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)

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.
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PMID:Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in Escherichia coli. 173 58

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.
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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.
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PMID:Chromosome assignment, biochemical and immunological studies on a human aldehyde dehydrogenase, ALDH3. 407 32

Aldehyde dehydrogenase subcellular distribution and activity were studied in the Yoshida hepatoma AH-130 and rat liver. NAD+- and NADP+-dependent dehydrogenase activities were lower in all hepatoma subfractions (except the cytosol) than in liver subfractions. In the presence of 0.025 mM substrate 78-80% of the liver NAD+- or NADP+-dependent aldehyde dehydrogenase was found in the mitochondria. With 10 mM substrate the enzyme activity was primarily in the mitochondria and microsomes. In the hepatoma a sharp increase of the soluble aldehyde dehydrogenase (either NAD+- or NADP+ dependent) was observed at all substrate concentrations. The Km of the different isoenzymes (either identified by their localization or coenzyme dependency) were of the same order for liver and hepatoma. However, a high Km enzyme was present in liver mitochondria outer membranes but not in hepatoma. Hepatoma acetaldehyde dehydrogenase was inhibited, as was the liver enzyme, by diethyldithiocarbamate. The return of activity was slower for the hepatoma and neonatal liver than for the adult liver enzyme.
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PMID:The subcellular distribution and properties of aldehyde dehydrogenase of hepatoma AH-130. 630 66

The mouse hepatoma cell line Hepa-1 is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for both CYP1A1 (aryl hydrocarbon hydroxylase, AHH) and class 3 aldehyde dehydrogenase (ALDH3) enzymes. To test the hypothesis of a common regulatory mechanism, several AHH deficient mutants of Hepa-1 were studied for their ALDH3 activities and specific mRNA levels before and after TCDD treatment. The recessive (with respect to the wild-type Hepa-1) mutants have defects in Cypla-1 structural gene (mutant c1) or in the Ah (aryl hydrocarbon) receptor (mutants c2 and c6 with decreased levels of Ah receptor; mutant c4 defective in the DNA binding of the Ah receptor). The results with these mutants suggested that Ah receptor nuclear translocator protein, ARNT, is needed for ALDH3 expression. Two dominant mutants, one of which is characterized by preventing the binding of the Ah receptor complex to DNA, were also studied. Surprisingly, these mutants possessed elevated levels of ALDH3 mRNA and enzyme activities which were also inducible by TCDD. The binding of Ah receptor-ligand complex to DNA was thus not needed for the expression of ALDH3. A dominant repressor for Cypla-1 gene transcription did not prevent the derepression or induction of ALDH3. The results thus suggest that Aldh-3 gene is regulated by a mechanism independent of the Ah receptor.
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PMID:Comparison of expression of aldehyde dehydrogenase 3 and CYP1A1 in dominant and recessive aryl hydrocarbon hydroxylase-deficient mutant mouse hepatoma cells. 782 19

The Long-Evans Cinnamon (LEC) rat is a mutant strain established from Long-Evans rats. LEC rats display hereditary hepatitis and spontaneous hepatocellular carcinoma (HCC). We first tried to examine effects of ethanol consumption on the development of HCC, and fed a Lieber's liquid diet containing 5% ethanol to LEC rats. However the rats died within 2 weeks because of acute alcohol intoxication. In LEC rats, the concentration of ethanol and acetaldehyde in blood was significantly higher, and liver alcohol dehydrogenase activity was slightly lower and acetaldehyde dehydrogenase activities were remarkably suppressed compared to those of Wistar rats. These results suggest that LEC rats have hereditary deficiencies of ethanol and acetaldehyde metabolizing enzymes.
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PMID:Abnormal ethanol metabolism in Long-Evans Cinnamon rats, a mutant strain developing spontaneous hepatoma. 800 22

We have cloned and sequenced the murine AHD4 cDNA encoding the 'Class 3' cytosolic aldehyde dehydrogenase (ALDH-3c). The cDNA is 1722 bp in length, excluding the poly(A+) tail, and has 5' and 3' nontranslated regions of 174 bp and 186 bp, respectively. AHD4 encodes a protein of 453 amino acids, including the first methionine (M(r) = 50,466). The murine AHD4 protein is 91% and 80% similar to the rat and human ALDH3c proteins, respectively, 64% identical to the rat microsomal ALDH3 protein, and < 28% similar to ALDH 'Class 1' and 'Class 2' proteins. Surprisingly, in contrast to the rat gene that is expressed in both cell cultures and the intact liver, the murine Ahd-4 gene is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) or benzo[a]pyrene in cell cultures but not in liver of the intact adult or newborn mouse. Southern hybridization analysis of mouse DNA probed with the full-length cDNA reveals that the Ahd-4 gene is likely to span less than a total of 15 kb, and was mapped to chromosome (Chr) 11 between the Mgat-1 and Shbg loci by analysis of two multilocus crosses. AHD4 mRNA levels are strikingly elevated in the untreated mouse hepatoma Hepa-1c1c7 mutant line c37 lacking CYP1A1 (aryl hydrocarbon hydroxylase) activity and in the untreated 14CoS/14CoS mouse cell line having a homozygous deletion of about 1.2 cM on Chr 7. Our data suggest that the Ahd-4 gene in murine cell cultures is regulated by three distinct mechanisms: Ah receptor-mediated induction by TCDD or benzo[a]pyrene, CYP1A1 metabolism-dependent repression, and Chr 7-mediated putative derepression.
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PMID:Mouse dioxin-inducible cytosolic aldehyde dehydrogenase-3: AHD4 cDNA sequence, genetic mapping, and differences in mRNA levels. 814 69

Tumor-associated aldehyde dehydrogenase (ALDH) was reported in cases of human hepatocellular carcinoma and animal hepatoma models. This ALDH isozyme is similar to ALDH3 which exists in the stomach and lung; however, the biochemical and clinical significance of this unique ALDH isozyme have not been established. Human tumor-associated ALDH was purified, and polyclonal antibodies prepared. Using these antibodies, specific development of tumor-associated ALDH was confirmed by immunohistochemical techniques. It was found that about 50% of hepatocellular carcinomas reacted with the antibody. This unique ALDH isozyme may be a novel tumor marker of hepatocellular carcinoma.
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PMID:Immunohistochemical study of hepatocellular carcinoma-specific aldehyde dehydrogenase. 906 10

The Class 3 aldehyde dehydrogenase gene (ALDH3) is expressed differentially in a tissue-specific manner, occurring constitutively in some tissues and in others as a result of xenobiotic induction via the Ah receptor/ARNT pathway. ARNT is also involved in regulating gene expression in response to hypoxia. It dimerizes with hypoxia-inducible factor 1 alpha (HIF-1 alpha) and enhances expression of hypoxia-responsive genes. To determine if ARNT plays a role in regulating ALDH3 in response to low oxygen tension, we studied the effects of 1% oxygen and the hypoxia mimic cobalt chloride on constitutive and inducible ALDH3 expression in rat hepatoma cells and rat corneal epithelial cells. Hypoxia sharply down-regulates constitutive ALDH3 expression in corneal epithelial cells. Likewise, aromatic hydrocarbon-induced ALDH3 expression in H4-II-EC3 cells is significantly reduced by hypoxia. In contrast, hypoxia has no effect on constitutive or aromatic hydrocarbon-inducible ALDH3 expression in HTC cells. Our data indicate that hypoxia exerts cell type-specific effects on both constitutive and induced ALDH3 expression.
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PMID:Hypoxia exerts cell-type-specific effects on expression of the class 3 aldehyde dehydrogenase gene. 973 Dec 2

The human ALDH3 gene is constitutively expressed in stomach, lung, esophagus, and cornea, but hardly detectable in the normal liver. However, it is highly activated in the hepatocellular carcinoma tissues from approximately 50% of patients. The nuclear DNA binding factors exist in both ALDH3-positive cancerous liver and ALDH3-positive HepG2 cells, but not in ALDH3-negative Hep3B cells and normal liver tissues. South-western blot hybridization showed the existence of two nuclear-binding protein components, 35 and 14 kDa, in ALDH3-positive cancerous liver tissues. These two DNA binding proteins were not found in normal stomach tissues and stomach carcinoma KATO III cells. DNaseI footprint analysis identified two protective regions within the ALDH3 promoter. The first protected region has one putative CCAAT-box and one putative Sp1-site. The second protected region contains a putative HiNF-A binding sequence. These findings suggest that a high level of expression of ALDH3 in cancerous liver tissues resulted from the expression or activation of at least two nuclear proteins reacting to the ALDH3 promoter region.
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PMID:Expression of human aldehyde dehydrogenase-3 associated with hepatocellular carcinoma: promoter regions and nuclear protein factors related to the expression. 985 7


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