Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat liver N-hydroxy-2-acetylaminofluorene (N-OH-2AAF) sulfotransferase activity is mediated by aryl sulfotransferase IV (AST IV) and causes the bioactivation of N-OH-2AAF to a highly reactive sulfuric acid ester form putatively capable of inducing liver cancer. Dietary administration of 2-acetylaminofluorene (2AAF) to induce hepatocarcinogenesis in rats has been shown to cause a rapid loss in N-OH-2AAF sulfotransferase activity. A possible mechanism for the in vivo loss in sulfotransferase activity may be the PAPS-dependent, sulfotransferase-catalyzed, reaction product inactivation of the enzyme by covalent reaction with the N-OH-2AAF sulfuric acid ester. In vitro studies to evaluate this possibility utilized a highly purified form of AST IV and measured the extent of PAPS-dependent interaction between the enzyme and N-OH-2[9-14C]AAF. The results showed the presence of a adenosine-3'-phospho-5'-phosphosulfate (PAPS)-dependent 14C-labeling of AST IV. The labeling could be blocked if the sulfotransferase inhibitor pentachlorophenol was present. Analysis of 14C-labeled AST IV following alkaline digestion and chromatography of digestion products indicated that AST IV cysteine and methionine residues were primary sites of 2[9-14C]AAF adduction. Studies involving the pretreatment of AST IV with PAPS and N-OH-2AAF prior to the measurement of N-OH-2AAF sulfotransferase activity showed a close parallel between formation of the AST IV cysteine-2AAF adduct and loss of activity. Similar studies showed that enzyme inactivation and cysteine-2AAF adduct formation could be blocked when excessive amounts of a competing nucleophile, methionine, were present during the pretreatment step, suggesting that inactivation does not proceed by a mechanism-based process. Finally, experiments involving prior reaction of AST IV with the thiol-blocking agent, N-ethylmaleimide, before measurement of enzyme activity showed essentially full loss of sulfotransferase activity and suggested that formation of AST IV cysteine-2AAF adducts could be a mechanism for enzyme inactivation. These results indicate that the in vitro inactivation of AST IV by the reactive N-OH-2AAF sulfuric acid ester is accompanied by covalent binding to AST IV, possibly through the formation of cysteine-2AAF adducts, and suggests that this mechanism merits further consideration as a basis for the loss of N-OH-2AAF sulfotransferase activity in vivo.
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PMID:Reaction product inactivation of aryl sulfotransferase IV following electrophilic substitution by the sulfuric acid ester of N-hydroxy-2-acetylaminofluorene. 173 62

The biochemical characteristics of cathepsin B secreted from cultured human liver cancer cells were examined. The enzyme activity of culture medium against a synthetic substrate, N-carbobenzoxy-L-arginyl-L-arginine-4-methyl-coumaryl-7-amide, was dependent on the addition of cysteine, and the optimal pH was found to be 6.0. No activity was observed when the enzyme source was fresh medium not used for culture. These results suggest that the enzyme released from liver cancer cells is the thiol-protease cathepsin B. The molecular weight of the enzyme with 90% of the total activity was 40,000. Two cathepsin B molecules were found in liver tissue from patients with hepatocellular carcinoma (HCC); one was equivalent in size to the secreted enzyme, and a smaller one was the same as normal liver cathepsin B (27,000), which was also obtained from HCC-bearing cirrhotic liver. These results demonstrate that two molecules of cathepsin B are synthesized in liver cancer, and that the larger one is released into the surrounding tissue.
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PMID:The secretion of high molecular weight cathepsin B from cultured human liver cancers. 271 72

Certain strains of Salmonella typhimurium and Escherichia coli, particularly those which are very sensitive to u.v. light, are killed when incubated with rat liver mixed function oxidases and aflatoxin B(1). UvrA or recA strains of E. coli are more susceptible than the wild-type strain, while the double mutant uvrA recA is the most sensitive strain yet tested. The aflatoxin B(1) metabolite is also able to induce reverse mutations in 2 histidine auxotrophic strains of S. typhimurium, one strain of which is reverted specifically by frame shift mutagens and the other by agents inducing base pair substitutions.Pretreatment of rats with either 3-methylcholanthrene or benzo(a)pyrene, both inducers of liver microsomal mixed function oxidases, did not alter the amount of lethal aflatoxin B(1) metabolite formed, whereas an increase was observed after phenobarbitone pretreatment. Addition of the nucleophiles methionine, cysteine, glutathione, sodium thiosulphate or sodium sulphide, or the epoxide hydrase inhibitor, cyclohexene oxide to the toxicity assay medium did not alter bacterial killing by the aflatoxin B(1) metabolite. 2,3-Dimercaptopropanol had some protective action.Toxic metabolites were also formed when 5-methoxysterigmatocystin, O-methylsterigmatocystin, parasiticol or versicolorin A, but not vericolorin B, were incubated with mixed function oxidases. The relationship between the metabolite of aflatoxin B(1) lethal to bacteria and that which initiates liver cancer is discussed.
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PMID:Induction of mutations in DNA-repair deficient bacteria by a liver microsomal metabolite of aflatoxin B1. 459 23

There is no clear indication that malnutrition, per se, is a principal cause of cancer in man, but the prevalence of liver cancer in areas where malnutrition exists supports this hypothesis. Liver damage and liver cancer have been induced in laboratory rats by diets consisting of peanut meal and proteins deficient in some essential amino acids. However, liver damage, but not cancer, was produced when the diets contained no peanut meal but consisted of a mixture of amino acids deficient in methionine and cysteine, so that it is possible that aflatoxin, a contaminant of peanut meal, may have been responsible for the malignancies seen in the earlier experiments. Liver cancer developes in a high proportion of mice allowed to feed ad libitum or given a diet containing a high proportion of fat (groundnut oil) or protein (casein). Dietary restriction reduced the incidences of this cancer. This findings lends some support to current thinking that diet may be a factor in the development of cancer in man.
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PMID:Malnutrition, liver damage, and cancer. 734 90

A comparative analysis of preC sequences of hepatitis B virus (HBV) in human hepatoma (hepatocellular carcinoma; HCC) tissues and non-tumoral liver samples from HCC patients was performed. Ten out of 17 HCC tissue samples exhibited an amino acid substitution at the level of the distal cysteine residue of the HBV preC region, while generation of a TAG translational stop codon was observed in 4 of these samples. Interestingly, substitution of the distal cysteine residue was not observed in non-tumoral liver (available from 8 of the 17 patients), thus suggesting either that a selection among different HBV variants occurs in HCC cells, or that modifications to the conformation and stability of the HBV capsid protein may play a role in the process of selection and escape of transformed liver cells.
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PMID:Hepatitis B virus preC mutants in human hepatocellular carcinoma tissues. 821 Jul 12

The hepatitis B virus (HBV) protein HBx has been implicated to induce liver cancer in transgenic mice and transactivates a variety of viral and cellular promoters. The 17 kDa protein HBx consists of 154 amino acids, contains 10 cysteine residues and is translated during the viral infection. It has been shown previously that the HBx protein is able to bind to singlestranded DNA and RNA. This nucleic acid binding activity might be relevant for HBx oncogenic character. Furthermore, HBx has been reported to interact with a series of cellular proteins, especially with transcription factors, including the tumor suppressor protein p53. To evaluate the importance of the cysteine residues in HBx for its interaction with RNA and p53 we expressed full-length HBx-wt as well as several truncated mini-HBx(18-142) proteins with multiple cysteine to serine point mutations as 6xHis fusion proteins in Escherichia coli. Using UV cross-linking assays we demonstrate that all truncated mini-HBx proteins with cysteine/serine point mutations maintained the ability to bind to an AU-38 RNA oligonucleotide. Furthermore, we performed in vitro binding assays of selected HBx mutants with GST-p53, circular dichroism spectroscopic analysis of the mutant HBx protein secondary structure and a p53 based transcription activation assay in yeast cells. In summary, our data suggest that the cysteine residues in the HBx protein are of minor importance for its interaction with both RNA and the p53 protein.
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PMID:The cysteine residues of the hepatitis B virus onco-protein HBx are not required for its interaction with RNA or with human p53. 1568 Oct 62

Infection with the hepatitis B virus has been identified as one of the major causes of liver cancer. A large body of experimental work points to a central role for the virally encoded protein HBx in this form of carcinogenesis. HBx is expressed in HBV-infected liver cells and interacts with a wide range of cellular proteins, thereby interfering in cellular processes including cell signaling, cycle regulation and apoptosis. In order to identify possible new targets of the HBx protein, we performed a yeast two-hybrid screen using a truncated protein mini-HBx(18-142) as the bait. In addition to known interacting partners, such as RXR and UVDDB1, we identified several new candidates including the human transcriptional regulatory protein p120E4F, which has been implicated in the regulation of mitosis and the cell cycle. In vitro pull down experiments confirmed the interaction and transcription activation assays in the yeast demonstrated that HBx protein was able to repress GAL4AD-p120E4F-dependent activation of a reporter gene under the control of E4F binding sites found in the adenovirus E4 promoter and the HBV enhancer II region. We also showed that the cysteine residues in HBx are necessary for its interaction with UVDDB1 but not for the interaction with RXR or p120E4F. The possible functional relevance of the interaction between HBx and E4F proteins is discussed in the contexts of cellular transformation and host-virus co-evolution.
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PMID:Interaction of the hepatitis B virus protein HBx with the human transcription regulatory protein p120E4F in vitro. 1611 66

Herbal medicines have been used in the treatment of liver diseases for a long time. A number of herbal preparations are available in the market. This article reviews four commonly used herbal preparations: (1) Phyllanthus, (2) Silybum marianum (milk thistle), (3) glycyrrhizin (licorice root extract), and (4) Liv 52 (mixture of herbs). Phyllanthus has a positive effect on clearance of HBV markers and there are no major adverse effects; there are no data from randomized controlled trials on clinically relevant outcomes, such as progression of chronic hepatitis to cirrhosis and/or liver cancer, and on survival. Silymarin does not reduce mortality and does not improve biochemistry and histology among patients with chronic liver disease; however, it appears to be safe and well tolerated. Stronger neominophagen C (SNMC) is a Japanese preparation that contains 0.2% glycyrrhizin, 0.1% cysteine, and 2% glyceine. SNMC does not have antiviral properties; it primarily acts as an anti-inflammatory or cytoprotective drug. It improves mortality in patients with subacute liver failure and improves liver functions in patients with subacute hepatic failure, chronic hepatitis, and cirrhosis with activity. SNMC does not reduce mortality among patients with cirrhosis with activity. SNMC may prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C, however, prospective data are lacking. Liv 52, an Ayurvedic hepatoprotective agent, is not useful in the management of alcohol-induced liver disease. Standardization of herbal medicines has been a problem and prospective, randomized, placebo-controlled clinical trials are lacking to support their efficacy. The methodological qualities of clinical trials of treatment with herbal preparations are poor. The efficacy of these herbal preparations need to be evaluated in rigorously designed, larger randomized, double-blind, placebo-controlled multicenter trials.
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PMID:Herbal medicines for liver diseases. 1618 78

CyDye DIGE Fluor saturation dye (saturation dye, GE Healthcare Amersham Biosciences) enables highly sensitive 2-D PAGE. As the dye reacts with all reduced cysteine thiols, 2-D PAGE can be performed with a lower amount of protein, compared with CyDye DIGE Fluor minimal dye (GE Healthcare Amersham Biosciences), the sensitivity of which is equivalent to that of silver staining. We constructed a 2-D map of the saturation dye-labeled proteins of a liver cancer cell line (HepG2) and identified by MS 92 proteins corresponding to 123 protein spots. Functional classification revealed that the identified proteins had chaperone, protein binding, nucleotide binding, metal ion binding, isomerase activity, and motor activity. The functional distribution and the cysteine contents of the proteins were similar to those in the most comprehensive 2-D database of hepatoma cells (Seow et al.., Electrophoresis 2000, 21, 1787-1813), where silver staining was used for protein visualization. Hierarchical clustering on the basis of the quantitative expression profiles of the 123 characterized spots labeled with two charge- and mass-matched saturation dyes (Cy3 and Cy5) discriminated between nine hepatocellular carcinoma cell lines and primary cultured hepatocytes from five individuals, suggesting the utility of saturation dye and our database for proteomic studies of liver cancer.
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PMID:Database of two-dimensional polyacrylamide gel electrophoresis of proteins labeled with CyDye DIGE Fluor saturation dye. 1642 55

Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes two proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at four downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 A resolution. The structure reveals a dimeric cysteine protease with two composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design.
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PMID:Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. 1713 77


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