Identification of a FOXA-dependent enhancer of human alcohol dehydrogenase 4 (ADH4).
- Authors
- Pochareddy, Sirisha; Edenberg, Howard J
- Year
- 2010
- Journal
- Gene
- PMID
- 20363298
- DOI
- 10.1016/j.gene.2010.03.013
- PMCID
- PMC2896571
Human alcohol dehydrogenase 4 (ADH4) is one of the key enzymes involved in the metabolism of alcohol. ADH4 is highly expressed in the liver, and previous studies have revealed several cis-acting elements in the proximal promoter region. In this study we have identified a distal upstream enhancer, 4E, of ADH4. In HepG2 human hepatoma cells, 4E increased the activity of an ADH4 basal promoter by 50-fold. 4E was cell-specific, as no enhancer activity was detected in a human lung cell line, H1299. We have narrowed the enhancer activity to a 565 bp region and have identified multiple liver-enriched transcription factor binding sites in the region. By electrophoretic mobility shift assays, we confirmed binding of FOXA proteins to these sites. Site-directed mutagenesis studies demonstrated that sites 1 and 4 have the biggest effect on enhancer function, and mutations in multiple sites have multiplicative effects. We also studied the effects of three variations in the minimal enhancer region. Two variations had a significant effect on enhancer activity, decreasing the activity to 0.6-fold, while one had small but significant effect. The differences in the functional activity in different haplotypes suggest that this region could play an important role in the risk for alcoholism.
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| Characterization of human alcohol dehydrogenase 4 and aldehyde dehydrogenase 2 as enzymes involved in the formation of 5-carboxylpirfenidone, a major metabolite of pirfenidone. | Sato R et al. | — | 2025 | → |
| Investigation of mitochondrial DNA methylation-related prognostic biomarkers in hepatocellular carcinoma using The Cancer Genome Atlas (TCGA) database. | Shi S et al. | — | 2025 | → |
| ADH4-a potential prognostic marker for hepatocellular carcinoma with possible immune-related implications. | Li L et al. | — | 2024 | → |
| ADH4—a potential prognostic marker for hepatocellular carcinoma with possible immune-related implications | 李 玲 et al. | — | 2024 | — |
| Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review. | Edenberg HJ et al. | — | 2018 | → |
| Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells. | Attignon EA et al. | — | 2017 | → |
| Polymorphisms in ADH1B and ALDH2 genes associated with the increased risk of gastric cancer in West Bengal, India. | Ghosh S et al. | — | 2017 | → |
| Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling. | Stiuso P et al. | — | 2016 | → |
| An enhancer-blocking element regulates the cell-specific expression of alcohol dehydrogenase 7. | Jairam S et al. | — | 2014 | → |
| Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation. | Rowe C et al. | — | 2013 | → |
| Genes encoding enzymes involved in ethanol metabolism. | Hurley TD et al. | — | 2012 | → |
| Pharmacogene regulatory elements: from discovery to applications. | Smith RP et al. | — | 2012 | → |