Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Inhibition of protein synthesis by cycloheximide or puromycin super-induced the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible isoform of aldehyde dehydrogenase (ALDH-3) in rat hepatoma cells. Treatment with cycloheximide did not affect the basal expression but markedly enhanced the TCDD-inducible expression of ALDH-3 mRNA. The co-treatment of cycloheximide and TCDD for 24 h caused a 10-fold greater accumulation of ALDH-3 mRNA than did TCDD alone. The transcription rate of the ALDH-3 gene in the co-treated cells was also 4- to 5-fold higher than that in the cells treated with TCDD alone. The superinduction of ALDH-3 mRNA was observed only when cycloheximide was added prior to or simultaneously with the addition of TCDD. These results suggest that the mechanism of TCDD-inducible transcription of the ALDH-3 gene involves a labile protein that modulates or represses the action of TCDD.
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PMID:Superinduction of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase by the inhibition of protein synthesis. 195 64

Retinoic acid regulation of one member of the human class I alcohol dehydrogenase (ADH) gene family was demonstrated, suggesting that the retinol dehydrogenase function of ADH may play a regulatory role in the biosynthetic pathway for retinoic acid. Promoter activity of human ADH3, but not ADH1 or ADH2, was shown to be activated by retinoic acid in transient transfection assays of Hep3B human hepatoma cells. Deletion mapping experiments identified a region in the ADH3 promoter located between -328 and -272 bp which confers retinoic acid activation. This region was also demonstrated to confer retinoic acid responsiveness on the ADH1 and ADH2 genes in heterologous promoter fusions. Within a 34-bp stretch, the ADH3 retinoic acid response element (RARE) contains two TGACC motifs and one TGAAC motif, both of which exist in RAREs controlling other genes. A block mutation of the TGACC sequence located at -289 to -285 bp eliminated the retinoic acid response. As assayed by gel shift DNA binding studies, the RARE region (-328 to -272 bp) of ADH3 bound the human retinoic acid receptor beta (RAR beta) and was competed for by DNA containing a RARE present in the gene encoding RAR beta. Since ADH catalyzes the conversion of retinol to retinal, which can be further converted to retinoic acid by aldehyde dehydrogenase, these results suggest that retinoic acid activation of ADH3 constitutes a positive feedback loop regulating retinoic acid synthesis.
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PMID:Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. 199 13

This communication describes a method and results for the immunohistochemical detection of a tumour-associated isoenzyme of aldehyde dehydrogenase (BALDH). The method is a substantial improvement over standard histochemical detection methods which require either frozen or mildly fixed tissues, since BALDH expression was detected in the cells of formalin-fixed paraffin-embedded liver tissues of both mice and rats. Using the immunohistochemical method, we detected BALDH expression diethylnitrosamine-induced hepatomas in the male Sprague-Dawley rat and in male B6C3F1 mouse hepatomas induced with either diethylnitrosamine, ethylnitrosourea or dichloroacetic acid. BALDH was also detected in three hepatoma cell culture lines which express different levels of BALDH. These results were compared to results with normal liver and hepatoma sections from the same animals and the three cell culture lines using a standard histochemical method to detect BALDH. In nearly all these tissue sections and cell cultures, expression of BALDH was detected in identical sites with either method. The diethylnitrosamine and dichloroacetic acid induction of the BALDH isozyme, as reported here, has not been reported previously and further substantiates the use of BALDH as a histochemical marker for mouse hepatocarcinogenesis. Given the few reliable histochemical markers for mouse hepatocarcinogenesis, the immunohistochemical method will be useful for further validation of BALDH as a histochemical marker for this species. Thus, BALDH expression could be detected in any number of carcinogen-induced lesions such as altered foci, nodule or hepatomas, from archived, formalin-fixed tissues of past mouse carcinogenesis studies which were based on a variety of mouse strains, carcinogens and induction protocols.
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PMID:Immunohistochemical detection of tumour-associated aldehyde dehydrogenase in formalin-fixed rat and mouse normal liver and hepatomas. 228 93

In normal rat liver, aldehyde dehydrogenase (Aldehyde:NAD+ oxidoreductase, EC 1.2.1.3; ALDH) is found primarily in mitochondrial and microsomal fractions. During hepatocarcinogenesis, an additional tumor-associated aldehyde dehydrogenase (T-ALDH) is detectable in the cytosol of preneoplastic and neoplastic cells. We report here differences in the ALDH distribution pattern in different rat hepatoma cell lines compared to normal rat hepatocytes. Of the four basal ALDH enzymes, one mitochondrial ALDH and one microsomal ALDH account for 96% of total ALDH molecules detectable with our probes in normal hepatocytes. The other two mitochondrial and microsomal ALDH enzymes are only detectable in the appropriate subcellular fraction from large populations of cells. The tumor-associated ALDH is not detectable in normal hepatocytes. In addition to varying amounts of T-ALDH in the six different rat hepatoma cell lines examined, differences in the amounts of mitochondrial and microsomal ALDHs also occur in both high and low T-ALDH activity hepatoma cell lines. Each of five ALDH enzymes examined has a characteristic half-life varying from 45 min to 95 h.
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PMID:Aldehyde dehydrogenase heterogeneity in rat hepatic cells. 231 Jan 96

The effects of certain in vivo inducers of tumor-associated aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 1.2.1.3; ALDH) activity on the expression of tumor-associated ALDH (T-ALDH) in vitro have been investigated using cultured rat hepatocytes and hepatoma cell lines. Two distinct groups of T-ALDH inducers have been identified. Three hepatocarcinogenic initiators 2-acetylaminofluorene, diethylnitrosamine and ethionine, which cause changes in T-ALDH in vivo, do not induce T-ALDH activity in cultured rat hepatocytes or hepatoma cell lines following either short-term or long-term exposures. In contrast, polycyclic aromatic hydrocarbons, such as 3-methylcholanthrene, benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, induce an immediate increase of T-ALDH activity in both cultured rat hepatocytes and hepatoma cell lines. Synthesis and degradation rates of T-ALDH mRNA and protein have also been determined. The synthesis of T-ALDH protein is coupled with the increased synthesis of T-ALDH mRNA when the T-ALDH gene is constitutively expressed or activated by an inducer. Both T-ALDH mRNA (t1/2 = 25 - 34 h) and protein (t1/2 = 88 - 95 h) in high T-ALDH activity cell lines or low-activity cell lines treated with an inducer are relatively stable. Combined with previous studies, the results suggest that at least two different mechanisms are involved in T-ALDH gene expression; events occurring during initiation as well as during promotion appear to be involved in the genetically stable changes in T-ALDH gene expression which occur in vivo. The results also indicate that the lack of T-ALDH activity in normal hepatocytes or low-activity hepatoma cell lines is due to repression of the T-ALDH gene rather than to the differential stability of T-ALDH mRNA or protein.
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PMID:Effects of hepatocarcinogenic initiators on aldehyde dehydrogenase gene expression in cultured rat hepatic cells. 237 65

Peptides from rat liver aldehyde dehydrogenase (AIDH) induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment match the AIDH structure from HTC rat hepatoma cells (HTC-AIDH) at all positions examined, indicating induction of the same gene product by two independent routes. This 452 amino acid residue, class 3 AIDH structure differs substantially from the 500-residue AIDH structures isolated from normal liver cytosol (class 1) and mitochondria (class 2). Despite a 29.8% identity in 429 overlapping amino acids vs the human class 1 enzyme (27.7% vs class 2), neither the N- nor C-termini coincide, and gaps are introduced to optimize the alignment. Two residues placed in the active site of human liver AIDH by chemical modification, Cys-302 and Glu-268, are conserved in class 3 AIDH as Cys-243 and Glu-209. Cys-243/302 is the only cysteine residue conserved in all known AIDH structures. Gly-245 and Gly-250 of class 1/2 AIDHs, fitting the patterns of glycine residues in coenzyme binding fold of other dehydrogenases, are also conserved. Otherwise, Cys-49, Cys-162, and Glu-487, to which functional importance has also been ascribed, are not retained in the class 3 structure. Overall, a high conservation of Gly, Pro, and Trp and similar patterns of predicted secondary structure indicate general conservation of tertiary structure, as noted with other distantly related proteins. Three exon boundaries from the human liver mitochondria AIDH gene directly correspond to the N-terminus of the rat class 3 protein and to two of the gaps in the alignment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inducible (class 3) aldehyde dehydrogenase from rat hepatocellular carcinoma and 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated liver: distant relationship to the class 1 and 2 enzymes from mammalian liver cytosol/mitochondria. 271 59

In some chemically-induced hepatomas and in cultured transformed cells the aldehyde dehydrogenase activity was found increased in the presence of aromatic aldehyde as substrate. We studied this enzyme during diethyl-nitrosamine carcinogenesis in rat liver by using an aliphatic aldehyde, 4-hydroxynonenal, as substrate. 4-Hydroxynonenal is an important product of lipid peroxidation. The NAD- and NADP-dependent aldehyde dehydrogenase of the cytosolic fraction and the NADP-dependent aldehyde dehydrogenase of the microsomes show higher values in nodules and hepatoma than in normal liver. These results suggest that increased aldehyde dehydrogenase, when 4-hydroxynonenal is used, can be considered a marker of the neoplastic process, in the same way as the level of aldehyde dehydrogenase increased in presence of aromatic aldehyde.
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PMID:Oxidative metabolism of 4-hydroxy-2,3-nonenal during diethyl-nitrosamine-induced carcinogenesis in rat liver. 273 11

Enzyme-inducing and cytotoxic effects of wood-based materials used as bedding for laboratory animals were studied in a cell culture system. Mouse hepatoma cell line, Hepa-1, was exposed to acetone extracts of hardwoods (alder and aspen), softwoods (pine and a mixture of pine and spruce) and cellulose materials. Cytotoxicity and induction of cytochrome P450IA1 (aryl hydrocarbon hydroxylase) and aldehyde dehydrogenase were measured. Both softwood and hardwood extracts were shown to contain inducers of these enzymes. Pine appeared to be the most potent inducer and softwoods more potent than hardwoods. The softwoods and alder were clearly more cytotoxic than aspen. The two bleached cellulose materials were found to contain inducers of aryl hydrocarbon hydroxylase. Unlike the wood beddings, the extracts of the cellulose materials were not found to be toxic to the cells. Hepa-1 cell culture system was found to be a rapid and sensitive method for screening and comparative purposes.
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PMID:Enzyme-inducing and cytotoxic effects of wood-based materials used as bedding for laboratory animals. Comparison by a cell culture study. 277 Apr 16

To study the mechanism(s) controlling expression of the tumor-associated aldehyde dehydrogenase (tumor ALDH), which appears during rat hepatocarcinogenesis, cDNAs encoding this isozyme were cloned and identified with an antibody probe. Poly(A)-containing RNA from HTC rat hepatoma cells, which have been shown to possess high levels of tumor ALDH, was used as template to synthesize double-stranded cDNA. The cDNA was methylated to protect internal sites. Two different synthetic DNA linkers were added sequentially to the cDNA to insure correct orientation for expression from the lac promoter of pUC8. A library of 100,000 independent members carrying inserts greater than 1 kilobase was obtained. From this library, two apparently identical tumor ALDH clones, differing only in size, were identified with an indirect immunological probe. The larger of the cDNA clones identified, pTALDH, was chosen for further study. Interestingly, since tumor ALDH is a dimeric enzyme, pTALDH directs synthesis of a functional tumor ALDH in the bacterial cell. The cDNA sequence has been confirmed by comparison to the amino acid sequence of tumor ALDH purified from HTC cells.
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PMID:Cloning and complete nucleotide sequence of a full-length cDNA encoding a catalytically functional tumor-associated aldehyde dehydrogenase. 283 37

Recent studies in our laboratory have shown that five established rat hepatoma cell lines provide a wide spectrum of tumor-associated aldehyde dehydrogenase (ALDH) activity representative of the range of activities of this enzyme seen in primary rat hepatocellular carcinomas. Four newly established rat hepatoma cell lines, RLT-2M, RLT-3C, RLT-9F, and RLT-5G, were derived from a primary hepatocellular carcinoma. The primary tumor was induced by a single injection of diethylnitrosamine (15 microM/g body weight) to a 1-d-old female S-D rat followed at weaning by chronic phenobarbital treatment. RLT-2M was established from outgrowths of minced tumor pieces. RLT-3C, RLT-9F, and RLT-5G were cloned from RLT-2M by the serial endpoint dilution. All four lines have been maintained in culture for over 100 passages. The ALDH phenotype in both the primary tumor and the four new cell lines was determined by total activity assay, gel electrophoresis, and histochemistry. By total activity assay, the primary tumor did not possess significant tumor-ALDH activity. In contrast, the four new cell lines expressed tumor-ALDH activity. However, they differed in their basal ALDH activities and in ALDH inducibility by 3-methylcholanthrene, benzo(a)pyrene, and phenobarbital. Additionally, significant decreases in tumor-ALDH activity occurred when cells from each line were passaged in vivo. The four lines have been characterized by light and electron microscopic morphology, tumorigenicity, chromosome number, doubling time, and colony formation efficiency in soft agar.
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PMID:Characteristics and aldehyde dehydrogenase activity of four rat hepatoma cell lines produced by diethylnitrosamine-phenobarbital treatment. 287


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