Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1995 Jul;69(7):4158–4165. doi: 10.1128/jvi.69.7.4158-4165.1995

YY1 binds to and regulates cis-acting negative elements in the Epstein-Barr virus BZLF1 promoter.

E A Montalvo 1, M Cottam 1, S Hill 1, Y J Wang 1
PMCID: PMC189152  PMID: 7769675

Abstract

A 48-bp cis-acting negative element in the Epstein-Barr virus BZLF1 gene P1 promoter has been described previously. By DNase I footprinting experiments, two regions were identified as the protein-binding sites (previously designated site I and site II). In this report, the cellular transcription factor YY1 has been identified as a protein which binds to both of these elements, now designated ZIVA and ZIVB. Both ZIVA and ZIVB conferred cis-acting negative regulation on an enhancerless simian virus 40 promoter. In cotransfection experiments, overexpression of YY1 caused further repression of the enhancerless simian virus 40 promoter containing either the ZIVA or ZIVB element. Cotransfection of a plasmid expressing antisense to YY1 increased the expression of the heterologous promoter containing ZIVA but not ZIVB. In similar experiments carried out with the P1 promoter, overexpression of YY1 caused downregulation of P1 whereas antisense RNA to YY1 caused a slight increase in expression. Analyses of various P1 mutant constructions revealed additional YY1 sites downstream of ZIVB. Overexpression of YY1 also caused downregulation of a P1 mutant with no apparent YY1-binding sites. TPA treatment of Raji cells caused a temporal loss of YY1-binding activity but had no effect on the intracellular levels of YY1 protein. Serum induction of quiescent B cells also caused loss of YY1 binding to the ZIVB site, which was found to be a weak serum response element. In contrast, anti-immunoglobulin G treatment of Akata cells had no effect on either the YY1-binding activity or protein levels. The binding of YY1 to the cis-acting negative elements in infected B cells may play a pivotal role in the maintenance of Epstein-Barr virus latency.

Full Text

The Full Text of this article is available as a PDF (376.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bauer G., Höfler P., Zur Hausen H. Epstein-Barr virus induction by a serum factor. I. Induction and cooperation with additional inducers. Virology. 1982 Aug;121(1):184–194. doi: 10.1016/0042-6822(82)90128-3. [DOI] [PubMed] [Google Scholar]
  2. Bauknecht T., Angel P., Royer H. D., zur Hausen H. Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO J. 1992 Dec;11(12):4607–4617. doi: 10.1002/j.1460-2075.1992.tb05563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biggin M., Bodescot M., Perricaudet M., Farrell P. Epstein-Barr virus gene expression in P3HR1-superinfected Raji cells. J Virol. 1987 Oct;61(10):3120–3132. doi: 10.1128/jvi.61.10.3120-3132.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen S., Mills L., Perry P., Riddle S., Wobig R., Lown R., Millette R. L. Transactivation of the major capsid protein gene of herpes simplex virus type 1 requires a cellular transcription factor. J Virol. 1992 Jul;66(7):4304–4314. doi: 10.1128/jvi.66.7.4304-4314.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Countryman J., Jenson H., Seibl R., Wolf H., Miller G. Polymorphic proteins encoded within BZLF1 of defective and standard Epstein-Barr viruses disrupt latency. J Virol. 1987 Dec;61(12):3672–3679. doi: 10.1128/jvi.61.12.3672-3679.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Farrell P. J., Rowe D. T., Rooney C. M., Kouzarides T. Epstein-Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J. 1989 Jan;8(1):127–132. doi: 10.1002/j.1460-2075.1989.tb03356.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Flanagan J. R., Becker K. G., Ennist D. L., Gleason S. L., Driggers P. H., Levi B. Z., Appella E., Ozato K. Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus. Mol Cell Biol. 1992 Jan;12(1):38–44. doi: 10.1128/mcb.12.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Flemington E., Speck S. H. Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol. 1990 Mar;64(3):1227–1232. doi: 10.1128/jvi.64.3.1227-1232.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Flemington E., Speck S. H. Epstein-Barr virus BZLF1 trans activator induces the promoter of a cellular cognate gene, c-fos. J Virol. 1990 Sep;64(9):4549–4552. doi: 10.1128/jvi.64.9.4549-4552.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Flemington E., Speck S. H. Identification of phorbol ester response elements in the promoter of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol. 1990 Mar;64(3):1217–1226. doi: 10.1128/jvi.64.3.1217-1226.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Garcia-Blanco M. A., Cullen B. R. Molecular basis of latency in pathogenic human viruses. Science. 1991 Nov 8;254(5033):815–820. doi: 10.1126/science.1658933. [DOI] [PubMed] [Google Scholar]
  13. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grogan E., Jenson H., Countryman J., Heston L., Gradoville L., Miller G. Transfection of a rearranged viral DNA fragment, WZhet, stably converts latent Epstein-Barr viral infection to productive infection in lymphoid cells. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1332–1336. doi: 10.1073/pnas.84.5.1332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gualberto A., LePage D., Pons G., Mader S. L., Park K., Atchison M. L., Walsh K. Functional antagonism between YY1 and the serum response factor. Mol Cell Biol. 1992 Sep;12(9):4209–4214. doi: 10.1128/mcb.12.9.4209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gutsch D. E., Holley-Guthrie E. A., Zhang Q., Stein B., Blanar M. A., Baldwin A. S., Kenney S. C. The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B. Mol Cell Biol. 1994 Mar;14(3):1939–1948. doi: 10.1128/mcb.14.3.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hariharan N., Kelley D. E., Perry R. P. Delta, a transcription factor that binds to downstream elements in several polymerase II promoters, is a functionally versatile zinc finger protein. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9799–9803. doi: 10.1073/pnas.88.21.9799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kenney S., Kamine J., Holley-Guthrie E., Lin J. C., Mar E. C., Pagano J. The Epstein-Barr virus (EBV) BZLF1 immediate-early gene product differentially affects latent versus productive EBV promoters. J Virol. 1989 Apr;63(4):1729–1736. doi: 10.1128/jvi.63.4.1729-1736.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Labow M. A., Baim S. B., Shenk T., Levine A. J. Conversion of the lac repressor into an allosterically regulated transcriptional activator for mammalian cells. Mol Cell Biol. 1990 Jul;10(7):3343–3356. doi: 10.1128/mcb.10.7.3343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Laux G., Freese U. K., Fischer R., Polack A., Kofler E., Bornkamm G. W. TPA-inducible Epstein-Barr virus genes in Raji cells and their regulation. Virology. 1988 Feb;162(2):503–507. doi: 10.1016/0042-6822(88)90496-5. [DOI] [PubMed] [Google Scholar]
  21. Lee J. S., Galvin K. M., Shi Y. Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp1. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6145–6149. doi: 10.1073/pnas.90.13.6145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lee T. C., Shi Y., Schwartz R. J. Displacement of BrdUrd-induced YY1 by serum response factor activates skeletal alpha-actin transcription in embryonic myoblasts. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9814–9818. doi: 10.1073/pnas.89.20.9814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lee T. C., Zhang Y., Schwartz R. J. Bifunctional transcriptional properties of YY1 in regulating muscle actin and c-myc gene expression during myogenesis. Oncogene. 1994 Apr;9(4):1047–1052. [PubMed] [Google Scholar]
  24. Lieberman P. M., Berk A. J. In vitro transcriptional activation, dimerization, and DNA-binding specificity of the Epstein-Barr virus Zta protein. J Virol. 1990 Jun;64(6):2560–2568. doi: 10.1128/jvi.64.6.2560-2568.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lieberman P. M., Hardwick J. M., Sample J., Hayward G. S., Hayward S. D. The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. J Virol. 1990 Mar;64(3):1143–1155. doi: 10.1128/jvi.64.3.1143-1155.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Luka J., Kallin B., Klein G. Induction of the Epstein-Barr virus (EBV) cycle in latently infected cells by n-butyrate. Virology. 1979 Apr 15;94(1):228–231. doi: 10.1016/0042-6822(79)90455-0. [DOI] [PubMed] [Google Scholar]
  27. MacLellan W. R., Lee T. C., Schwartz R. J., Schneider M. D. Transforming growth factor-beta response elements of the skeletal alpha-actin gene. Combinatorial action of serum response factor, YY1, and the SV40 enhancer-binding protein, TEF-1. J Biol Chem. 1994 Jun 17;269(24):16754–16760. [PubMed] [Google Scholar]
  28. Manet E., Gruffat H., Trescol-Biemont M. C., Moreno N., Chambard P., Giot J. F., Sergeant A. Epstein-Barr virus bicistronic mRNAs generated by facultative splicing code for two transcriptional trans-activators. EMBO J. 1989 Jun;8(6):1819–1826. doi: 10.1002/j.1460-2075.1989.tb03576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Margolis D. M., Somasundaran M., Green M. R. Human transcription factor YY1 represses human immunodeficiency virus type 1 transcription and virion production. J Virol. 1994 Feb;68(2):905–910. doi: 10.1128/jvi.68.2.905-910.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Miller G., Rabson M., Heston L. Epstein-Barr virus with heterogeneous DNA disrupts latency. J Virol. 1984 Apr;50(1):174–182. doi: 10.1128/jvi.50.1.174-182.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mills L. K., Shi Y., Millette R. L. YY1 is the cellular factor shown previously to bind to regulatory regions of several leaky-late (beta gamma, gamma 1) genes of herpes simplex virus type 1. J Virol. 1994 Feb;68(2):1234–1238. doi: 10.1128/jvi.68.2.1234-1238.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Montalvo E. A., Parmley R. T., Grose C. Structural analysis of the varicella-zoster virus gp98-gp62 complex: posttranslational addition of N-linked and O-linked oligosaccharide moieties. J Virol. 1985 Mar;53(3):761–770. doi: 10.1128/jvi.53.3.761-770.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Montalvo E. A., Shi Y., Shenk T. E., Levine A. J. Negative regulation of the BZLF1 promoter of Epstein-Barr virus. J Virol. 1991 Jul;65(7):3647–3655. doi: 10.1128/jvi.65.7.3647-3655.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Natesan S., Gilman M. Z. DNA bending and orientation-dependent function of YY1 in the c-fos promoter. Genes Dev. 1993 Dec;7(12B):2497–2509. doi: 10.1101/gad.7.12b.2497. [DOI] [PubMed] [Google Scholar]
  35. Norman C., Runswick M., Pollock R., Treisman R. Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element. Cell. 1988 Dec 23;55(6):989–1003. doi: 10.1016/0092-8674(88)90244-9. [DOI] [PubMed] [Google Scholar]
  36. Packham G., Economou A., Rooney C. M., Rowe D. T., Farrell P. J. Structure and function of the Epstein-Barr virus BZLF1 protein. J Virol. 1990 May;64(5):2110–2116. doi: 10.1128/jvi.64.5.2110-2116.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Park K., Atchison M. L. Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3' enhancer and the immunoglobulin heavy-chain mu E1 site. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9804–9808. doi: 10.1073/pnas.88.21.9804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Raught B., Khursheed B., Kazansky A., Rosen J. YY1 represses beta-casein gene expression by preventing the formation of a lactation-associated complex. Mol Cell Biol. 1994 Mar;14(3):1752–1763. doi: 10.1128/mcb.14.3.1752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Riggs K. J., Saleque S., Wong K. K., Merrell K. T., Lee J. S., Shi Y., Calame K. Yin-yang 1 activates the c-myc promoter. Mol Cell Biol. 1993 Dec;13(12):7487–7495. doi: 10.1128/mcb.13.12.7487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rivera V. M., Sheng M., Greenberg M. E. The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. Genes Dev. 1990 Feb;4(2):255–268. doi: 10.1101/gad.4.2.255. [DOI] [PubMed] [Google Scholar]
  41. Rooney C. M., Rowe D. T., Ragot T., Farrell P. J. The spliced BZLF1 gene of Epstein-Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. J Virol. 1989 Jul;63(7):3109–3116. doi: 10.1128/jvi.63.7.3109-3116.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rooney C., Taylor N., Countryman J., Jenson H., Kolman J., Miller G. Genome rearrangements activate the Epstein-Barr virus gene whose product disrupts latency. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9801–9805. doi: 10.1073/pnas.85.24.9801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schwarzmann F., Prang N., Reichelt B., Rinkes B., Haist S., Marschall M., Wolf H. Negatively cis-acting elements in the distal part of the promoter of Epstein-Barr virus trans-activator gene BZLF1. J Gen Virol. 1994 Aug;75(Pt 8):1999–2006. doi: 10.1099/0022-1317-75-8-1999. [DOI] [PubMed] [Google Scholar]
  44. Seto E., Lewis B., Shenk T. Interaction between transcription factors Sp1 and YY1. Nature. 1993 Sep 30;365(6445):462–464. doi: 10.1038/365462a0. [DOI] [PubMed] [Google Scholar]
  45. Shi Y., Seto E., Chang L. S., Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. doi: 10.1016/0092-8674(91)90189-6. [DOI] [PubMed] [Google Scholar]
  46. Shimizu N., Takada K. Analysis of the BZLF1 promoter of Epstein-Barr virus: identification of an anti-immunoglobulin response sequence. J Virol. 1993 Jun;67(6):3240–3245. doi: 10.1128/jvi.67.6.3240-3245.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sixbey J. W., Nedrud J. G., Raab-Traub N., Hanes R. A., Pagano J. S. Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med. 1984 May 10;310(19):1225–1230. doi: 10.1056/NEJM198405103101905. [DOI] [PubMed] [Google Scholar]
  48. Takada K., Ono Y. Synchronous and sequential activation of latently infected Epstein-Barr virus genomes. J Virol. 1989 Jan;63(1):445–449. doi: 10.1128/jvi.63.1.445-449.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tovey M. G., Lenoir G., Begon-Lours J. Activation of latent Epstein-Barr virus by antibody to human IgM. Nature. 1978 Nov 16;276(5685):270–272. doi: 10.1038/276270a0. [DOI] [PubMed] [Google Scholar]
  50. Urier G., Buisson M., Chambard P., Sergeant A. The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J. 1989 May;8(5):1447–1453. doi: 10.1002/j.1460-2075.1989.tb03527.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Usheva A., Shenk T. TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA. Cell. 1994 Mar 25;76(6):1115–1121. doi: 10.1016/0092-8674(94)90387-5. [DOI] [PubMed] [Google Scholar]
  52. Zhang Q., Gutsch D., Kenney S. Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency. Mol Cell Biol. 1994 Mar;14(3):1929–1938. doi: 10.1128/mcb.14.3.1929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. zur Hausen H., O'Neill F. J., Freese U. K., Hecker E. Persisting oncogenic herpesvirus induced by the tumour promotor TPA. Nature. 1978 Mar 23;272(5651):373–375. doi: 10.1038/272373a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES