ADH1, 2 AND 3 - GENES WHOSE TIMES HAVE COME

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 α (C/EBPα), 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/EBPα, and a significant synergism between C/EBPα and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBPα and LAP homo‐ and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBPα (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/EBPα 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. Copyright © 1992 American Association for the Study of Liver Diseases