Cellular factors controlling the activity of woodchuck hepatitis virus enhancer II.
Woodchuck hepatitis virus (WHV) efficiently induces hepatocellular carcinoma in chronically infected hosts. A key step in hepatocarcinogenesis by WHV is insertional activation of the cellular N-myc gene by integrated viral DNA. WHV enhancer II (En II) is the major cis-acting element involved in this activation. Here we characterize this viral enhancer element and define the cellular factors involved in its activity. WHV En II activity is strongly liver specific and maps to an 88-nucleotide DNA segment (nucleotides 1772 to 1859) located 5' to the pregenomic RNA start site. Genetic analyses and electrophoretic mobility shift assays indicate that the enhancer contains three subregions important to its activity. The core elements of the enhancer are recognition sites for the liver-enriched factors HNF1 and HNF4; together, these signals account for the bulk of En II activity as well as its strong liver specificity. Multimerization of either recognition site produced strong activity even in the absence of other En II sequences. 5' to these elements is a binding site for the ubiquitous Oct-1 transcription factor, which further augments enhancer activity ca. twofold.
Ueda
K
K
Department of Microbiology and Immunology, Howard Medical Institute, University of California Medical Center, San Francisco, California 94143, USA.
Wei
Y
Y
Ganem
D
D
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D002460:Cell Line; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D006367:HeLa Cells; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins / Q000378:metabolism*; D051863:Host Cell Factor C1; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C497693:Hcfc1 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; C403128:MLX protein, human; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D010750:Phosphoproteins; C494166:Pou2f1 protein, mouse; C494168:Pou2f1 protein, rat; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta