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

Jones, David; Brennan, Michael; Hempel, John; Lindahl, Ronald

doi:10.1073/pnas.85.6.1782

Cited by 76 publications

(42 citation statements)

References 40 publications

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“…The result is an Ah receptor-mediated positive transcriptional activation of each of the genes in the [Ah] battery (16,(26)(27)(28)(29). For some of these genes, a component of posttranscriptional regulation may also be present, such as has been characterized most completely for the mouse CYP1A2 gene (26).…”

Section: Role Of Cytotoxicity In Tumor Promotionmentioning

confidence: 99%

“…Only a small percentage of preneoplastic nodules actually proceed to frank malignancy. Interestingly, the CYPlAl and CYP1A2 enzymes are undetectable, while the Nmo-1, Aldh-1, Ugt-1, and Gt-1 enzyme activities in the preneoplastic nodules are elevated (16,27,29,50,51). It appears likely that these previous results with rat liver preneoplastic nodules are related to our recent observations that the murine [Ah] battery Phase II gene regulation is independent of the [Ah] battery Phase I gene regulation.…”

Section: Rat Liver Preneoplastic Nodulesmentioning

confidence: 99%

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Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Nebert¹,

Petersen²,

Fornace³

1990

Environmental Health Perspectives

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A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in which we can study metabolically coordinated enzymes that respond to phytoalexin-induced oxidative stress. In the mouse, the [Ah] battery comprises at least six genes: two Phase I genes, CYPIAI and CYPIA2; and four Phase II genes, Nmo-1, Aldh-i, Ugt-1, and Gt-l. All six genes appear to be regulated positively by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor. In the absence of foreign inducer, the control of Nmo-l gene expression is independent of the control of CYPIAI and CYPIA2 gene expression. The radiation deletion homozygote c 4Cot/C14Co5mouse is lacking about 1.1 centiMorgans of chromosome 7. Although having no detectable CYPIAI or CYPIA2 activation, the untreated C14CI/C14Cos mouse exhibits markedly elevated transcripts of the Nmo-i gene and three growth arrest-and DNA damage-inducible (gadd) genes. These data suggest that the missing region on chromosome 7 in the C14CoS/C14CoS mouse contains a gene(s), which we propose to call Nmo-In, encoding a trans-acting factor(s) that is a negative effector of the Nmo-l and gadd genes. The three other [Ah] battery Phase II genes behave similarly to Nmo-1 in the C14CoS/C14CoS mouse. This coordinated response to oxidative stress and DNA damage, by way of the release of a mammalian battery of genes from negative control, bears an interesting resemblance to the SOS response in bacteria.

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Section: Role Of Cytotoxicity In Tumor Promotionmentioning

confidence: 99%

Section: Rat Liver Preneoplastic Nodulesmentioning

confidence: 99%

Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Nebert¹,

Petersen²,

Fornace³

1990

Environmental Health Perspectives

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“…Unlike the liver enzymes, the yeast enzyme is activated by K+ ions (4, 32). Whereas the mammalian enzymes have been sequenced at the cDNA (16,19,29,34) as well as the protein (24, 33, 60) level, no sequence work has been reported for the yeast enzyme.One of our interests was to study the subcellular localization of acetaldehyde metabolism in S. cerevisiae. In the mammalian liver tissue, this was studied by selectively inhibiting the cytosolic or the mitochondrial isozyme of ALDH (11,52).…”

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confidence: 99%

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confidence: 99%

Molecular cloning of the mitochondrial aldehyde dehydrogenase gene of Saccharomyces cerevisiae by genetic complementation

et al. 1991

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Mutants of Saccharomyces cerevisiae deficient in mitochondrial aldehyde dehydrogenase (ALDH) activity were isolated by chemical mutagenesis with ethyl methanesulfonate. The mutants were selected by their inability to grow on ethanol as the sole carbon source. The ALDH mutants were distinguished from alcohol dehydrogenase mutants by an aldehyde indicator plate test and by immunoscreening. The ALDH gene was isolated from a yeast genomic DNA library on a 5.7-kb insert of a recombinant DNA plasmid by functional complementation of the aldh mutation in S.cerevisiae. An open reading frame which specifies 533 codons was found within the 2.0-kb BamHI-BstEII fragment in the 5.7-kb genomic insert which can encode a protein with a molecular weight of 58,630. The N-terminal portion of the protein contains many positively charged residues which may serve as a signal sequence that targets the protein to the mitochondria. The amino acid sequence of the proposed mature yeast enzyme shows 30% identity to each of the known ALDH sequences from eukaryotes or prokaryotes. The amino acid residues corresponding to mammalian cysteine 302 and glutamates 268 and 487, implicated to be involved at the active site, were conserved. S. cerevisiae ALDH was found to be localized in the mitochondria as a tetrameric enzyme. Thius, that organelle is responsible for acetaldehyde oxidation, as was found in mammalian liver.Saccharomyces cerevisiae, unlike higher eukaryotes, can metabolize as well as produce ethanol. During fermentation, the consumption of sugars results in the accumulation of ethanol. When glucose or any other fermentable sugar is absent from the culture medium, S. cerevisiae can utilize ethanol as the carbon source aerobically. The metabolism of ethanol is well understood in mammals. In the liver, cytosolic alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde and then mitochondrial aldehyde dehydrogenase (ALDH) oxidizes the intermediate to acetate (14). In S. cerevisiae, it appears that a mitochondrial alcohol dehydrogenase (ADH3) is responsible for the initial oxidation (65,67). Little is known about the role of ALDHs in the next step.Various groups have purified and characterized yeast ALDH (12,49,54). It was reported to be a tetrameric enzyme with a subunit molecular mass of 60 kDa and a low Km for acetaldehyde. Unlike the liver enzymes, the yeast enzyme is activated by K+ ions (4, 32). Whereas the mammalian enzymes have been sequenced at the cDNA (16,19,29,34) as well as the protein (24, 33, 60) level, no sequence work has been reported for the yeast enzyme.One of our interests was to study the subcellular localization of acetaldehyde metabolism in S. cerevisiae. In the mammalian liver tissue, this was studied by selectively inhibiting the cytosolic or the mitochondrial isozyme of ALDH (11,52). An alternative approach would be to introduce the enzyme into a cell deficient in ALDH activity. S. cerevisiae would be a suitable model system, as it can metabolize ethanol and could serve as a host for the expression of foreign g...

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“…Recently, an aldehyde dehydrogenase from Aspergilltis niduluns [54] and one from rat tumor [55] were sequenced, being just 56% and 29% identical, respectively, to the mitochondrial enzymes. Of the above residues Cys-49 and Glu-268 were absent in the enzyme from A .…”

Section: Discussionmentioning

confidence: 99%

Primary structures of rat and bovine liver mitochondrial aldehyde dehydrogenases deduced from cDNA sequences

Farrés

Guan

Weiner

1989

European Journal of Biochemistry

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The cDNA coding for rat liver mitochondrial aldehyde dehydrogenase was cloned and sequenced. It contained an open reading frame of 1557 bp. Of the deduced 519 amino acid residues, 19 were proposed to correspond to the signal peptide necessary to allow the protein to enter the mitochondria [Farrts, J., Weiner, H. (1987) Biochem. Biophys. Res. Commun. 1.50, 1083-10871. The sequence of the 500 amino acid residues comprising the mature subunit was 96% identical to that of the corresponding human liver mitochondrial enzyme. The longest cDNA isolated coding for the bovine liver enzyme contained sequence information corresponding to residues 72 -500 of the rat or human enzyme. The deduced protein sequence of these residues was 94% identical to those of the human enzyme.Over 60% of the bases in the coding region of the rat cDNA were G and C. These residues were clustered non-randomly and two potentially stable stem-loop structures could be calculated as existing in the mRNA. One would be found in the region coding for amino acid residues 64 -79; a similar secondary structure could be responsible for the existing truncated cDNAs from the bovine-cDNA libraries. Comparisons with the amino acid sequences of other aldehyde dehydrogenases support the suggestion that the NAD-binding domain may be located in the middle portion of the mature enzyme.Mammalian mitochondrial aldehyde dehydrogenase, a ubiquitous and constitutive NAD-dependent enzyme, is involved in the oxidation of biogenic aldehydes, as well as acetaldehyde formed during the metabolism of ethanol. The enzyme from most species is isolated as a tetramer of molecular mass 220 -250 kDa, resulting in a subunit molecular mass of 55 -60 kDa [l], which is larger than that of most dehydrogenases.The amino acid sequences of the human [2] and horse [3] liver mitochondrial enzymes have been published. They share 94% identity. Cytosolic enzymes from human [4] and horse [5] liver have also been sequenced and they share 91 O h identity. In contrast, mitochondrial and cytoplasmic aldehyde dehydrogenases show just 66 -68% identity.

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

Cited by 76 publications

References 40 publications

Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Molecular cloning of the mitochondrial aldehyde dehydrogenase gene of Saccharomyces cerevisiae by genetic complementation

Primary structures of rat and bovine liver mitochondrial aldehyde dehydrogenases deduced from cDNA sequences

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