Abstract
Upon infection of human B lymphocytes, the 172-kbp Epstein-Barr virus genome forms a covalently closed circle via its terminal repeats. This event brings all of the promoters that control expression of the latent gene products, and the viral origin of plasmid replication, oriP, within a 20-kbp stretch of contiguous DNA. We have found that the EBNA-1-dependent transcriptional enhancer FR, located in oriP, increased the expression of a tagged viral oncogene encoding the latent membrane protein (LMP) up to 200-fold in normal Epstein-Barr virus-positive cells. The effect of FR was exerted across 10 kbp of viral DNA that spans the circularized ends of the viral genome. Enhancement of the tagged LMP gene by FR/EBNA-1 did not require the EBNA-2-responsive element.
Full Text
The Full Text of this article is available as a PDF (167.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alfieri C., Birkenbach M., Kieff E. Early events in Epstein-Barr virus infection of human B lymphocytes. Virology. 1991 Apr;181(2):595–608. doi: 10.1016/0042-6822(91)90893-g. [DOI] [PubMed] [Google Scholar]
- Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Farrell P. J., Gibson T. J., Hatfull G., Hudson G. S., Satchwell S. C., Séguin C. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984 Jul 19;310(5974):207–211. doi: 10.1038/310207a0. [DOI] [PubMed] [Google Scholar]
- Cohen J. I., Wang F., Mannick J., Kieff E. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9558–9562. doi: 10.1073/pnas.86.23.9558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fennewald S., van Santen V., Kieff E. Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol. 1984 Aug;51(2):411–419. doi: 10.1128/jvi.51.2.411-419.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fåhraeus R., Jansson A., Ricksten A., Sjöblom A., Rymo L. Epstein-Barr virus-encoded nuclear antigen 2 activates the viral latent membrane protein promoter by modulating the activity of a negative regulatory element. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7390–7394. doi: 10.1073/pnas.87.19.7390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gahn T. A., Schildkraut C. L. The Epstein-Barr virus origin of plasmid replication, oriP, contains both the initiation and termination sites of DNA replication. Cell. 1989 Aug 11;58(3):527–535. doi: 10.1016/0092-8674(89)90433-9. [DOI] [PubMed] [Google Scholar]
- Gahn T. A., Sugden B. Marked, transient inhibition of expression of the Epstein-Barr virus latent membrane protein gene in Burkitt's lymphoma cell lines by electroporation. J Virol. 1993 Nov;67(11):6379–6386. doi: 10.1128/jvi.67.11.6379-6386.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hammerschmidt W., Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature. 1989 Aug 3;340(6232):393–397. doi: 10.1038/340393a0. [DOI] [PubMed] [Google Scholar]
- Henkel T., Ling P. D., Hayward S. D., Peterson M. G. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science. 1994 Jul 1;265(5168):92–95. doi: 10.1126/science.8016657. [DOI] [PubMed] [Google Scholar]
- Hurley E. A., Thorley-Lawson D. A. B cell activation and the establishment of Epstein-Barr virus latency. J Exp Med. 1988 Dec 1;168(6):2059–2075. doi: 10.1084/jem.168.6.2059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ling P. D., Hsieh J. J., Ruf I. K., Rawlins D. R., Hayward S. D. EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J Virol. 1994 Sep;68(9):5375–5383. doi: 10.1128/jvi.68.9.5375-5383.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ling P. D., Rawlins D. R., Hayward S. D. The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9237–9241. doi: 10.1073/pnas.90.20.9237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Middleton T., Gahn T. A., Martin J. M., Sugden B. Immortalizing genes of Epstein-Barr virus. Adv Virus Res. 1991;40:19–55. doi: 10.1016/s0065-3527(08)60276-6. [DOI] [PubMed] [Google Scholar]
- Pallesen G., Hamilton-Dutoit S. J., Zhou X. The association of Epstein-Barr virus (EBV) with T cell lymphoproliferations and Hodgkin's disease: two new developments in the EBV field. Adv Cancer Res. 1993;62:179–239. doi: 10.1016/s0065-230x(08)60319-x. [DOI] [PubMed] [Google Scholar]
- Rawlins D. R., Milman G., Hayward S. D., Hayward G. S. Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region. Cell. 1985 Oct;42(3):859–868. doi: 10.1016/0092-8674(85)90282-x. [DOI] [PubMed] [Google Scholar]
- Reisman D., Sugden B. trans activation of an Epstein-Barr viral transcriptional enhancer by the Epstein-Barr viral nuclear antigen 1. Mol Cell Biol. 1986 Nov;6(11):3838–3846. doi: 10.1128/mcb.6.11.3838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reisman D., Yates J., Sugden B. A putative origin of replication of plasmids derived from Epstein-Barr virus is composed of two cis-acting components. Mol Cell Biol. 1985 Aug;5(8):1822–1832. doi: 10.1128/mcb.5.8.1822. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rooney C. M., Brimmell M., Buschle M., Allan G., Farrell P. J., Kolman J. L. Host cell and EBNA-2 regulation of Epstein-Barr virus latent-cycle promoter activity in B lymphocytes. J Virol. 1992 Jan;66(1):496–504. doi: 10.1128/jvi.66.1.496-504.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rooney C., Howe J. G., Speck S. H., Miller G. Influence of Burkitt's lymphoma and primary B cells on latent gene expression by the nonimmortalizing P3J-HR-1 strain of Epstein-Barr virus. J Virol. 1989 Apr;63(4):1531–1539. doi: 10.1128/jvi.63.4.1531-1539.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sugden B., Warren N. A promoter of Epstein-Barr virus that can function during latent infection can be transactivated by EBNA-1, a viral protein required for viral DNA replication during latent infection. J Virol. 1989 Jun;63(6):2644–2649. doi: 10.1128/jvi.63.6.2644-2649.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsang S. F., Wang F., Izumi K. M., Kieff E. Delineation of the cis-acting element mediating EBNA-2 transactivation of latent infection membrane protein expression. J Virol. 1991 Dec;65(12):6765–6771. doi: 10.1128/jvi.65.12.6765-6771.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woisetschlaeger M., Jin X. W., Yandava C. N., Furmanski L. A., Strominger J. L., Speck S. H. Role for the Epstein-Barr virus nuclear antigen 2 in viral promoter switching during initial stages of infection. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3942–3946. doi: 10.1073/pnas.88.9.3942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zimber-Strobl U., Suentzenich K. O., Laux G., Eick D., Cordier M., Calender A., Billaud M., Lenoir G. M., Bornkamm G. W. Epstein-Barr virus nuclear antigen 2 activates transcription of the terminal protein gene. J Virol. 1991 Jan;65(1):415–423. doi: 10.1128/jvi.65.1.415-423.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]