1887

Abstract

The ZEBRA protein encoded by the Epstein–Barr virus (EBV) genome activates a switch from the latent to the lytic gene expression programme of the virus. ZEBRA, a member of the basic leucine zipper family of DNA-binding proteins, is a transcriptional activator capable of inducing expression from several virus lytic cycle promoters by binding to activator protein 1 (AP-1)-like sites. The Epstein–Barr virus HI F promoter, Fp, was for some time believed to initiate EBNA1-specific transcription in EBV-transformed latent cells. More recent data, however, show that Fp is an early lytic promoter and that the dominant EBNA1 gene promoter in latent cells is Qp, located about 200 bp downstream of Fp. In the present investigation we confirm that Fp displays the characteristics of a lytic promoter. Fp is downregulated in latently EBV-infected cells, both in the endogenous virus genome and in reporter plasmids that carry Fp regulatory sequences upstream of position −136 and down to +10 relative to the Fp transcription start site (+1), and is activated on induction of the virus lytic cycle. We show that the repression of Fp in latent stages of infection can be abolished by ZEBRA, and demonstrate that ZEBRA activates Fp through a direct interaction with an AP-1-like site at position −52/−46 in the promoter-proximal Fp region.

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2002-08-01
2019-10-22
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References

  1. Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. ( 1998; ). EBV persistence in memory B cells in vivo. Immunity 9, 395-404.[CrossRef]
    [Google Scholar]
  2. 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., Seguin, C. and others ( 1984; ). DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature 310, 207–211.[CrossRef]
    [Google Scholar]
  3. Biggin, M., Bodescot, M., Perricaudet, M. & Farrell, P. ( 1987; ). Epstein–Barr virus gene expression in P3HR1-superinfected Raji cells. Journal of Virology 61, 3120-3132.
    [Google Scholar]
  4. Bodescot, M., Perricaudet, M. & Farrell, P. J. ( 1987; ). A promoter for the highly spliced EBNA family of RNAs of Epstein–Barr virus. Journal of Virology 61, 3424-3430.
    [Google Scholar]
  5. Bulfone-Paus, S., Dempsey, L. A. & Maizels, N. ( 1995; ). Host factors LR1 and Sp1 regulate the Fp promoter of Epstein–Barr virus. Proceedings of the National Academy of Sciences, USA 92, 8293-8297.[CrossRef]
    [Google Scholar]
  6. Countryman, J. & Miller, G. ( 1985; ). Activation of expression of latent Epstein–Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. Proceedings of the National Academy of Sciences, USA 82, 4085-4089.[CrossRef]
    [Google Scholar]
  7. Dempsey, L. A., Hanakahi, L. A. & Maizels, N. ( 1998; ). A specific isoform of hnRNP D interacts with DNA in the LR1 heterodimer: canonical RNA binding motifs in a sequence-specific duplex DNA binding protein. Journal of Biological Chemistry 273, 29224-29229.[CrossRef]
    [Google Scholar]
  8. Dignam, J. D., Lebovitz, R. M. & Roeder, R. G. ( 1983; ). Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Research 11, 1475-1489.[CrossRef]
    [Google Scholar]
  9. Farrell, P. J., Rowe, D. T., Rooney, C. M. & Kouzarides, T. ( 1989; ). Epstein–Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO Journal 8, 127-132.
    [Google Scholar]
  10. Flemington, E. K., Goldfeld, A. E. & Speck, S. H. ( 1991; ). Efficient transcription of the Epstein–Barr virus immediate-early BZLF1 and BRLF1 genes requires protein synthesis. Journal of Virology 65, 7073-7077.
    [Google Scholar]
  11. Greenspan, J. S., Greenspan, D., Lennette, E. T., Abrams, D. I., Conant, M. A., Petersen, V. & Freese, U. K. ( 1985; ). Replication of Epstein–Barr virus within the epithelial cells of oral ‘hairy’ leukoplakia, an AIDS-associated lesion. New England Journal of Medicine 313, 1564-1571.[CrossRef]
    [Google Scholar]
  12. Hardwick, J. M., Lieberman, P. M. & Hayward, S. D. ( 1988; ). A new Epstein–Barr virus transactivator, R, induces expression of a cytoplasmic early antigen. Journal of Virology 62, 2274-2284.
    [Google Scholar]
  13. Hudson, G. S., Farrell, P. J. & Barrell, B. G. ( 1985; ). Two related but differentially expressed potential membrane proteins encoded by the EcoRI Dhet region of Epstein–Barr virus B95-8. Journal of Virology 53, 528-535.
    [Google Scholar]
  14. Hunter, T. & Karin, M. ( 1992; ). The regulation of transcription by phosphorylation. Cell 70, 375-387.[CrossRef]
    [Google Scholar]
  15. Ikuta, K., Satoh, Y., Hoshikawa, Y. & Sairenji, T. ( 2000; ). Detection of Epstein–Barr virus in salivas and throat washings in healthy adults and children. Microbes and Infection 2, 115-120.[CrossRef]
    [Google Scholar]
  16. Kenney, S., Kamine, J., Holley-Guthrie, E., Lin, J. C., Mar, E. C. & Pagano, J. ( 1989; ). The Epstein–Barr virus (EBV) BZLF1 immediate-early gene product differentially affects latent versus productive EBV promoters. Journal of Virology 63, 1729-1736.
    [Google Scholar]
  17. Kieff, E. & Rickinson, A. B. ( 2001; ). Epstein–Barr virus and its replication. In Fields Virology , pp. 2511-2574. Edited by D. M. Knipe & P. M. Howley. Philadelphia:Lippincott–Raven.
  18. Längle-Rouault, F., Patzel, V., Benavente, A., Taillez, M., Silvestre, N., Bompard, A., Sczakiel, G., Jacobs, E. & Rittner, K. ( 1998; ). Up to 100-fold increase of apparent gene expression in the presence of Epstein–Barr virus oriP sequences and EBNA1: implications of the nuclear import of plasmids. Journal of Virology 72, 6181-6185.
    [Google Scholar]
  19. Lear, A. L., Rowe, M., Kurilla, M. G., Lee, S., Henderson, S., Kieff, E. & Rickinson, A. B. ( 1992; ). The Epstein–Barr virus (EBV) nuclear antigen 1 BamHI F promoter is activated on entry of EBV-transformed B cells into the lytic cycle. Journal of Virology 66, 7461-7468.
    [Google Scholar]
  20. Masucci, M. G., Contreras-Salazar, B., Ragnar, E., Falk, K., Minarovits, J., Ernberg, I. & Klein, G. ( 1989; ). 5-Azacytidine up regulates the expression of Epstein–Barr virus nuclear antigen 2 (EBNA-2) through EBNA-6 and latent membrane protein in the Burkitt′s lymphoma line rael. Journal of Virology 63, 3135-3141.
    [Google Scholar]
  21. Miyashita, E. M., Yang, B., Lam, K. M., Crawford, D. H. & Thorley-Lawson, D. A. ( 1995; ). A novel form of Epstein–Barr virus latency in normal B cells in vivo. Cell 80, 593-601.[CrossRef]
    [Google Scholar]
  22. Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. ( 1997; ). Identification of the site of Epstein–Barr virus persistence in vivo as a resting B cell. Journal of Virology 71, 4882-4891.
    [Google Scholar]
  23. Nonkwelo, C., Henson, E. B. & Sample, J. ( 1995; ). Characterization of the Epstein–Barr virus Fp promoter. Virology 206, 183-195.[CrossRef]
    [Google Scholar]
  24. Öfverstedt, L. G., Hammarström, K., Balgobin, N., Hjerten, S., Pettersson, U. & Chattopadhyaya, J. ( 1984; ). Rapid and quantitative recovery of DNA fragments from gels by displacement electrophoresis (isotachophoresis). Biochimica et Biophysica Acta 782, 120-126.[CrossRef]
    [Google Scholar]
  25. Potter, H., Weir, L. & Leder, P. ( 1984; ). Enhancer-dependent expression of human kappa immunoglobulin genes introduced into mouse pre-B lymphocytes by electroporation. Proceedings of the National Academy of Sciences, USA 81, 7161-7165.[CrossRef]
    [Google Scholar]
  26. Rickinson, A. B. & Kieff, E. ( 2001; ). Epstein–Barr virus. In Fields Virology , pp. 2575-2627. Edited by D. M. Knipe & P. M. Howley. Philadelphia:Lippincott–Raven.
  27. Ricksten, A., Olsson, A., Andersson, T. & Rymo, L. ( 1988; ). The 5′ flanking region of the gene for the Epstein–Barr virus-encoded nuclear antigen 2 contains a cell type specific cis-acting regulatory element that activates transcription in transfected B-cells. Nucleic Acids Research 16, 8391-8410.[CrossRef]
    [Google Scholar]
  28. Rooney, C. M., Rowe, D. T., Ragot, T. & Farrell, P. J. ( 1989; ). The spliced BZLF1 gene of Epstein–Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. Journal of Virology 63, 3109-3116.
    [Google Scholar]
  29. Rowe, M., Lear, A. L., Croom-Carter, D., Davies, A. H. & Rickinson, A. B. ( 1992; ). Three pathways of Epstein–Barr virus gene activation from EBNA1-positive latency in B lymphocytes. Journal of Virology 66, 122-131.
    [Google Scholar]
  30. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. ( 1999; ). The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446-450.[CrossRef]
    [Google Scholar]
  31. Sambrook, J., Fritsch, E. F. & Maniatis, T. (1989). Extraction and purification of RNA. In Molecular Cloning, a Laboratory Manual, 2nd edn, pp. 7.12–7.15. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.
  32. Sample, J., Brooks, L., Sample, C., Young, L., Rowe, M., Gregory, C., Rickinson, A. & Kieff, E. ( 1991; ). Restricted Epstein–Barr virus protein expression in Burkitt lymphoma is due to a different Epstein–Barr nuclear antigen 1 transcriptional initiation site. Proceedings of the National Academy of Sciences, USA 88, 6343-6347.[CrossRef]
    [Google Scholar]
  33. Sanger, F., Nicklen, S. & Coulson, A. R. ( 1977; ). DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, USA 74, 5463-5467.[CrossRef]
    [Google Scholar]
  34. Schaefer, B. C., Woisetschlaeger, M., Strominger, J. L. & Speck, S. H. ( 1991; ). Exclusive expression of Epstein–Barr virus nuclear antigen 1 in Burkitt lymphoma arises from a third promoter, distinct from the promoters used in latently infected lymphocytes. Proceedings of the National Academy of Sciences, USA 88, 6550-6554.[CrossRef]
    [Google Scholar]
  35. Schaefer, B. C., Strominger, J. L. & Speck, S. H. ( 1995a; ). The Epstein–Barr virus BamHI F promoter is an early lytic promoter: lack of correlation with EBNA 1 gene transcription in group 1 Burkitt′s lymphoma cell lines. Journal of Virology 69, 5039-5047.
    [Google Scholar]
  36. Schaefer, B. C., Strominger, J. L. & Speck, S. H. ( 1995b; ). Redefining the Epstein–Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription initiation site in group I Burkitt lymphoma cell lines. Proceedings of the National Academy of Sciences, USA 92, 10565-10569.[CrossRef]
    [Google Scholar]
  37. Speck, S. H., Chatila, T. & Flemington, E. ( 1997; ). Reactivation of Epstein–Barr virus: regulation and function of the BZLF1 gene. Trends in Microbiology 5, 399-405.[CrossRef]
    [Google Scholar]
  38. Sung, N. S., Wilson, J., Davenport, M., Sista, N. D. & Pagano, J. S. ( 1994; ). Reciprocal regulation of the Epstein–Barr virus BamHI-F promoter by EBNA-1 and an E2F transcription factor. Molecular and Cellular Biology 14, 7144-7152.
    [Google Scholar]
  39. Takada, K. & Ono, Y. ( 1989; ). Synchronous and sequential activation of latently infected Epstein–Barr virus genomes. Journal of Virology 63, 445-449.
    [Google Scholar]
  40. Taylor, N., Flemington, E., Kolman, J. L., Baumann, R. P., Speck, S. H. & Miller, G. ( 1991; ). ZEBRA and a Fos–GCN4 chimeric protein differ in their DNA-binding specificities for sites in the Epstein–Barr virus BZLF1 promoter. Journal of Virology 65, 4033-4041.
    [Google Scholar]
  41. Thorley-Lawson, D. A., Miyashita, E. M. & Khan, G. ( 1996; ). Epstein–Barr virus and the B cell: that′s all it takes. Trends in Microbiology 4, 204-208.[CrossRef]
    [Google Scholar]
  42. Tsai, C. N., Liu, S. T. & Chang, Y. S. ( 1995; ). Identification of a novel promoter located within the BamHI Q region of the Epstein–Barr virus genome for the EBNA 1 gene. DNA and Cell Biology 14, 767-776.[CrossRef]
    [Google Scholar]
  43. Weigel, R., Fischer, D. K., Heston, L. & Miller, G. ( 1985; ). Constitutive expression of Epstein–Barr virus-encoded RNAs and nuclear antigen during latency and after induction of Epstein–Barr virus replication. Journal of Virology 53, 254-259.
    [Google Scholar]
  44. Wingender, E., Chen, X., Hehl, R., Karas, H., Liebich, I., Matys, V., Meinhardt, T., Pruss, M., Reuter, I. & Schacherer, F. ( 2000; ). TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Research 28, 316-319.[CrossRef]
    [Google Scholar]
  45. Zetterberg, H., Stenglein, M., Jansson, A., Ricksten, A. & Rymo, L. ( 1999; ). Relative levels of EBNA1 gene transcripts from the C/W, F and Q promoters in Epstein–Barr virus-transformed lymphoid cells in latent and lytic stages of infection. Journal of General Virology 80, 457-466.
    [Google Scholar]
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