Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human class I alcohol dehydrogenase (ADH) gene family consists of ADH1, 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 ADH1 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 ADH1 or ADH3 promoter, was shown to respond to CCAAT/enhancer-binding protein alpha (C/EBP alpha), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADH1, 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/EBP alpha, and a significant synergism between C/EBP alpha and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBP alpha and LAP homo- and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBP alpha (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 of ADH2 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/EBP alpha 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.
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PMID: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. 162 Jan 13

Expression of the Drosophila melanogaster alcohol dehydrogenase-encoding gene (ADH) in the adult fat body is controlled by the ADH adult enhancer site (AAE). The D. melanogaster transcription repressor, adult enhancer factor-1 (AEF-1), binds to AAE at a site which overlaps with a sequence recognized by the mammalian transcription factor, CCAAT/enhancer-binding protein alpha [C/EBP alpha; Falb and Maniatis, Genes Dev. 6 (1992a) 454-465]. C/EBP alpha also activates the promoter of the rat class-I ADH gene in a sequence-specific manner [Potter et al., Arch. Biochem. Biophys. 285 (1991a) 246-251]. In this study, we explored the possibility that D. melanogaster AEF-1 influences transcription of the rat class-I ADH. By DNase I footprint analysis, bacterially produced AEF-1 protects a region of DNA between nucleotides (nt) -22 and -36 of the rat class-I ADH promoter (pADH), just 5' to the binding site of C/EBP alpha, a result confirmed by the electrophoretic mobility shift assay (EMSA). Co-transfection of a rat pADH-CAT reporter construct with expression vectors containing C/EBP alpha, AEF-1, or both, indicates that AEF-1 inhibits induction of the rat pADH by C/EBP alpha. Moreover, rat liver nuclear extracts appear to contain AEF-1-like-binding activities to AAE by EMSA. These experiments suggest an evolutionarily conserved mechanism by which AEF-1 modulates expression of the D. melanogaster and rat ADH genes.
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PMID:The adult enhancer factor-1, a Drosophila melanogaster transcriptional repressor, modulates the promoter activity of the rat class-I alcohol dehydrogenase-encoding gene. 795 11

The human alcohol dehydrogenase gene ADH2 is expressed at high levels in liver, at lower levels in kidney and several other tissues, and is not expressed in other tissues such as spleen. This pattern of expression suggests a complex regulatory region that responds to a variety of transcription factors in different cellular contexts. Seven cis-acting sequences in the proximal 271 bp of the ADH2 promoter were mapped. The occupancy of these sites differed markedly among extracts from liver, kidney, spleen, H4IIE-C3 cells, HeLa cells, and CV-1 cells. These differences in occupancy were accompanied by differences in gene expression in the three cell lines. The ADH2 promoter directed substantial CAT expression in H4IIE-C3 cells (rat hepatoma) and in HeLa cells, but only minimal expression in CV-1 cells (monkey kidney fibroblasts). The three cell lines differed in the effects of deletions within the promoter. An ADH2 promoter that contained both the USF/MLTF site and the G3T site gave four- to eight-fold higher expression in both H4IIE-C3 and HeLa cells than a smaller promoter that lacked these sites; in contrast, these sequences did not significantly stimulate transcription in CV-1 cells. A CTF/NF-I-related site acted as a negative element in all three cell lines. Coexpression of C/EBP alpha altered the cell specificity. The ADH2 promoter was moderately stimulated (two-fold) by coexpression of C/EBP alpha in H4IIE-C3 cells, but markedly stimulated in HeLa cells and in CV-1 cells (11- and 20-fold, respectively). These results demonstrate the differential importance of cis-acting sequences and of specific transcription factors in different cells, which allows regulated expression of ADH2 in multiple tissues.
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PMID:Tissue-specific differences in the expression of the human ADH2 alcohol dehydrogenase gene and in binding of factors to cis-acting elements in its promoter. 817 54

Three human alcohol dehydrogenase genes, ADH1, ADH2, and ADH3, were formed by tandem duplications and have diverged in their tissue-specific and developmental expression. Their proximal promoters remain 80-84% identical in sequence, approximately the same degree of identity as at synonymous sites in the coding regions of these three genes. To understand the evolution of tissue specificity, gene expression must be studied in many different cells and tissues. A systematic comparison of their promoters reveals the effects of subtle sequence differences on the binding of nuclear proteins to their cis-acting elements. There are differences in the affinity with which some proteins are bound to altered sites including C/EBP sites, USF/MLTF sites, and the G3T site (which binds Sp1). There are also differences in the sites that are occupied, e.g. CTF/NFI-related sites. These sequence differences are reflected in differences in gene expression in three cell lines. In H4IIE-C3 hepatoma cells, the ADH1 promoter was more active than the ADH2 promoter, and the ADH3 promoter was nearly nonfunctional. In HeLa cells, both ADH1 and ADH2 promoters directed expression; again the ADH3 promoter was extremely weak. None of the three promoters had much activity in CV-1 cells. Coexpression of C/EBP alpha greatly stimulated expression of the ADH1 promoter in HeLa cells and in CV-1 cells, but only weakly stimulated expression in H4IIE-C3 cells. The stimulation of the ADH1 promoter by C/EBP alpha was comparable to that of ADH2, despite the weaker binding to the C/EBP sites that flank the TATA box in ADH1. The ADH3 promoter was not greatly stimulated by C/EBP alpha, despite good binding of C/EBP alpha. These results demonstrate that small differences in the cis-acting elements affect affinity of binding by transcription factors and the pattern of gene expression.
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PMID:Gene expression in a young multigene family: tissue-specific differences in the expression of the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3. 863 48