Abstract
The human hepatitis B virus (HBV) is a hepatotropic virus that replicates through an RNA intermediate referred to as the pregenome. The promoter that directs the synthesis of the pregenome and several other transcripts with heterogeneous 5' ends is of particular interest because of its role in regulating key functions during the viral life cycle. We have examined the liver-specific characteristics of this promoter by DNA-protein interactions and by demonstrating the in vivo function of the promoter using the luciferase reporter gene expression system. The DNA-protein interactions in this region appear to be almost entirely liver-specific. Among these, a liver-specific nuclear factor, CCAAT/enhancer binding protein, binds to at least five sites on this promoter. Transient cotransfection experiments using CCAAT/enhancer binding protein expression vectors and the core promoter in the context of either the native hepatitis B virus genome or the luciferase reporter gene demonstrate that CCAAT/enhancer binding protein at low concentration modestly activates expression from the core promoter but represses at high concentration.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Antonucci T. K., Rutter W. J. Hepatitis B virus (HBV) promoters are regulated by the HBV enhancer in a tissue-specific manner. J Virol. 1989 Feb;63(2):579–583. doi: 10.1128/jvi.63.2.579-583.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Birkenmeier E. H., Gwynn B., Howard S., Jerry J., Gordon J. I., Landschulz W. H., McKnight S. L. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 1989 Aug;3(8):1146–1156. doi: 10.1101/gad.3.8.1146. [DOI] [PubMed] [Google Scholar]
- Cattaneo R., Will H., Hernandez N., Schaller H. Signals regulating hepatitis B surface antigen transcription. Nature. 1983 Sep 22;305(5932):336–338. doi: 10.1038/305336a0. [DOI] [PubMed] [Google Scholar]
- Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Friedman A. D., Landschulz W. H., McKnight S. L. CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Genes Dev. 1989 Sep;3(9):1314–1322. doi: 10.1101/gad.3.9.1314. [DOI] [PubMed] [Google Scholar]
- Galas D. J., Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res. 1978 Sep;5(9):3157–3170. doi: 10.1093/nar/5.9.3157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ganem D., Varmus H. E. The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987;56:651–693. doi: 10.1146/annurev.bi.56.070187.003251. [DOI] [PubMed] [Google Scholar]
- Graves B. J., Johnson P. F., McKnight S. L. Homologous recognition of a promoter domain common to the MSV LTR and the HSV tk gene. Cell. 1986 Feb 28;44(4):565–576. doi: 10.1016/0092-8674(86)90266-7. [DOI] [PubMed] [Google Scholar]
- Honigwachs J., Faktor O., Dikstein R., Shaul Y., Laub O. Liver-specific expression of hepatitis B virus is determined by the combined action of the core gene promoter and the enhancer. J Virol. 1989 Feb;63(2):919–924. doi: 10.1128/jvi.63.2.919-924.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jameel S., Siddiqui A. The human hepatitis B virus enhancer requires trans-acting cellular factor(s) for activity. Mol Cell Biol. 1986 Feb;6(2):710–715. doi: 10.1128/mcb.6.2.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson P. F., Landschulz W. H., Graves B. J., McKnight S. L. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987 Apr;1(2):133–146. doi: 10.1101/gad.1.2.133. [DOI] [PubMed] [Google Scholar]
- Johnson P. F., McKnight S. L. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. doi: 10.1146/annurev.bi.58.070189.004055. [DOI] [PubMed] [Google Scholar]
- Karpen S., Banerjee R., Zelent A., Price P., Acs G. Identification of protein-binding sites in the hepatitis B virus enhancer and core promoter domains. Mol Cell Biol. 1988 Dec;8(12):5159–5165. doi: 10.1128/mcb.8.12.5159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Landschulz W. H., Johnson P. F., Adashi E. Y., Graves B. J., McKnight S. L. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988 Jul;2(7):786–800. doi: 10.1101/gad.2.7.786. [DOI] [PubMed] [Google Scholar]
- Landschulz W. H., Johnson P. F., McKnight S. L. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science. 1989 Mar 31;243(4899):1681–1688. doi: 10.1126/science.2494700. [DOI] [PubMed] [Google Scholar]
- Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
- Patel N. U., Jameel S., Isom H., Siddiqui A. Interactions between nuclear factors and the hepatitis B virus enhancer. J Virol. 1989 Dec;63(12):5293–5301. doi: 10.1128/jvi.63.12.5293-5301.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rall L. B., Standring D. N., Laub O., Rutter W. J. Transcription of hepatitis B virus by RNA polymerase II. Mol Cell Biol. 1983 Oct;3(10):1766–1773. doi: 10.1128/mcb.3.10.1766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roossinck M. J., Jameel S., Loukin S. H., Siddiqui A. Expression of hepatitis B viral core region in mammalian cells. Mol Cell Biol. 1986 May;6(5):1393–1400. doi: 10.1128/mcb.6.5.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryden T. A., Beemon K. Avian retroviral long terminal repeats bind CCAAT/enhancer-binding protein. Mol Cell Biol. 1989 Mar;9(3):1155–1164. doi: 10.1128/mcb.9.3.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaul Y., Rutter W. J., Laub O. A human hepatitis B viral enhancer element. EMBO J. 1985 Feb;4(2):427–430. doi: 10.1002/j.1460-2075.1985.tb03646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siddiqui A., Jameel S., Mapoles J. Expression of the hepatitis B virus X gene in mammalian cells. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2513–2517. doi: 10.1073/pnas.84.8.2513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siddiqui A., Jameel S., Mapoles J. Transcriptional control elements of hepatitis B surface antigen gene. Proc Natl Acad Sci U S A. 1986 Feb;83(3):566–570. doi: 10.1073/pnas.83.3.566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Standring D. N., Rutter W. J., Varmus H. E., Ganem D. Transcription of the hepatitis B surface antigen gene in cultured murine cells initiates within the presurface region. J Virol. 1984 May;50(2):563–571. doi: 10.1128/jvi.50.2.563-571.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yaginuma K., Koike K. Identification of a promoter region for 3.6-kilobase mRNA of hepatitis B virus and specific cellular binding protein. J Virol. 1989 Jul;63(7):2914–2920. doi: 10.1128/jvi.63.7.2914-2920.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yee J. K. A liver-specific enhancer in the core promoter region of human hepatitis B virus. Science. 1989 Nov 3;246(4930):658–661. doi: 10.1126/science.2554495. [DOI] [PubMed] [Google Scholar]
- de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]