1887

Abstract

Here, we demonstrate that human herpesvirus 6B (HHV-6B) infection upregulates the tumour suppressor p53 and induces phosphorylation of p53 at Ser392. Interestingly, phosphorylation at the equivalent site has previously been shown to correlate with p53 tumour suppression in murine models. Although the signalling pathways leading to Ser392 phosphorylation are poorly understood, they seem to include casein kinase 2 (CK2), double-stranded RNA-activated protein kinase (PKR), p38 or cyclin-dependent kinase 9 (Cdk9). By using column chromatography and kinase assays, CK2 and p38, but not PKR or Cdk9, eluted in column fractions that phosphorylated p53 at Ser392. However, treatment of cells with neither the CK2 and Cdk9 inhibitor 5,6-dichloro-1---ribofuranosylbenzimidazole (DRB) nor p38 kinase inhibitors reduced HHV-6B-induced Ser392 phosphorylation significantly. Knockdown of the CK2 subunit or p38 by small interfering RNA had no effect on HHV-6B-induced phosphorylation of p53 at Ser392. Thus, HHV-6B induces p53 Ser392 phosphorylation by an atypical pathway independent of CK2 and p38 kinases, whereas mitogen-activated protein (MAP) kinase signalling pathways are involved in viral replication.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83136-0
2008-01-01
2020-01-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/1/87.html?itemId=/content/journal/jgv/10.1099/vir.0.83136-0&mimeType=html&fmt=ahah

References

  1. Adamson, A. L., Darr, D., Holley-Guthrie, E., Johnson, R. A., Mauser, A., Swenson, J. & Kenney, S. ( 2000; ). Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 and c-Jun N-terminal kinases. J Virol 74, 1224–1233.[CrossRef]
    [Google Scholar]
  2. Blaydes, J. P., Craig, A. L., Wallace, M., Ball, H. M., Traynor, N. J., Gibbs, N. K. & Hupp, T. R. ( 2000a; ). Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. Oncogene 19, 3829–3839.[CrossRef]
    [Google Scholar]
  3. Blaydes, J. P., Vojtesek, B., Bloomberg, G. B. & Hupp, T. R. ( 2000b; ). The development and use of phospho-specific antibodies to study protein phosphorylation. Methods Mol Biol 99, 177–189.
    [Google Scholar]
  4. Bonin, L. R. & McDougall, J. K. ( 1997; ). Human cytomegalovirus IE2 86-kilodalton protein binds p53 but does not abrogate G1 checkpoint function. J Virol 71, 5861–5870.
    [Google Scholar]
  5. Boutell, C. & Everett, R. D. ( 2004; ). Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner. J Virol 78, 8068–8077.[CrossRef]
    [Google Scholar]
  6. Bradham, C. & McClay, D. R. ( 2006; ). p38 MAPK in development and cancer. Cell Cycle 5, 824–828.[CrossRef]
    [Google Scholar]
  7. Braun, D. K., Dominguez, G. & Pellett, P. E. ( 1997; ). Human herpesvirus 6. Clin Microbiol Rev 10, 521–567.
    [Google Scholar]
  8. Bruins, W., Zwart, E., Attardi, L. D., Iwakuma, T., Hoogervorst, E. M., Beems, R. B., Miranda, B., van Oostrom, C. T., van den Berg, J. & other authors ( 2004; ). Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24, 8884–8894.[CrossRef]
    [Google Scholar]
  9. Buchou, T., Vernet, M., Blond, O., Jensen, H. H., Pointu, H., Olsen, B. B., Cochet, C., Issinger, O. G. & Boldyreff, B. ( 2003; ). Disruption of the regulatory β subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23, 908–915.[CrossRef]
    [Google Scholar]
  10. Bulavin, D. V., Saito, S., Hollander, M. C., Sakaguchi, K., Anderson, C. W., Appella, E. & Fornace, A. J., Jr ( 1999; ). Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 18, 6845–6854.[CrossRef]
    [Google Scholar]
  11. Castillo, J. P., Frame, F. M., Rogoff, H. A., Pickering, M. T., Yurochko, A. D. & Kowalik, T. F. ( 2005; ). Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J Virol 79, 11467–11475.[CrossRef]
    [Google Scholar]
  12. Claudio, P. P., Cui, J., Ghafouri, M., Mariano, C., White, M. K., Safak, M., Sheffield, J. B., Giordano, A., Khalili, K. & other authors ( 2006; ). Cdk9 phosphorylates p53 on serine 392 independently of CKII. J Cell Physiol 208, 602–612.[CrossRef]
    [Google Scholar]
  13. Collot-Teixeira, S., Bass, J., Denis, F. & Ranger-Rogez, S. ( 2004; ). Human tumor suppressor p53 and DNA viruses. Rev Med Virol 14, 301–319.[CrossRef]
    [Google Scholar]
  14. Cuddihy, A. R., Wong, A. H., Tam, N. W., Li, S. & Koromilas, A. E. ( 1999; ). The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18, 2690–2702.[CrossRef]
    [Google Scholar]
  15. De Bolle, L., Hatse, S., Verbeken, E., De, C. E. & Naesens, L. ( 2004; ). Human herpesvirus 6 infection arrests cord blood mononuclear cells in G2 phase of the cell cycle. FEBS Lett 560, 25–29.[CrossRef]
    [Google Scholar]
  16. de Falco, G. & Giordano, A. ( 1998; ). CDK9 (PITALRE): a multifunctional cdc2-related kinase. J Cell Physiol 177, 501–506.[CrossRef]
    [Google Scholar]
  17. Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. ( 1995; ). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92, 7686–7689.[CrossRef]
    [Google Scholar]
  18. Hanna, D. E., Rethinaswamy, A. & Glover, C. V. ( 1995; ). Casein kinase II is required for cell cycle progression during G1 and G2/M in Saccharomyces cerevisiae. J Biol Chem 270, 25905–25914.[CrossRef]
    [Google Scholar]
  19. Hoogervorst, E. M., Bruins, W., Zwart, E., van Oostrom, C. T., van den Aardweg, G. J., Beems, R. B., van den Berg, J., Jacks, T., van Steeg, H. & de Vries, A. ( 2005; ). Lack of p53 Ser389 phosphorylation predisposes mice to develop 2-acetylaminofluorene-induced bladder tumors but not ionizing radiation-induced lymphomas. Cancer Res 65, 3610–3616.[CrossRef]
    [Google Scholar]
  20. Huang, C., Ma, W. Y., Maxiner, A., Sun, Y. & Dong, Z. ( 1999; ). p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem 274, 12229–12235.[CrossRef]
    [Google Scholar]
  21. Hupp, T. R. & Lane, D. P. ( 1994; ). Allosteric activation of latent p53 tetramers. Curr Biol 4, 865–875.[CrossRef]
    [Google Scholar]
  22. Hupp, T. R., Meek, D. W., Midgley, C. A. & Lane, D. P. ( 1992; ). Regulation of the specific DNA binding function of p53. Cell 71, 875–886.[CrossRef]
    [Google Scholar]
  23. Hupp, T. R., Lane, D. P. & Ball, K. L. ( 2000; ). Strategies for manipulating the p53 pathway in the treatment of human cancer. Biochem J 352, 1–17.[CrossRef]
    [Google Scholar]
  24. Jin, S. & Levine, A. J. ( 2001; ). The p53 functional circuit. J Cell Sci 114, 4139–4140.
    [Google Scholar]
  25. Kashanchi, F., Araujo, J., Doniger, J., Muralidhar, S., Hoch, R., Khleif, S., Mendelson, E., Thompson, J., Azumi, N. & other authors ( 1997; ). Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53. Oncogene 14, 359–367.[CrossRef]
    [Google Scholar]
  26. Keller, D., Zeng, X., Li, X., Kapoor, M., Iordanov, M. S., Taya, Y., Lozano, G., Magun, B. & Lu, H. ( 1999; ). The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53. Biochem Biophys Res Commun 261, 464–471.[CrossRef]
    [Google Scholar]
  27. Keller, D. M., Zeng, X., Wang, Y., Zhang, Q. H., Kapoor, M., Shu, H., Goodman, R., Lozano, G., Zhao, Y. & Lu, H. ( 2001; ). A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell 7, 283–292.[CrossRef]
    [Google Scholar]
  28. Kudoh, A., Fujita, M., Zhang, L., Shirata, N., Daikoku, T., Sugaya, Y., Isomura, H., Nishiyama, Y. & Tsurumi, T. ( 2005; ). Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment. J Biol Chem 280, 8156–8163.[CrossRef]
    [Google Scholar]
  29. Langland, J. O., Cameron, J. M., Heck, M. C., Jancovich, J. K. & Jacobs, B. L. ( 2006; ). Inhibition of PKR by RNA and DNA viruses. Virus Res 119, 100–110.[CrossRef]
    [Google Scholar]
  30. Levine, A. J. ( 1997; ). p53, the cellular gatekeeper for growth and division. Cell 88, 323–331.[CrossRef]
    [Google Scholar]
  31. Liang, S. H., Hong, D. & Clarke, M. F. ( 1998; ). Cooperation of a single lysine mutation and a C-terminal domain in the cytoplasmic sequestration of the p53 protein. J Biol Chem 273, 19817–19821.[CrossRef]
    [Google Scholar]
  32. Litchfield, D. W. ( 2003; ). Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369, 1–15.[CrossRef]
    [Google Scholar]
  33. MacPherson, D., Kim, J., Kim, T., Rhee, B. K., van Oostrom, C. T., DiTullio, R. A., Vanere, M., Halazonetis, T. D., Bronson, R. & other authors ( 2004; ). Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23. EMBO J 23, 3689–3699.[CrossRef]
    [Google Scholar]
  34. Mauser, A., Saito, S., Appella, E., Anderson, C. W., Seaman, W. T. & Kenney, S. ( 2002; ). The Epstein-Barr virus immediate-early protein BZLF1 regulates p53 function through multiple mechanisms. J Virol 76, 12503–12512.[CrossRef]
    [Google Scholar]
  35. Meek, D. W., Simon, S., Kikkawa, U. & Eckhart, W. ( 1990; ). The p53 tumour suppressor protein is phosphorylated at serine 389 by casein kinase II. EMBO J 9, 3253–3260.
    [Google Scholar]
  36. Muralidhar, S., Doniger, J., Mendelson, E., Araujo, J. C., Kashanchi, F., Azumi, N., Brady, J. N. & Rosenthal, L. J. ( 1996; ). Human cytomegalovirus mtrII oncoprotein binds to p53 and down-regulates p53-activated transcription. J Virol 70, 8691–8700.
    [Google Scholar]
  37. Naranatt, P. P., Akula, S. M., Zien, C. A., Krishnan, H. H. & Chandran, B. ( 2003; ). Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-ζ-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol 77, 1524–1539.[CrossRef]
    [Google Scholar]
  38. Øster, B. & Höllsberg, P. ( 2002; ). Viral gene expression patterns in human herpesvirus 6B-infected T cells. J Virol 76, 7578–7586.[CrossRef]
    [Google Scholar]
  39. Øster, B., Bundgaard, B. & Höllsberg, P. ( 2005; ). Human herpesvirus 6B induces cell cycle arrest concomitant with p53 phosphorylation and accumulation in T cells. J Virol 79, 1961–1965.[CrossRef]
    [Google Scholar]
  40. Øster, B., Kaspersen, M. D., Kofod-Olsen, E., Bundgaard, B. & Höllsberg, P. ( 2006; ). Human herpesvirus 6B inhibits cell proliferation by a p53-independent pathway. J Clin Virol 37, S63–S68.[CrossRef]
    [Google Scholar]
  41. Pan, H., Xie, J., Ye, F. & Gao, S. J. ( 2006; ). Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol 80, 5371–5382.[CrossRef]
    [Google Scholar]
  42. Pise-Masison, C. A., Radonovich, M., Sakaguchi, K., Appella, E. & Brady, J. N. ( 1998; ). Phosphorylation of p53: a novel pathway for p53 inactivation in human T-cell lymphotropic virus type 1-transformed cells. J Virol 72, 6348–6355.
    [Google Scholar]
  43. Radhakrishnan, S. K. & Gartel, A. L. ( 2006; ). CDK9 phosphorylates p53 on serine residues 33, 315 and 392. Cell Cycle 5, 519–521.[CrossRef]
    [Google Scholar]
  44. Reed, L. J. & Muench, H. ( 1938; ). A simple method of estimating fifty per cent endpoints. Am J Hyg 27, 493–497.
    [Google Scholar]
  45. Resnick, M. A., Tomso, D., Inga, A., Menendez, D. & Bell, D. ( 2005; ). Functional diversity in the gene network controlled by the master regulator p53 in humans. Cell Cycle 4, 1026–1029.[CrossRef]
    [Google Scholar]
  46. Sakaguchi, K., Sakamoto, H., Lewis, M. S., Anderson, C. W., Erickson, J. W., Appella, E. & Xie, D. ( 1997; ). Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. Biochemistry 36, 10117–10124.[CrossRef]
    [Google Scholar]
  47. Seeber, S., Issinger, O. G., Holm, T., Kristensen, L. P. & Guerra, B. ( 2005; ). Validation of protein kinase CK2 as oncological target. Apoptosis 10, 875–885.[CrossRef]
    [Google Scholar]
  48. Shaulsky, G., Goldfinger, N., Ben-Ze'ev, A. & Rotter, V. ( 1990; ). Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 10, 6565–6577.
    [Google Scholar]
  49. Shirata, N., Kudoh, A., Daikoku, T., Tatsumi, Y., Fujita, M., Kiyono, T., Sugaya, Y., Isomura, H., Ishizaki, K. & Tsurumi, T. ( 2005; ). Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection. J Biol Chem 280, 30336–30341.[CrossRef]
    [Google Scholar]
  50. Speir, E., Modali, R., Huang, E. S., Leon, M. B., Shawl, F., Finkel, T. & Epstein, S. E. ( 1994; ). Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265, 391–394.[CrossRef]
    [Google Scholar]
  51. Takaoka, A., Hayakawa, S., Yanai, H., Stoiber, D., Negishi, H., Kikuchi, H., Sasaki, S., Imai, K., Shibue, T. & other authors ( 2003; ). Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523.[CrossRef]
    [Google Scholar]
  52. Takemoto, M., Mori, Y., Ueda, K., Kondo, K. & Yamanishi, K. ( 2004; ). Productive human herpesvirus 6 infection causes aberrant accumulation of p53 and prevents apoptosis. J Gen Virol 85, 869–879.[CrossRef]
    [Google Scholar]
  53. Takemoto, M., Koike, M., Mori, Y., Yonemoto, S., Sasamoto, Y., Kondo, K., Uchiyama, Y. & Yamanishi, K. ( 2005; ). Human herpesvirus 6 open reading frame U14 protein and cellular p53 interact with each other and are contained in the virion. J Virol 79, 13037–13046.[CrossRef]
    [Google Scholar]
  54. Tsai, H. L., Kou, G. H., Chen, S. C., Wu, C. W. & Lin, Y. S. ( 1996; ). Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem 271, 3534–3540.[CrossRef]
    [Google Scholar]
  55. Xie, J., Pan, H., Yoo, S. & Gao, S. J. ( 2005; ). Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 79, 15027–15037.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83136-0
Loading
/content/journal/jgv/10.1099/vir.0.83136-0
Loading

Data & Media loading...

Most cited articles

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error