Promoters for the human alcohol dehydrogenases genes ADH1, ADH2, and ADH3: interaction of CCAAT/enhancer-binding protein with elements flanking the ADH2 TATA box

Stewart, Mark J.; McBride, M S; Winter, Laurie A.; Duester, Gregg

doi:10.1016/0378-1119(90)90190-3

Cited by 47 publications

(20 citation statements)

References 37 publications

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“…Fusion of various lengths of the 5'-flanking sequences of the human ADHI, ADH2, and ADH3 genes to the chloramphenicol acetyltransferase (cat) gene has been described elsewhere (41,43). A human albumin-cat construction containing albumin DNA from -3100 bp to -17 bp was provided by D. Wilson (Baylor College of Medicine).…”

Section: Materuils and Methodsmentioning

confidence: 99%

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein.

Ooij¹,

Snyder²,

Paeper³

et al. 1992

Mol. Cell. Biol.

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The human class I alcohol dehydrogenase (ADH) gene family consists ofADHI ,ADH2, and ADH3, which are sequentially activated in early fetal, late fetal, and postnatal liver, respectively. Analysis of ADH promoters revealed differential activation by several factors previously shown to control liver transcription. In cotransfection assays, the ADHI promoter, but not the ADH2 or ADH3 promoter, was shown to respond to hepatocyte nuclear factor 1 (HNF-1), which has previously been shown to regulate transcription in early liver development. The ADH2 promoter, but not the ADHI or ADH3 promoter, was shown to respond to CCAAT/enhancer-binding protein a (C/EBPa), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADHI, ADH2, and ADH3 promoters all responded to the liver transcription factors liver activator protein (LAP) and D-element-binding protein (DBP), which are most active in postnatal liver. For all three promoters, the activation by LAP or DBP was higher than that seen by HNF-1 or C/EBPa4 and a significant synergism between C/EBPa and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBPa and LAP homo-and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBPa (i.e., -160, -120, -40, and -20 bp), but DBP bound strongly only to the site located at -40 bp relative to the transcriptional start. Mutational analysis ofADH2 indicated that the -40 bp element accounts for most of the promoter regulation by the bZIP factors analyzed. These studies suggest that HNF-1 and C/EBPa help establish ADH gene family transcription in fetal liver and that LAP and DBP help maintain high-level ADH gene family transcription in postnatal liver.Human class I alcohol dehydrogenase (ADH) is encoded by three genes (ADHI, ADH2, and ADH3) which display differential patterns of tissue-specific and developmental gene expression (12,39). In early human fetal liver development (second trimester), ADHI is expressed, with the additional expression of ADH2 during late fetal liver development (third trimester) and the additional expression ofADH3 during postnatal liver development at about 5 months after birth (39). ADH catalyzes the oxidation of a wide variety of xenobiotic or endogenous alcohols (12,15). In addition to the rate-limiting step in ethanol metabolism (27), human class I ADH catalyzes vitamin A (retinol) oxidation (30), which is the rate-limiting step in the conversion of retinol to retinoic acid, a hormone known to control gene expression at the transcriptional level (19,32,45). Retinoic acid has been implicated as a control molecule for differentiation of epithelial tissues (37, 40), and mammalian class I ADH gene expression in the adult is restricted to epithelial cells, with highest levels in liver epithelia (39). Thus, it is suspected that a major physiological function of ADH in epithelial cells is to catalyze retinoic...

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Section: Materuils and Methodsmentioning

confidence: 99%

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein.

Ooij¹,

Snyder²,

Paeper³

et al. 1992

Mol. Cell. Biol.

View full text Add to dashboard Cite

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“…Fusion of various lengths of the 5'-flanking sequences of the human ADHI, ADH2, and ADH3 genes to the chloramphenicol acetyltransferase (CAT) gene (cat) has been described (35). The genomic sequences were derived from XADH26 for ADH1, XADH15 for ADH2, and XADH8 for ADH3 (11).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

“…The three human class I ADH genes display differential patterns of expression in many tissues throughout development, with highest expression occurring in adult liver (2,34). The 5'-flanking regions of human ADH1, ADH2, and ADH3 have been characterized (11,35). Activation of the ADH2 promoter by the transcription factor CCAAT/enhancer-binding protein (36) as well as glucocorticoids (47) (42).…”

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confidence: 99%

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Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis.

et al. 1991

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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 ADHI 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 controiling 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 , (RAR,3) and was competed for by DNA containing a RARE present in the gene encoding RARI. 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.Retinoic acid has profound effects on vertebrate limb and nervous system morphogenesis as well as epithelial cell differentiation (12,31,40). The effects of retinoic acid are transduced by binding to a nuclear retinoic acid receptor (RAR) which, in the presence of ligand, is transformed into a transcription factor (6,14,28). Recently, a RAR gene family (RARa, -,B, and --y) has been discovered (3, 49), and differential expression of these receptors is undoubtedly important for correct transduction of the retinoic acid signal in various target tissues (9). There also exists another nuclear retinoic acid receptor, designated RXRc, which is not part of the RAR family and which is expressed highly in liver (23). Genes that respond to retinoic acid have been identified, and characterization of the retinoic acid response element (RARE) has been accomplished for genes encoding growth hormone (42), laminin Bi (45), RAR1 (7), and osteocalcin (33).One important aspect of retinoic acid-induced differentiation that is not understood is the mechanism regulating synthesis of retinoic acid from retinol (vitamin A). In mammals, retinol is reversibly oxidized to retinal by a cytosolic retinol dehydrogenase that is identical to class I alcohol dehydrogenase (ADH; EC 1.1.1.1), the enzyme which also functions as an ethanol dehydrogenase (21,22,26,29,44,48 tide subunits encoded by three closely related genes ADHI, ADH2, and ADH3, respectively (34). The substrate specificities of the various class I ADH isozymes (i.e., aa, 13, yy, a1, ay, and P-y) are very similar (43). Human ADH classes II and III are encoded by A...

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“…TATAA-binding factors, upstream stimulatory factor (Potter et al 1991a), CCAAT box-binding transcription factor, or nuclear factor 1, which appears to function as a negative factor (Edenberg et al 1993), and Sp1-like factors (Brown et al 1992)) as well as tissue-specific factors (e.g. hepatocyte nuclear factor 1, D-box-binding protein and CCAAT-enhancer-binding proteins (C/EBP; C/EBP a and b; Stewart et al 1990Stewart et al , 1991Potter et al 1991b)). Exceptions are the ADH5 and ADH7 promoters, which lack TATAA boxes.…”

Section: Alcohol Dehydrogenasesmentioning

confidence: 99%

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

et al. 2004

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Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH β2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene–environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

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Promoters for the human alcohol dehydrogenases genes ADH1, ADH2, and ADH3: interaction of CCAAT/enhancer-binding protein with elements flanking the ADH2 TATA box

Cited by 47 publications

References 37 publications

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein.

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein.

Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis.

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

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