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)

The human metallothionein (MT) IB gene (hMT-IB) is located in a region of human DNA containing at least four tandemly arranged MT genes. As deduced from its sequence, hMT-IB is likely to encode a functional protein. However, the predicted amino acid sequence differed from the hMT-I amino acid sequence in four positions. Most remarkable was the presence of an additional cysteine. Like other MT genes, hMT-IB has at least two copies of the metal-responsive element upstream from the transcription initiation site. These elements probably are responsible for the metal responsiveness of the hMT-IB promoter, leading to inducible expression of fused heterologous genes. Unlike the hMT-IIA and hMT-IA genes described previously, which are expressed in many different cell types, a high level of expression of the endogenous hMT-IB gene could be detected only in human hepatoma and renal carcinoma cell lines. Therefore, this is the first MT gene described which exhibits tissue specificity of expression. This specificity is controlled by a cis-acting mechanism involving methylation, since incubation of nonexpressing cells with an inhibitor of DNA methylation led to activation of the hMT-IB gene. In support of this notion, we found that the 5' flanking region of the hMT-IB gene was highly methylated in HeLa cells, a nonexpressing cell type, but it was not methylated in a hepatoma (expressing) cell line.
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PMID:Structure and tissue-specific expression of the human metallothionein IB gene. 378 91

Cell growth using homocysteine as a source of cysteine-sulphur requires two enzymes, cystathionine synthase (CS) and gamma-cystathionase (CT). The second of these enzymes, CT, is apparently present in most cell lines regardless of their tissues of origin, since most cells can grow in vitro in the absence of cystine if they are provided with cystathionine, the intermediate in the pathway. Likewise, homocysteine will support the growth of many human cells. However, of a wide range of rodent cells, only well-differentiated rat hepatoma cells were found to grow using homocysteine in place of cystine. It is shown that cell growth in homocysteine-medium correlates well with the presence in the cells of detectable levels of CS. Furthermore, in cells able to grow in homocysteine-medium, it is possible to demonstrate the homocysteine-dependent trans-sulphuration of serine to cysteine. Growth in homocysteine-medium is not dependent on the release of preformed cysteine from disulphide complexes with serum proteins. In cell hybrids, and in 'dedifferentiated' variants of rat hepatomas, CS, but not CT, is subject to extinction coordinately with well-characterized liver-specific traits. For rodent cells, homocysteine-medium thus acts as a selective medium requiring the expression of a single liver-specific trait, CS. In addition it is shown that, in certain hepatoma variants, CS is regulated co-ordinately with a urea-cycle enzyme (carbamoyl phosphate synthetase I) by glucocorticoids and cyclic-AMP. Cell death through cysteine starvation is briefly considered. The immediate cause of death is apparently an insufficient supply of reduced glutathione. Selenium and vitamin E assist cell growth when the supply of cysteine is limiting.
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PMID:Characterization of cystathionine synthase as a selectable, liver-specific trait in rat hepatomas. 379 84

The non-specific lipid transfer protein (nsL-TP) purified from rat and bovine liver accelerates the transfer of all common diacylglycerophospholipids, cholesterol as well as glycosphingolipids and gangliosides between membranes. These proteins have molecular weights in the order of 14 500 and are highly basic (isoelectric points between 8.5 and 9.5). The primary structure of nsL-TP from bovine liver has been elucidated yielding a single polypeptide chain of 121 aminoacid residues. The protein contains one cysteine residue, essential for transfer activity, a single tryptophan residue and lacks histidine, arginine and tyrosine residues. Rat liver nsL-TP was found to be identical to sterol carrier protein 2, stimulating the microsomal conversion of intermediates between lanosterol and cholesterol. Evidence was presented that nsL-TP binds cholesterol, suggesting that it acts as a carrier. On the other hand, failure to bind phospholipids disagrees with this proposed mode of action. A sensitive enzyme immunoassay was developed to determine levels of nsL-TP in rat tissues. By use of this assay, nsL-TP was found to be most prominently present in liver and intestinal mucosa (0.78 and 0.46 microgram nsL-TP per mg protein in 105 000 X g supernatant, respectively). Subfractionation studies showed that approx. 70% of nsL-TP was present in the membrane-free cytosol. However, application of an immunosorbent-purified antibody and protein A-linked gold particles to rat liver slices demonstrated a concentration of label over the peroxisomes. By way of immunoblotting it was shown that nsL-TP was absent from peroxisomes and that the immunoreactive material was a protein of mol. wt. 58 000. nsL-TP is capable of mediating net transfer of cholesterol to membranes, deficient in this lipid. Under such conditions of net transfer, nsL-TP stimulated the microsomal esterification of cholesterol and its conversion to pregnenolone by adrenal mitochondria. Levels of nsL-TP in Reuber H35 hepatoma cells was six per cent of that found in rat hepatocytes. This very low level of nsL-TP had no effect on de novo cholesterol biosynthesis and intracellular cholesterol esterification. These results raise doubts as to whether nsL-TP has a function in in situ cholesterol metabolism.
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PMID:The non-specific lipid transfer protein (sterol carrier protein 2) from rat and bovine liver. 406 21

Inorganic pyrophosphatase (EC 3.6.1.1) has been purified to electrophoretic homogeneity from the soluble portion of the cytoplasm of rat Hepatoma 3924A and rat liver. It has a specific activity of 600 to 700 mumol inorganic orthophosphate liberated per min per mg protein at 25 degrees, a value in the same range as the highly purified enzymes from yeast and Escherichia coli. By all criteria applied, the hepatoma inorganic pyrophosphatase is identical with the liver enzyme. It is a dimer with subunits with molecular weights of approximately 30,000 to 33,000 and has a pH optimum of 7.4, a Km for pyrophosphate of 5 microM, and a Ka for Mg2+ of 0.3 mM with a pyrophosphate concentration of 0.2 mM. It is not inhibited by high Mg2+ concentrations up to 20 mM. Other metal ions such as Zn2+ and Ca2+ do not activate. Mn2+ activates to less than 10% that of Mg2+ at 0.6 mM and has no effect at 1 mM or higher. In the presence of optimal (4 mM) Mg2+ concentration, Ca2+, Mn2+, Hg2+, and F- at 0.2 mM inhibited strongly, but Zn2+ at 1 mM was not inhibitory. The enzyme had no phosphatase activity toward any of the purine or pyrimidine nucleoside mono-, di-, and triphosphates or toward p-nitrophenyl phosphate, beta-glycerophosphate, glucose 6-phosphate, or glucose 1-phosphate. Bromo- or iodoacetate at high concentration had no inhibitory effect, but p-chloromercuribenzoate and p-chloromercuriphenylsulfonate inhibited strongly at low concentration. The purified enzyme was very unstable but was protected markedly at or above the pH optimum of 7.4 by cysteine, dithiothreitol, and glutathione.
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PMID:Purification and properties of inorganic pyrophosphatase of rat liver and hepatoma 3924A. 612 58

Two-dimensional PAGE analysis of proteins associated with the slowly sedimenting "fibrillar" structures of HeLa nucleoli revealed a protein with a M of 19,000 and a pI of 4.5 which was highly labeled both with 32P-orthophosphate and 35S-methionine. The protein was isolated from Novikoff hepatoma nucleoli by extraction in 0.35 M NaCl and 5 mM DTT followed by chromatography in EDTA on DEAE-cellulose and Sephadex G-100. The protein was homogeneous with respect to two-dimensional PAGE, number of tryptic peptides and carboxyl terminal analysis. The protein contained an acidic/basic amino acid ratio of 2.1, 7 residues of methionine, 2 residues of cysteine, a blocked amino terminus and a carboxyl terminal lysylleucine.
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PMID:Purification and partial characterization of a 19kD/pI 4.5 nucleolar phosphoprotein. 674 47

To elucidate the recently advanced hypothesis that glutathione [L-gamma-glutamyl-L-cysteinyl glycine (GSH)] regulates deiodinating enzyme activities, accounting for the decreased conversion of T4 to T3 in the liver of fetal and starved animals, we investigated thyroid hormone metabolism in GSH-depleted neoplastic and normal hepatocytes. In monkey hepatocarcinoma cells, intracellular total GSH decreased below 10% of the control value (approximately 25 micrograms/mg protein) when cells were grown for 44 h in medium deficient in cystine and methionine or in cystine alone. The latter finding indicated that transsulfuration from methionine to cysteine was defective in these neoplastic cells. In primary cultured adult rat hepatocytes, on the other hand, the transsulfuration pathway was intact, and total GSH decreased below 10% of control (approximately 20 micrograms/mg protein) only in cells grown in cystine- and methionine-deficient medium. In both cell types, the oxidized GSH fraction remained constant (2-5% of total). Incubation with 125I-labeled T4 and T3, followed by chromatography, was used to evaluate 5-deiodination in hepatocarcinoma cells and both 5- and 5'-deiodination in normal hepatocytes. Deiodination was not decreased by GSH deficiency in either case, but was actually increased in hepatocarcinoma cells. This resulted from an increase in the Vmax of 5-deiodinase related to growth arrest. Diamide at 2 mM reversibly inhibited both 5'- and 5'-deiodination in rat hepatocytes, accompanied by decreased total GSH as well as increased GSH disulfide (27% of total). The data suggest that GSH is so abundant in the liver that hepatocytes can tolerate a greater than 90% decrease in intracellular concentration without any change in thyroid hormone deiodination and indicate that altered thyroid hormone metabolism in the fetus and in starvation cannot be accounted for by a decreased hepatic GSH concentration.
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PMID:Glutathione deficiency induced by cystine and/or methionine deprivation does not affect thyroid hormone deiodination in cultured rat hepatocytes and monkey hepatocarcinoma cells. 679 Feb 65

We find that the two wide-range Na+-dependent transport systems A and ASC for various neutral amino acid can be discriminated more sharply in the hepatoma cell line HTC than in any cell yet studied by us in which the two systems co-exist. The gain comes partly from a higher reproducibility and a higher relative ASC rate for HTC than in ordinary rat hepatocytes, also a repressed condition of System A unless first deprived of amino acids, but mainly from our finding that in the hepatoma cell threonine serves as a nearly specific substrate and inhibitor of System ASC, thus decisively supplementing older discriminatory techniques. In ordinary hepatocytes cysteine is quite specific to ASC as a substrate but not as an inhibitor, whereas threonine is specific in neither role. In the hepatoma cell cysteine in turn is specific in neither role. In addition to these and other differences between the two cells in analog specificity, which are partly assignable to System ASC and partly to System A, System ASC of the hepatoma cell shows an inhibition on lowering the pH from 6.5 to 5 not seen in the ordinary hepatocyte. Furthermore, threonine uptake by the hepatoma cell undergoes no stimulation when Li+ is substituted for choline in a Na+-free medium, whereas ASC uptake by the ordinary rat hepatocyte is stimulated much as is System A uptake. As in other occurrences, and in contrast to System A, ASC transport in the hepatoma cell is stimulated neither by amino acid deprivation nor by insulin, glucagon, or dexamethasone. Trans-stimulation, both inward and outward, via System ASC is vigorous in the hepatoma cell. Despite the surprising differences observed, common features of each system in various occurrences continue to justify the use of the abbreviations ASC and A as long as they are understood as generic designations.
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PMID:Surprising differences in substrate selectivity and other properties of systems A and ASC between rat hepatocytes and the hepatoma cell line HTC. 679 May 28

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

Adult rat hepatocytes placed in primary culture contain at least two distinct Na+-independent transport systems for neutral amino acids. The characteristics of the two systems do not allow assignment to previously described Na+ independent agencies, so we have tentatively termed the two processes Systems L1 and L2. Uptake by System L1 is substantially inhibited by cysteine, valine, isoleucine, leucine, methionine, histidine, tryptophan, tyrosine, phenylalanine, and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. In contrast, System L2-mediated transport is completely inhibited by isoleucine, leucine, phenylalanine, and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. Amino acids transported by both systems show biphasic kinetics yielding Km values for the System L1 component in the micromolar range, whereas the corresponding values for System L2 are an order of magnitude higher. In freshly isolated hepatocytes, the activity of System L2 is relatively high and declines over the initial 24 to 48 h of culture. The Na+-dependent Systems N and ASC also show a significant decay in activity during this time period. In contrast to the decrease in uptake by System L2, transport by System L1 increases during culture following an initial lag period of 12 to 24 h. The increase in System L1 activity can be blocked by the addition of either cycloheximide or actinomycin D. System L1 appears to be present also in fetal hepatocytes, although, in the hepatoma cell line, HTC, the Na+-independent component appears to be homogeneous as though one of the two systems present in the normal adult hepatocyte is not expressed in these transformed cells.
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PMID:Evidence for two Na+-independent neutral amino acid transport systems in primary cultures of rat hepatocytes. Time-dependent changes in activity. 711 28

What we had seen previously as two Na+-dependent agencies of amino acid transport in the hepatoma cell line HTC, now also in the cultured rat hepatocyte, fetal and mature, in primary culture, turns out, on the basis of 1) their pH profiles for transport, 2) mutual competitive interaction between their substrates, 3) similarity in selectivity for amino acid chain length, and 4) stimulation of threonine exodus by the anionic cysteine sulfinate, to represent a single mediating system. We conclude that protonation of the mediating ASC system, possibly substrate-assisted, rather than od the free anionic amino acid, converts the system from function for various short chained amino acids to function for aspartate, cysteine sulfinate, and cysteate. Other systems for anionic amino acid transport have shown no such relation to ASC.
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PMID:Hepatic transport system interconverted by protonation from service for neutral to service for anionic amino acids. 717 59


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