1887

Abstract

Small DNA tumour viruses, such as simian virus 40 (SV40), papilloma viruses and adenoviruses, encode proteins that form complexes with and inactivate the p53 and retinoblastoma (RB) proteins. This convergent evolution reflectsthe common need of these viruses to inactivate these two important regulators of cell cycle progression and cell survival. Polyomavirus, a close relative of SV40, is different. Its large T protein complexes only with RB, not with p53. We have examined whether this is compensated by the frequent appearance of p53 mutations in polyomavirus-induced tumours. We tested the p53 status of 15 polyomavirus-induced sarcomas. Two sarcomas were p53-negative while six carried mutant p53. Another six sarcomas expressed low levels of wild-type p53. One tumour expressed high levels of wild-type p53 protein as shown by DNA sequencing and immunofluorescence staining. MDM2 amplification was not detected in any of the tumours, but Northern blotting showed that MDM2 was overexpressed in at least two tumours that expressed wild-type p53 and in one tumour that expressed both wild-type and mutant p53. Treatment with the DNA-damaging agent mitomycin C caused p53 protein accumulation followed by induction of MDM2 and WAF1/p21 mRNA in four of the tumours expressing wild-type p53, indicating that p53-mediated transcriptional activation was unaltered in these tumours. However, p53-mediated transactivation of WAF1/p21 was impaired in the wild-type p53-expressing tumours that expressed elevated levels of MDM2. These results demonstrate that p53 mutation and inactivation are frequently but not invariably involved in polyomavirus-induced tumorigenesis.

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1997-04-01
2022-05-26
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References

  1. Asselin C., Bastin M. 1985; Sequences from polyomavirus and simian virus 40 large T genes capable of immortalizing primary rat embryo fibroblasts. Journal of Virology 56:958–968
    [Google Scholar]
  2. Asselin C., Gelinas C., Bastin M. 1983; Role of the three polyomavirus early proteins in tumorigenesis. Molecular and Cellular Biology 3:1451–1459
    [Google Scholar]
  3. Asselin C., Vass-Marego J., Bastin M. 1986; Mutation in the polyomavirus genome that activates the properties of large T associated with neoplastic transformation. Journal of Virology 57:165–172
    [Google Scholar]
  4. Barak Y., Gottlieb E., Juven-Gershon T., Oren M. 1994; Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translational potential. Genes & Development 8:1739–1749
    [Google Scholar]
  5. Chomczynski P., Sacchi N. 1987; Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162:156–159
    [Google Scholar]
  6. Cowie A., de Villiers J., Kamen R. 1986; Immortalization of rat embryo fibroblasts by mutant polyomavirus large T antigen deficient in DNA binding. Molecular and Cellular Biology 6:4344–4352
    [Google Scholar]
  7. Debbas M., White E. 1993; Wild type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes & Development 7:546–554
    [Google Scholar]
  8. DeCaprio J. A., Ludlow J. W., Figge J., Shew J. Y., Huang C. M., Lee W. H., Marsilio E., Paucha E., Livingston D. M. 1988; SV40 large T tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54:275–283
    [Google Scholar]
  9. Deng C., Zhang P., Harper J. W., Elledge S. J., Leder P. 1995; Mice lacking p21-CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82:675–684
    [Google Scholar]
  10. de Oca Luna R. M., Wagner D. S., Lozano G. 1995; Rescue of early embryonic lethality in mdm-2 deficient mice by deletion of p53. Nature 378:203–206
    [Google Scholar]
  11. Depamphilis M. L., Bradley M. K. 1986; Replication of SV40 and polyoma virus chromosomes. In The Papovaviridae 1 pp. 99–244 Salzman N. P. Edited by New York: Plenum;
    [Google Scholar]
  12. Dilworth S. M. 1995; Polyoma virus middle T antigen: meddler or mimic. Trends in Microbiology 3:31–35
    [Google Scholar]
  13. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A.Jr Butel J. S., Bradley A. 1992; Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215–221
    [Google Scholar]
  14. Dooley S., Ehrhart E., Radtke J., Unteregger G., Blin N. 1989; A procedure for simultaneous isolation of undegraded RNA, DNA and nuclear proteins suitable for interaction analysis in homologous systems. Methods in Molecular and Cellular Biology 1:95–105
    [Google Scholar]
  15. Dyson N., Bernards R., Friend S. H., Gooding L. R., Hassell J. A., Major E. O., Pipas J. M., Van Dyke T., Harlow E. 1990; Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. Journal of Virology 64:1353–1356
    [Google Scholar]
  16. Fakharzadeh S. S., Trusko S. P., George D. L. 1991; Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO Journal 10:1565–1569
    [Google Scholar]
  17. Finlay C. A. 1993; The mdm-2 oncogene can overcome wild-type p53 suppression oftransformed cell growth. Molecularand Cellular Biology 13:301–306
    [Google Scholar]
  18. Freund R., Bronson R. T., Benjamin T. L. 1992; Separation of immortalization from tumor induction with polyoma large T mutants that fail to bind the retinoblastoma gene product. Oncogene 7:1979–1987
    [Google Scholar]
  19. Freund R., Bauer P. H., Crissman H. A., Bradbury E. M., Benjamin T. L. 1994; Host range and cell cycle activation of properties of polyomavirus large T-antigen mutants defective in pRB binding. Journal of Virology 68:7227–7234
    [Google Scholar]
  20. Fritsche M., Haessler C., Brandner G. 1993; Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene 8:307–318
    [Google Scholar]
  21. Graeber T. G., Osmanian C., Jacks T., Housman D. E., Koch C. J., Lowe S. W., Giaccia A. J. 1996; Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379:88–91
    [Google Scholar]
  22. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. 1994; Mutations in the p53 tumor suppressor gene : clues to cancer etiology and molecular pathogenesis. Cancer Research 54:4855–4878
    [Google Scholar]
  23. Grodzicker T., Hopkins N. 1981; Origins of contemporary DNA tumor virus research. In DNA Tumor Viruses: Molecular Biology of Tumor Viruses pp. 7–8 Tooze J. Edited by Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  24. Hermeking H., Eick D. 1994; Mediation ofc-Myc-induced apoptosis by p53. Science 265:2091–2093
    [Google Scholar]
  25. Hultman T., Bergh S., Moks T., Uhlén M. 1991; Bidirectional solid phase sequencing of in vitro amplified plasmid DNA. BioTechniques 10:84–93
    [Google Scholar]
  26. Jat P. S., Sharp P. A. 1986; Large T antigens of simian virus 40 and polyomavirus efficiently establish primary fibroblasts. Journal of Virology 59:746–750
    [Google Scholar]
  27. Jones S. N., Roe A. E., Donehower L. A., Bradley A. 1995; Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378:206–208
    [Google Scholar]
  28. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. 1991; Participation of p53 protein in the cellular response to DNA damage. Cancer Research 51:6304–6311
    [Google Scholar]
  29. Ko L. J., Prives C. 1996; p53: puzzle and paradigm. Genes & Development 10:1054–1072
    [Google Scholar]
  30. Larose A., Dyson N., Sullivan M., Harlow E., Bastin M. M. 1991; Polyomavirus large T mutants affected in retinoblastoma protein binding are defective in immortalization. Journal of Virology 65:2308–2313
    [Google Scholar]
  31. Levine A. J. 1990; The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses. Virology 177:419–426
    [Google Scholar]
  32. Lin J. Y., Simmons D. T. 1991; The ability of large T antigen to complex with p53 is necessary for the increased life span and partial transformation of human cells by simian virus 40. Journal of Virology 65:6447–6453
    [Google Scholar]
  33. Lowe S. W., Jacks T., Housman D. E., Ruley H. E. 1994; Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proceedingsofthe NationalAcademy ofSciences, USA 91:2026–2030
    [Google Scholar]
  34. Magnusson K. P., Minarovits J., Klein G., Wiman K. G. 1995; A splice donor site mutation results in the insertion of five extra amino acids into p53 from SEWA mouse sarcoma cells. Gene 162:231–234
    [Google Scholar]
  35. Maltzman W., Czyzyk L. 1984; UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Molecular and Cellular Biology 4:1689–1694
    [Google Scholar]
  36. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. 1994; Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Research 54:3391–3395
    [Google Scholar]
  37. Oliner J. D., Kinzler K. W., Meltzer D. L., George D. L., Vogelstein B. 1992; Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83
    [Google Scholar]
  38. Oliner J. D., Pietenpol J. A., Thiagalingams S., Gyuris J., Kinzler K. W., Vogelstein B. 1993; Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53. Nature 362:857–860
    [Google Scholar]
  39. Parker S. B., Eichele G., Zhang P., Rawls A., Sands A. T., Bradley A., Olson E. N., Harper J. W., Elledge S. J. 1995; p53-independent expression of p21-Cip1 in muscle and other terminally differentiating cells. Science 267:1024–1027
    [Google Scholar]
  40. Sambrook J., Fritsch E. F., Maniatis T. 1989; Analysis and cloning of eukaryotic genomic DNA. In Molecular Cloning: A Laboratory Manual, 2nd edn. pp. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  41. Selivanova G., Wiman K. G. 1995; p53: a cell cycle regulator activated by DNA damage. Advances in Cancer Research 66:143–180
    [Google Scholar]
  42. Soeda E., Arrand J. R., Smolar N., Walsh J. E., Griffin B. E. 1980; Coding potential and regulatory signals of the polyoma virus genome. Nature 283:445–453
    [Google Scholar]
  43. Topp W. C., Lane D. P., Poolack R. 1981; Transformation by simian virus 40 & polyoma virus. In DNA Tumor Viruses: Molecular Biology of Tumor Viruses pp. 206–207 Tooze J. Edited by Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  44. Treisman R., Noval U., Favaloro J., Kamen R. 1981; Transformation of rat cells by an altered polyoma virus genome expressing only the middle-T protein. Nature 292:595–600
    [Google Scholar]
  45. Turler H. 1980; The tumor antigens and the early functions of polyoma virus. Molecular and Cellular Biology 32:63–93
    [Google Scholar]
  46. Villareal L. P., Fan H. 1989; History and biological strategy of polyomavirus, adenovirus and papillomavirus. In Common Mechanisms of Transformation by Small DNA Tumor Viruses pp. 1–17 Villareal L. P. Edited by Washington, DC: American Society for Microbiology;
    [Google Scholar]
  47. Voss H., Wiemann S., Wirkner S., Schwager C., Zimmermann J., Stegemann J., Erfle H., Hewitt N. A., Rupp T., Ansorge W. 1992; Automated DNA sequencing system resolving 1000 bases with fluorescein-15*dATP as internal label. Methods in Molecular and Cellular Biology 3:153–155
    [Google Scholar]
  48. Wagner A. J., Kokontis J. M., Hay N. 1994; Myc -mediated apoptosis requires wild type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21-Waf1/Cip1. Genes & Development 8:2817–2830
    [Google Scholar]
  49. Waldman T., Kinzler K. W., Vogelstein B. 1995; p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Research 55:5187–5190
    [Google Scholar]
  50. Wang E. H., Friedman P. N., Prives C. 1989; The murine p53 protein blocks replication of SV40 DNA in vitro by inhibiting the initiation functions of SV40 large T antigen. Cell 57:379–392
    [Google Scholar]
  51. Warburg O., Hiepler E. 1952; Versuche mit Ascites-Tumorzellen. Zeitschrift fur Naturforschung Section B Chemical Sciences 7:193–194
    [Google Scholar]
  52. Weinberg R. A. 1995; The retinoblastoma protein and cell cycle control. Cell 81:323–330
    [Google Scholar]
  53. Williams C. A., Krawisz B. R. 1989; Aurintricarboxylic acid as a ribonuclease inhibitor. Methods in Molecular and Cellular Biology 1:35–40
    [Google Scholar]
  54. Wiman K. G., Magnusson K. P., Ramqvist T., Klein G. 1991; Mutant p53 detected in a majority of Burkitt lymphoma cell lines by monoclonal antibody PAb240. Oncogene 6:1633–1639
    [Google Scholar]
  55. Wu X., Bayle J. H., Olson D., Levine A. J. 1993; The p53-mdm-2 auto-regulatory feedback loop. Genes & Development 7:1126–1132
    [Google Scholar]
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