma cells are first pulse-labeled and then incubated in medium containing n-butyrate which blocks histone deacetylation, these newly synthesized histones become acetylated to a far greater extent than do their older homologues. As judged by its increased susceptibility to acetylation, the new chromatin matures at a surprisingly slow rate, the estimated half-time for maturation being about 35 min. Based on this data, we suggest that newly synthesized chromatin is in a relatively extended, accessible conformation, and that it slowly returns to a more compact conformation as it matures.
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PMID:Accessibility of newly synthesized chromatin to histone acetylase. 706 19

A fraction containing liver- and hepatoma-specific non-histone proteins has been isolated from the chromatin of mice. Amino acid analysis of this fraction shows that it contains 16 mol of glutamic acid, 10 mol aspartic acid, 7 mol of both arginine and lysine per 100 mol and contains no cysteine or tyrosine. The proteins in this fraction are strongly associated with DNA and are co-extracted with histones from chromatin with 0.25 M HCl. In chromatin from age-related hepatomas, the amount of this fraction increased six-fold. This increase in concentrations of these chromatin proteins may be associated with changes of chromatin structure necessary to initiate malignant growth in liver cells.
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PMID:The characterization of non-histone proteins whose amounts increase in chromatin from mouse hepatocarcinomas. 711 99

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

The plasma tripeptide glycyl-L-lysine (GHL), when added at nanomolar concentrations to a wide group of cultured systems, produces a disparate set of responses ranging from the stimulation of growth and differentiation to outright toxicity. Such diverse actions imply that this tripeptide mediates some basic biochemical function common to many types of cells and organisms. During the isolation of GHL we found the compound to co-isolate through a number of steps with approximately equimolar copper and about 1/5 molar iron. Maximal effects on hepatoma cells (HTC4) were seen when the peptide was added with copper and iron to the growth medium. Structure-function studies revealed that several tripeptides with a histidyl-lysyl linkage were nearly as active as GHL. The association of GHL with copper and a homology similarity between the tripeptide and the copper transport sites on albumin and alpha-fetoprotein, where the cupric atom is bound to a histidyl residue adjacent to a basic residue, suggested that GHL may act as a copper transport factor. We report here that the tripeptide readily forms complexes with copper(II) and enhances the uptake of the metal into cultured hepatoma cells.
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PMID:Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. 745 2

In contrast to the increased uptake of amino acids which has been found in many neoplastic cells, we have observed a decrease in the net uptake of [14C]aspartate and [14C]glutamate in rapidly growing hepatomas relative to rat host liver. When measured 10 min after s.c. injection, the radioactivity from 14C-labeled dicarboxylic amino acids was greater in liver than in all other tissues examined (blood, skeletal, muscle, heart, spleen, lung, and brain) except kidney, where there was an approximately 2-fold greater uptake of aspartate and 10-fold greater uptake of glutamate. Mean uptakes in the rapidly growing Morris hepatomas 7288CTC and 7777 were 19 to 26% of corresponding values for the host livers. Comparison with uptake of 3H2O indicated that these low values were not solely due to differences in circulation. Decreased uptake was not accompanied by equivalent decreases in the concentration of aspartate and glutamate in the tumors. There were small changes in the net uptake of these amino acids in the slowly growing hepatoma 7787 and no significant differences in regenerating liver and hepatoma 5123C, a tumor of intermediate growth rate. The net uptake of [14C]arginine and [14C]lysine in the hepatomas was similar to that in host livers, except for a 250% increase in uptake of [14C]lysine in hepatoma 5123C. A decreased uptake of the magnitude seen with dicarboxylic amino acids in rapidly growing hepatomas has not been observed with other amino acids.
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PMID:Decreased uptake of 14C-labeled dicarboxylic amino acids in rapidly growing hepatomas. 747 Oct 51

The effect of angiotensin II (Ang II) on the transport of cationic amino acids has been examined in vascular smooth muscle cells (VSMC) isolated from rat aortae. Ang II stimulated the uptake rates of radiolabeled arginine and lysine in a time- and concentration-dependent manner. The stimulated arginine uptake could be blocked by pretreatments with cycloheximide and actinomycin D or co-treatment with valsartan, an antagonist specific for Ang II receptor subtype-1. The modulation by Ang II was bidirectional as the efflux of arginine was also stimulated, 5-fold over basal. Using reverse transcription-coupled polymerase chain reaction methodology, a partial cDNA with 94% sequence identity to that of cationic amino acid transporter subtype-1 (CAT-1) of mouse fibroblasts was obtained from VSMC. This sequence also exhibited 14 base changes compared with the sequence of ecotropic retrovirus receptor (ERR)/CAT-1 from rat hepatoma. Northern analyses with this partial CAT-1 cDNA and CAT-2 cDNA of mouse T-lymphocytes showed that Ang II rapidly stimulated the expression of both CAT-1 and CAT-2 in VSMC. Both signals peaked at 2 h after exposure to Ang II. The CAT-1 signal decayed over the next 6 h to levels 3-fold above basal, which are maintained up until 24 h. The induced CAT-2 mRNA concentration also decayed rapidly but increased again between 16 and 24 h to levels comparable with those observed at 2 h.
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PMID:Angiotensin II stimulates system y+ and cationic amino acid transporter gene expression in cultured vascular smooth muscle cells. 749 19


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