This is the proposal to identify the mechanisms involved in the regulation of human alcohol dehydrogenase (ADH) gene expression. Specifically: (1) Characterization of genomic clones containing human Class 1 ADH genes will be performed to analyze the structure of this multigene family. (2) DNA probes specific for the Alpha, Beta and Gamma ADH genes will be used to determine the size and amount of mRNA transcribed from these genes in various human tissues. (3) The precise locations of the transcription initiation sites for the Class I ADH genes will be determined and the promoter-regulatory regions will be subject to DNA sequence analysis. (4) The promoter-regulatory regions of the Class I ADH genes will be fused to the easily assayable chloramphenicol acetyltransferase gene and introduced into various mammalian cell lines to assess the DNA sequences necessary for ADH gene expression. Since this class of genes exhibits a very interesting pattern of tissue specific and developmental regulation, an in-depth analysis of the promoters and regulatory regions of these genes may help shed some light on how genes are turned on and off at specific times in differentiated cells. This problem is at the heart of research in developmental biology; it underlies research on the molecular basis of cancer, and it must be resolved if gene therapy is ever to come into widespread use.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol Biomedical Research Review Committee (ALCB)
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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Mic, Felix A; Haselbeck, Robert J; Cuenca, Arnold E et al. (2002) Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129:2271-82
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Haselbeck, R J; Duester, G (1998) ADH4-lacZ transgenic mouse reveals alcohol dehydrogenase localization in embryonic midbrain/hindbrain, otic vesicles, and mesencephalic, trigeminal, facial, and olfactory neural crest. Alcohol Clin Exp Res 22:1607-13
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Haselbeck, R J; Ang, H L; Duester, G (1997) Class IV alcohol/retinol dehydrogenase localization in epidermal basal layer: potential site of retinoic acid synthesis during skin development. Dev Dyn 208:447-53
Ang, H L; Duester, G (1997) Initiation of retinoid signaling in primitive streak mouse embryos: spatiotemporal expression patterns of receptors and metabolic enzymes for ligand synthesis. Dev Dyn 208:536-43
Satre, M A; Zgombic-Knight, M; Duester, G (1994) The complete structure of human class IV alcohol dehydrogenase (retinol dehydrogenase) determined from the ADH7 gene. J Biol Chem 269:15606-12
Duester, G (1994) Retinoids and the alcohol dehydrogenase gene family. EXS 71:279-90

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