1887

Abstract

The repression of human cytomegalovirus immediate-early (IE) lytic gene expression is crucial for the maintenance of the latent viral state. By using conditionally permissive cell lines, which provide a good model for the differentiation state-dependent repression of IE gene expression, we have identified several cellular factors that bind to the major immediate-early promoter (MIEP) and whose expression is down-regulated after differentiation to a permissive phenotype. Here we show that the cellular protein Ets-2 Repressor Factor (ERF) physically interacts with the MIEP and represses MIEP activity in undifferentiated non-permissive T2 embryonal carcinoma cells. This factor binds to the dyad element and the 21 bp repeats within the MIEP – regions known to be important for the negative regulation of MIEP activity. Finally, we show that following differentiation to a permissive phenotype ERF's repressive effects are severely abrogated.

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2003-01-01
2024-03-29
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References

  1. Alford C. A., Britt W. J. 1993 Cytomegalovirus. In The Human Herpesviruses pp. 227–255 Edited by Roizman B., Whitely R. J., Lopez C. New York: Raven Press;
    [Google Scholar]
  2. Andrews P. W., Damjanov I., Simon D., Banting G. S., Carlin C., Dracopoli N. C., Fogh J. 1984; Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest 50:147–162
    [Google Scholar]
  3. Austen M., Luscher B., Luscher-Firzlaff J. M. 1997; Characterization of the transcriptional regulator YY1. The bipartite transactivation domain is independent of interaction with the TATA box-binding protein, transcription factor IIB, TAFII55, or cAMP-responsive element-binding protein (CBP)-binding protein. J Biol Chem 272:1709–1717
    [Google Scholar]
  4. Chan Y. J., Chiou C. J., Huang Q., Hayward G. S. 1996; Synergistic interactions between overlapping binding sites for the serum response factor and ELK-1 proteins mediate both basal enhancement and phorbol ester responsiveness of primate cytomegalovirus major immediate-early promoters in monocyte and T-lymphocyte cell types. J Virol 70:8590–8605
    [Google Scholar]
  5. Dittmer J., Nordheim A. 1998; Ets transcription factors and human disease. Biochim Biophys Acta 1377:F1–11
    [Google Scholar]
  6. Donohoe M. E., Zhang X., McGinnis L., Biggers J., Li E., Shi Y. 1999; Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol 19:7237–7244
    [Google Scholar]
  7. Galvagni F., Cartocci E., Oliviero S. 1998; The dystrophin promoter is negatively regulated by YY1 in undifferentiated muscle cells. J Biol Chem 273:33708–33713
    [Google Scholar]
  8. Gonczol E., Andrews P. W., Plotkin S. A. 1984; Cytomegalovirus replicates in differentiated but not in undifferentiated human embryonal carcinoma cells. Science 224:159–161
    [Google Scholar]
  9. Hagemeier C., Bannister A. J., Cook A., Kouzarides T. 1993; The activation domain of transcription factor PU. 1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Proc Natl Acad Sci U S A 90:1580–1584
    [Google Scholar]
  10. Huang T. H., Oka T., Asai T., Okada T., Merrills B. W., Gertson P. N., Whitson R. H., Itakura K. 1996; Repression by a differentiation-specific factor of the human cytomegalovirus enhancer. Nucleic Acids Res 24:1695–1701
    [Google Scholar]
  11. Klemsz M. J., McKercher S. R., Celada A., Van B. C., Maki R. A. 1990; The macrophage and B cell-specific transcription factor PU. 1 is related to the ets oncogene. Cell 61:113–124
    [Google Scholar]
  12. Kothari S., Baillie J., Sissons J. G., Sinclair J. H. 1991; The 21 bp repeat element of the human cytomegalovirus major immediate early enhancer is a negative regulator of gene expression in undifferentiated cells. Nucleic Acids Res 19:1767–1771
    [Google Scholar]
  13. Le G. L., Sgouras D., Beal G. J., Mavrothalassitis G. 1999; Transcriptional repressor ERF is a Ras/mitogen-activated protein kinase target that regulates cellular proliferation. Mol Cell Biol 19:4121–4133
    [Google Scholar]
  14. Lee T. C., Zhang Y., Schwartz R. J. 1994; Bifunctional transcriptional properties of YY1 in regulating muscle actin and c-myc gene expression during myogenesis. Oncogene 9:1047–1052
    [Google Scholar]
  15. Liu R., Baillie J., Sissons J. G., Sinclair J. H. 1994; The transcription factor YY1 binds to negative regulatory elements in the human cytomegalovirus major immediate early enhancer/promoter and mediates repression in non-permissive cells. Nucleic Acids Res 22:2453–2459
    [Google Scholar]
  16. Liu D., Pavlopoulos E., Modi W., Moschonas N., Mavrothalassitis G. 1997; ERF: genomic organization, chromosomal localization and promoter analysis of the human and mouse genes. Oncogene 14:1445–1451
    [Google Scholar]
  17. Lubon H., Ghazal P., Hennighausen L., Reynolds-Kohler C., Lockshin C., Nelson J. 1989; Cell-specific activity of the modulator region in the human cytomegalovirus major immediate-early gene. Mol Cell Biol 9:1342–1345
    [Google Scholar]
  18. Malone C. L., Vesole D. H., Stinski M. F. 1990; Transactivation of a human cytomegalovirus early promoter by gene products from the immediate-early gene IE2 and augmentation by IE1: mutational analysis of the viral proteins. J Virol 64:1498–1506
    [Google Scholar]
  19. Martin M. E., Piette J., Yaniv M., Tang W. J., Folk W. R. 1988; Activation of the polyomavirus enhancer by a murine activator protein 1 (AP1) homolog and two contiguous proteins. Proc Natl Acad Sci U S A 85:5839–5843
    [Google Scholar]
  20. Mavrothalassitis G., Ghysdael J. 2000; Proteins of the ETS family with transcriptional repressor activity. Oncogene 19:6524–6532
    [Google Scholar]
  21. Meier J. L. 2001; Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator. J Virol 75:1581–1593
    [Google Scholar]
  22. Meier J. L., Pruessner J. A. 2000; The human cytomegalovirus major immediate-early distal enhancer region is required for efficient viral replication and immediate-early gene expression. J Virol 74:1602–1613
    [Google Scholar]
  23. Meier J. L., Stinski M. F. 1996; Regulation of human cytomegalovirus immediate-early gene expression. Intervirology 39:331–342
    [Google Scholar]
  24. Meier J. L., Stinski M. F. 1997; Effect of a modulator deletion on transcription of the human cytomegalovirus major immediate-early genes in infected undifferentiated and differentiated cells. J Virol 71:1246–1255
    [Google Scholar]
  25. Meier J. L., Keller M. J., McCoy J. J. 2002; Requirement of multiple cis-acting elements in the human cytomegalovirus major immediate-early distal enhancer for viral gene expression and replication. J Virol 76:313–326
    [Google Scholar]
  26. Murphy J. C., Fischle W., Verdin E., Sinclair J. H. 2002; Control of cytomegalovirus lytic gene expression by histone acetylation. EMBO J 21:1112–1120
    [Google Scholar]
  27. Nelson J. A., Reynolds-Kohler C., Smith B. A. 1987; Negative and positive regulation by a short segment in the 5′-flanking region of the human cytomegalovirus major immediate-early gene. Mol Cell Biol 7:4125–4129
    [Google Scholar]
  28. Pizzorno M. C. 2001; Nuclear cathepsin B-like protease cleaves transcription factor YY1 in differentiated cells. Biochim Biophys Acta 1536:31–42
    [Google Scholar]
  29. Pizzorno M. C., O'Hare P., Sha L., LaFemina R. L., Hayward G. S. 1988; trans-activation and autoregulation of gene expression by the immediate-early region 2 gene products of human cytomegalovirus. J Virol 62:1167–1179
    [Google Scholar]
  30. Sambrook J., Fritsch E., Maniatis T. 1989 Molecular Cloning: a Laboratory Manual Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  31. Seto E., Shi Y., Shenk T. 1991; YY1 is an initiator sequence-binding protein that directs and activates transcription in vitro. Nature 354:241–245
    [Google Scholar]
  32. Sgouras D. N., Athanasiou M. A., Beal G. J. J., Fisher R. J., Blair D. G., Mavrothalassitis G. J. 1995; ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J 14:4781–4793
    [Google Scholar]
  33. Shelbourn S. L., Kothari S. K., Sissons J. G., Sinclair J. H. 1989; Repression of human cytomegalovirus gene expression associated with a novel immediate early regulatory region binding factor. Nucleic Acids Res 17:9165–9171
    [Google Scholar]
  34. Shi Y., Lee J. S., Galvin K. M. 1997; Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1332:F49–66
    [Google Scholar]
  35. Sinclair J. H. 1999; Sites and mechanisms of latency of human cytomegalovirus. In Frontiers in Molecular Biology: DNA Virus Replication . pp 156–172 Edited by Cann A. J. Oxford: Oxford University Press;
  36. Sissons J. G., Bain M., Wills M. R. 2002; Latency and reactivation of human cytomegalovirus. J Infect 44:73–77
    [Google Scholar]
  37. Soderberg-Naucler C., Fish K. N., Nelson J. A. 1997; Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91:119–126
    [Google Scholar]
  38. Taylor-Wiedeman J., Sissons J. G., Borysiewicz L. K., Sinclair J. H. 1991; Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72:2059–2064
    [Google Scholar]
  39. Taylor-Wiedeman J., Sissons P., Sinclair J. 1994; Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol 68:1597–1604
    [Google Scholar]
  40. Thomas M. J., Seto E. 1999; Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?. Gene 236:197–208
    [Google Scholar]
  41. Usheva A., Shenk T. 1994; TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA. Cell 76:1115–1121
    [Google Scholar]
  42. Walowitz J. L., Bradley M. E., Chen S., Lee T. 1998; Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression. J Biol Chem 273:6656–6661
    [Google Scholar]
  43. Wasylyk C., Wasylyk B. 1992; Oncogenic conversion alters the transcriptional properties of ets. Cell Growth & Differ 3:617–625
    [Google Scholar]
  44. Wasylyk C., Flores P., Gutman A., Wasylyk B. 1989; PEA3 is a nuclear target for transcription activation by non-nuclear oncogenes. EMBO J 8:3371–3378
    [Google Scholar]
  45. Wasylyk B., Wasylyk C., Flores P., Begue A., Leprince D., Stehelin D. 1990; The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature 346:191–193
    [Google Scholar]
  46. Weinshenker B. G., Wilton S., Rice G. P. 1988; Phorbol ester-induced differentiation permits productive human cytomegalovirus infection in a monocytic cell line. J Immunol 140:1625–1631
    [Google Scholar]
  47. Yao Y. L., Dupont B. R., Ghosh S., Fang Y., Leach R. J., Seto E. 1998; Cloning, chromosomal localization and promoter analysis of the human transcription factor YY1. Nucleic Acids Res 26:3776–3783
    [Google Scholar]
  48. Yao Y. L., Yang W. M., Seto E. 2001; Regulation of transcription factor YY1 by acetylation and deacetylation. Mol Cell Biol 21:5979–5991
    [Google Scholar]
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