1887

Abstract

Infection with human cytomegalovirus (HCMV) modulates the expression of a number of cellular receptors and is known to inhibit expression of the epidermal growth factor receptor (EGFR), a cell surface receptor that can promote cell proliferation through a cascade of intracellular signalling events. We have examined the mechanisms by which HCMV mediates downregulation of EGFR expression and show that virus infection results in the profound upregulation of Wilms' Tumour 1 (WT1) protein, a transcription factor associated with the negative regulation of a number of growth factors and growth factor receptors, including EGFR. Moreover, chromatin immunoprecipitation experiments also show that HCMV infection results in increased binding of WT1 to the EGFR promoter. Finally, we show that depleting the cell of WT1 using small interfering RNA abrogates virus-mediated downregulation of EGFR. Taken together, our observations suggest that HCMV-mediated repression of EGFR expression results from a virus-mediated increase in cellular WT1, a known pleiotropic regulator of mitogenesis, apoptosis and differentiation.

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2009-07-01
2024-12-02
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References

  1. Ahn J. H., Brignole E. J., III & Hayward G. S. 1998; Disruption of PML subnuclear domains by the acidic IE1 protein of human cytomegalovirus is mediated through interaction with PML and may modulate a RING finger-dependent cryptic transactivator function of PML. Mol Cell Biol 18:4899–4913
    [Google Scholar]
  2. Baillie J., Sahlender D. A., Sinclair J. H. 2003; Human cytomegalovirus infection inhibits tumor necrosis factor alpha (TNF- α ) signaling by targeting the 55-kilodalton TNF- α receptor. J Virol 77:7007–7016 [CrossRef]
    [Google Scholar]
  3. Beutler T., Höflich C., Stevens P. A., Krüger D. H., Prösch S. 2003; Downregulation of the epidermal growth factor receptor by human cytomegalovirus infection in human fetal lung fibroblasts. Am J Respir Cell Mol Biol 28:86–94 [CrossRef]
    [Google Scholar]
  4. Compton T. 2004; Receptors and immune sensors: the complex entry path of human cytomegalovirus. Trends Cell Biol 14:5–8 [CrossRef]
    [Google Scholar]
  5. Englert C., Hou X., Maheswaran S., Bennett P., Ngwu C., Re G. G., Garvin A. J., Rosner M. R., Haber D. A. 1995; WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J 14:4662–4675
    [Google Scholar]
  6. Fairley J. A., Baillie J., Bain M., Sinclair J. H. 2002; Human cytomegalovirus infection inhibits epidermal growth factor (EGF) signalling by targeting EGF receptors. J Gen Virol 83:2803–2810
    [Google Scholar]
  7. Fortunato E. A., McElroy A. K., Sanchez I., Spector D. H. 2000; Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus. Trends Microbiol 8:111–119 [CrossRef]
    [Google Scholar]
  8. Gredmark S., Strååt K., Homman-Loudiyi M., Kannisto K., Söderberg-Nauclér C. 2007; Human cytomegalovirus downregulates expression of receptors for platelet-derived growth factor by smooth muscle cells. J Virol 81:5112–5120 [CrossRef]
    [Google Scholar]
  9. Hoffman P., Carlin C. 1994; Adenovirus E3 protein causes constitutively internalized epidermal growth factor receptors to accumulate in a prelysosomal compartment, resulting in enhanced degradation. Mol Cell Biol 14:3695–3706
    [Google Scholar]
  10. Isaacson M. K., Feire A. L., Compton T. 2007; Epidermal growth factor receptor is not required for human cytomegalovirus entry or signaling. J Virol 81:6241–6247 [CrossRef]
    [Google Scholar]
  11. Ishii S., Imamoto F., Yamanashi Y., Toyoshima K., Yamamoto T. 1987; Characterization of the promoter region of the human c- erbB-2 proto-oncogene. Proc Natl Acad Sci U S A 84:4374–4378 [CrossRef]
    [Google Scholar]
  12. Jorissen R. N., Walker F., Pouliot N., Garrett T. P., Ward C. W., Burgess A. W. 2003; Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284:31–53 [CrossRef]
    [Google Scholar]
  13. Kim J. M., Hong Y., Semba K., Kim S. 2000; Physical and functional interaction between the HCMV IE2 protein and the Wilms' tumor suppressor WT1. Biochem Biophys Res Commun 267:59–63 [CrossRef]
    [Google Scholar]
  14. Liang Y., Kurakin A., Roizman B. 2005; Herpes simplex virus 1 infected cell protein 0 forms a complex with CIN85 and Cbl and mediates the degradation of EGF receptor from cell surfaces. Proc Natl Acad Sci U S A 102:5838–5843 [CrossRef]
    [Google Scholar]
  15. Ludes-Meyers J. H., Subler M. A., Shivakumar C. V., Munoz R. M., Jiang P., Bigger J. E., Brown D. R., Deb S. P., Deb S. 1996; Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol 16:6009–6019
    [Google Scholar]
  16. Maekawa T., Imamoto F., Merlino G. T., Pastan I., Ishii S. 1989; Cooperative function of two separate enhancers of the human epidermal growth factor receptor proto-oncogene. J Biol Chem 264:5488–5494
    [Google Scholar]
  17. 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 [CrossRef]
    [Google Scholar]
  18. Nishi H., Senoo M., Nishi K. H., Murphy B., Rikiyama T., Matsumura Y., Habu S., Johnson A. C. 2001; p53 Homologue p63 represses epidermal growth factor receptor expression. J Biol Chem 276:41717–41724 [CrossRef]
    [Google Scholar]
  19. Nishi H., Nishi K. H., Johnson A. C. 2002; Early growth response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 62:827–834
    [Google Scholar]
  20. Rikiyama T., Curtis J., Oikawa M., Zimonjic D. B., Popescu N., Murphy B. A., Wilson M. A., Johnson A. C. 2003; GCF2: expression and molecular analysis of repression. Biochim Biophys Acta 162915–25 [CrossRef]
    [Google Scholar]
  21. Sinclair J., Baillie J., Bryant L., Caswell R. 2000; Human cytomegalovirus mediates cell cycle progression through G1 into early S phase in terminally differentiated cells. J Gen Virol 81:1553–1565
    [Google Scholar]
  22. Sinzger C., Kahl M., Laib K., Klingel K., Rieger P., Plachter B., Jahn G. 2000; Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus. J Gen Virol 81:3021–3035
    [Google Scholar]
  23. Soroceanu L., Akhavan A., Cobbs C. S. 2008; Platelet-derived growth factor- α receptor activation is required for human cytomegalovirus infection. Nature 455:391–395 [CrossRef]
    [Google Scholar]
  24. Sweet C. 1999; The pathogenicity of cytomegalovirus. FEMS Microbiol Rev 23:457–482 [CrossRef]
    [Google Scholar]
  25. Vallian S., Chin K. V., Chang K. S. 1998; The promyelocytic leukemia protein interacts with Sp1 and inhibits its transactivation of the epidermal growth factor receptor promoter. Mol Cell Biol 18:7147–7156
    [Google Scholar]
  26. Wang X., Huong S. M., Chiu M. L., Raab-Traub N., Huang E. S. 2003; Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424:456–461 [CrossRef]
    [Google Scholar]
  27. Wells A. 1999; EGF receptor. Int J Biochem Cell Biol 31:637–643 [CrossRef]
    [Google Scholar]
  28. Yan D. H., Chang L. S., Hung M. C. 1991; Repressed expression of the HER-2/c- erbB-2 proto-oncogene by the adenovirus E1a gene products. Oncogene 6:343–345
    [Google Scholar]
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