Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces the expression of a number of genes. The biochemical process of the induction of aldehyde dehydrogenase (ALDH-3) was investigated in rat H4IIE hepatoma cells in culture. The kinetics of ALDH-3-induction exhibited parallel increases in the rate of transcription, mRNA, protein, and enzyme activity, all reaching a plateau at 36-48 h after addition of TCDD. Half maximal and maximal inductions occurred at 0.1 and 1 nM of TCDD, respectively. No significant changes in the half-life of ALDH-3 mRNA (14 h) were observed in the cells exposed to three different concentrations of TCDD. Other inducers of xenobiotic metabolism, such as 3-methylcholanthrene and beta-naphthoflavone, also induced ALDH-3 mRNA to a similar level as TCDD, whereas antioxidants or electrophiles, such as tert-butylhydroquinone and dimethyl fumarate, did not show any induction of ALDH-3 mRNA. To examine the involvement of the aryl hydrocarbon receptor (Ah receptor) in the induction of ALDH-3, mouse variant cell lines defective in cytochrome P450IA1-induction and a parental wild type cell line (Hepa1c1c7) were studied. ALDH-3 mRNA and the transcription of its gene were detected in TCDD-treated wild type cells, but not in the treated and untreated variant cells. These results demonstrate that TCDD induces transcription of the ALDH-3 gene via its binding to the Ah receptor.
 ...
PMID:Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase in hepatoma cells. 141 78

An aldehyde dehydrogenase isozyme, ALDH3, which is strongly expressed in the stomach, may play a role in the oxidation of toxic aldehydes. Using reverse genetic approach, we cloned and characterized the cDNA and the gene for the ALDH3. The full length cDNA is 1624 base pairs (bp) in length and contains an open reading frame encoding 453 amino acid residues. The deduced amino acid sequence shows a high degree of resemblance to that of rat hepatocarcinoma ALDH. The human ALDH3 gene spans about 8 kb in length and consists of 10 exons. The putative TATA and CCAAT boxes are located in the consensus upstream distance from the transcription initiation site. Southern blot analysis of total genomic DNA argues against the proposed two-gene model for the ALDH3 isozymes (Yin, S.-J., Cheng, T.-C., Chang, C.-P., Chen, Y.-J., Chao, Y.-C., Tang, H.-S., Chang, T.-M., and Wu, C.-W. (1988) Biochem. Genet. 26, 343-360). Northern blot hybridization and analysis of PCR amplification products of cellular RNA demonstrated the existence of a high level of ALDH3 mRNA in human stomach and hepatoma cells, but a very low level in the normal liver. Expression of ALDH3 cDNA in Escherichia coli yielded a protein of 55 kDa, which exhibited kinetic properties similar to that found in ALDH3 isozyme purified from human stomach and liver, and was hybridizable with rabbit anti-human-hepatoma ALDH serum.
 ...
PMID:Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in Escherichia coli. 173 58

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.
 ...
PMID:Superinduction of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase by the inhibition of protein synthesis. 195 64

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.
 ...
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.
 ...
PMID:Effects of hepatocarcinogenic initiators on aldehyde dehydrogenase gene expression in cultured rat hepatic cells. 237 65

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.
 ...
PMID:Cloning and complete nucleotide sequence of a full-length cDNA encoding a catalytically functional tumor-associated aldehyde dehydrogenase. 283 37

ALDH isozymes have been characterized in terms of substrate and coenzyme specificity, heat stability, tissue distribution and electrophoretic properties. The activity of the isozymes has also been examined in rodent-human somatic cell hybrids in order to map the structural genes to specific chromosomes and to study the control of gene expression. One isozyme, designated ALDH3, which is very active against benzaldehyde, was found to show variable expression in hybrids made between rat hepatoma cells and human fibroblasts or fetal liver. Segregation analysis of these hybrids indicates that the structural locus for human ALDH3 may be on chromosome 17. The expression of rodent ALDH3 in these hybrids was extremely variable and not correlated with the appearance of the human enzyme. In hybrids expressing human and rodent ALDH3 no heteromeric isozymes were observed. The human "cytosolic" ALDH1 and "mitochondrial" ALDH2 isozymes did not appear to be expressed in any of the somatic cell hybrids examined.
 ...
PMID:Biochemical genetic analysis of human and rodent aldehyde dehydrogenase (ALDH). 401 40

The biochemical properties of ALDH isozymes have been examined in human tissues and one set, designated ALDH3, has been studied in detail. These components occur at highest levels in lung and stomach, but were not expressed in fetal tissues, or in blood, hair roots and fibroblasts. The ALDH3 isozymes show optimal activity with benzaldehyde and can use either NAD or NADP as cofactor. Antiserum against a partially purified ALDH3, from stomach, selectively precipitates this isozyme from human tissues and selectively recognizes an homologous component in the rat. Human and rodent ALDH3 were not immunoprecipitated by anti-ALDH1 or anti-ALDH2 antisera. High levels of expression were found in human-rodent hybrids, constructed using rat hepatoma cells, and these hybrids were used to assign the human ALDH3 gene to chromosome 17.
 ...
PMID:Chromosome assignment, biochemical and immunological studies on a human aldehyde dehydrogenase, ALDH3. 407 32

Human cytosolic aldehyde dehydrogenase 1 (ALDH1) plays a role in the biosynthesis of retinoic acid that is a modulator for gene expression and cell differentiation. Northern blot analysis showed that liver tissue, pancreas tissue, hepatoma cells, and genital skin fibroblast cells expressed high levels of ALDH1. Sequence analysis showed that the 5'-flanking region contains a number of putative regulatory elements, such as NF-IL6, HNF-5, GATA binding sites, and putative response elements for interleukin-6, phenobarbital and androgen, in addition to a noncanonical TATA box (ATAAA) and a CCAAT box. Functional characterization of the 5'-regulatory region of the human ALDH1 gene was carried out by a fusion to the chloramphenicol acetyltransferase gene. A construct containing 2.6 kilobase pairs of the 5'-flanking region was efficiently expressed in hepatoma Hep3B cells, but not in erythroleukemic K562 cells or in fibroblast LTK- cells, which do not express ALDH1. Within this region, we define a minimal promoter (-91 to +53) that contains positive regulatory elements. The study using site-directed mutagenesis demonstrated that the CCAAT box region is the major cis-acting element involved in basal ALDH1 promoter activity in Hep3B cells. Gel mobility shift assays showed that NF-Y and other octamer factors bound CCAAT box and an octamer motif sequence, but not GATA site existing in the minimal promoter region. Two additional DNA binding activities associated with the minimal promoter were found in the nuclear extract from Hep3B cells, but not from K562 cells. These results offer the possible molecular mechanism of the cell type-specific expression of ALDH1 gene.
 ...
PMID:The transcriptional regulation of human aldehyde dehydrogenase I gene. The structural and functional analysis of the promoter. 761 57

The development of hepatocellular carcinoma in rodents treated with different chemical compounds is associated with the appearance in the cytosol of neoplastic liver cells of an unusual aldehyde dehydrogenase isozyme of class 3 (ALDH-3) which is very active with aromatic aldehydes. This tumor-associated isozyme is readily detected by enzyme cytochemistry using the substrate benzaldehyde with NADP as coenzyme. To determine whether human hepatocellular carcinomas express ALDH-3, the activity of this isozyme was examined in frozen sections from 68 echo-guided human liver biopsies. In 54 cases the guided biopsy was performed on one or more nodules suggestive for hepatocellular carcinoma found at ultrasonography within the liver parenchyma. The remaining 14 patients were affected by chronic active hepatitis or cirrhosis. An intense enzymatic activity was ascertained in 5 out of 36 hepatocellular carcinomas. In non-neoplastic liver, in macroregenerative nodules and in metastatic adenocarcinomas enzymatic activity was not detectable. ALDH-3-positive tumors were typical hepatocellular carcinomas (histological grade II and III). These results suggest that ALDH-3 is a phenotype associated with malignancy in human liver tumors.
 ...
PMID:Cytochemical detection of a class 3 aldehyde dehydrogenase in human hepatocellular carcinoma. 779 43


1 2 3 Next >>