Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Simian virus-40 large-T antigen binds p53 in human mesotheliomas

Nature Medicine volume 3, pages 908–912 (1997)Cite this article

Abstract

We found that simian virus 40 (SV40) induces mesotheliomas in hamsters1 and that 60% of human mesotheiiomas contain and express SV40 sequences2, results now confirmed by others [ref. 3–5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallÈ, and H.I.P. at “Simian virus 40: A possible human polyoma virus,” NIH workshop, 27–28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma6–8, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop mesothelioma6–8. Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human mesotheliomas should be carefully investigated.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Cicala, C., Pompetti, F. & Carbone, M. SV40 induces mesotheliomas in hamsters. Am. J. Pathol. 142, 1524–1533 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Carbone, M. et al. Simian virus 40-like sequences in human pleural mesothelioma. Oncogene 9, 1781–1790 (1994).

    CAS  PubMed  Google Scholar 

  3. Cristaudo, A. et al. Molecular biology studies on mesothelioma tumor samples: Preliminary data on H-ras, p21, and SV40. J. Environ. Pathol. Toxicol. Oncol. 14, 29–34 (1995).

    CAS  PubMed  Google Scholar 

  4. Pepper, C., Jasani, B., Navabi, H., Wynford-Thomas, D. & Gibbs, A.R. Simian virus 40 large T antigen (SV40LTag) primer specific DNA amplification in human pleural mesothelioma tissue. Thorax 51, 1074–1076 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. De Luca, A. et al. Association of the retinoblastoma gene family proteins and SV40 large T-antigen in human mesotheliomas. Nature Med. 3, 913–916 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Mossman, B.T., Kamp, D. & Weitzman, S.A. Mechanisms of carcinogenesis and clinical features of asbestos-associated cancers. Cancer Invest. 14, 464–478 (1996).

    Article  Google Scholar 

  7. Peto, J., Hodgson, J.T., Matthews, F.E. & Jones, J. Continuing increase in mesothelioma mortality in Britain. Lancet 345, 535–539 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Carbone, M., Rizzo, P. & Pass, H.I. Simian Virus 40, Pdliovaccines, and Human Tumors: A Review of Recent Developments. Oncogene. (in the press)

  9. Carbone, M. et al. SV40-like sequences in human bone tumors. Oncogene 13, 527–535 (1996).

    CAS  PubMed  Google Scholar 

  10. Lednicky, J.A., Garcea, R.L., Bergsagel, D.J. & Butel, J.S. Natural simian virus 40 strains are present in human choroid plexus and ependymoma tumors. Virology 212, 710–717 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Lednicky, J.A., Stewart, A.R., Jenkins, J.J., III, Finegold, M.J. & Butel, J.S. SV40 DNA in human osteosarcomas shows sequence variation among T-antigen genes. Int. J. Cancer (in the press).

  12. Bergsagel, D.J., Finegold, M.J., Butel, J.S., Kupsky, W.J. & Garcea, R. DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. N. Engl. J. Med. 36, 988–993 (1992).

    Article  Google Scholar 

  13. Martini, F. et al Simian virus 40 early region and large T antigen in human brain tumors, peripheral blood cells, and sperm fluids from healthy individuals. Cancer Res. 56, 4820–4825 (1996).

    CAS  PubMed  Google Scholar 

  14. Strickler, H.D. et al. Simian virus 40 and pleural mesothelioma in humans. Cancer Epidemiol. Biostatist. Prevent. 5, 473–475 (1995).

    Google Scholar 

  15. Jensen, F., Koprowski, H., Pagano, J.S., Ponten, J. & Ravdin, R.G. Autologous and homologous implantation of human cells transformed in vitro by SV40. J. Natl. Cancer Inst. 32, 917–937 (1964).

    Google Scholar 

  16. Avantaggiati, M.L., Carbone, M., Graessmann, A., Howard, B. & Levine, A.S. The SV40 large T antigen and Adenovirus E1 A oncoproteins interact with different isoforms of the transcriptional coactivator, p300. EMBO J. 15, 2236–2248 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Simmons, D.T. Transformation by polyomaviruses: Role of tumor suppressor proteins. in: DNA Tumor Viruses: Oncogenic Mechanisms. (eds. Barbanti Brodano, G., Bendinelli, M. & Friedman, H.) 27–50 (Plenum, New York & London, 1995).

    Chapter  Google Scholar 

  18. Tiemann, F., Zerrhan, J. & Deppert, W. Cooperation of simian virus 40 large and small T antigens in metabolic stabilization of tumor suppressor p53 during cellular transformation. J. Virol. 69, 6115–6121 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Metha, C.R., Patel, N.R. & Tsiatis, A.A. Exact significance testing establishing treatment equivalent with ordered categorical data. Biometrics 40, 819–825 (1984).

    Article  Google Scholar 

  20. Mayall, F.G., Goddard, H. & Gibbs, A.R. The frequency of p53 immunostaining in asbestos-associated mesotheliomas and non-asbestos associated mesotheliomas. Histopathology 22, 383–386 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Metcalf, R. et al. p53 and Kirsten-ras mutations in human mesothelioma cell lines. Cancer Res. 52, 2610–2615 (1992).

    CAS  PubMed  Google Scholar 

  22. Andersson, M. et al. Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: Incidence, histology, and p53 status. Int. J. Cancer. 63, 330–336 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Greenblatt, M.S., Bennett, W.P., Hollstein, M. & Harris, C.C. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res. 54, 4855–4878 (1994).

    CAS  PubMed  Google Scholar 

  24. Ruley, H.E. p53 and response to chemotherapy and radiotherapy. in: Important Advances in Oncology. (eds. De Vita, V.T., Jr., Hellman S. & Rosenberg, S.A.) 37–56 (Lippincott, Philadelphia, 1996).

    Google Scholar 

  25. Buchman, V.L., Chumakov, P.M., Ninkina, N.N., Samarina, O.P. & Georgiev, G.P. A variation in the structure of the protein-coding region of the human p53 gene. Gene 70, 245–252 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Marshall, J., Smith, A.E. & Cheng, S.H. Monoclonal antibody specific for BK virus large-T antigen allows discrimination among the different papovaviral large-T antigens. Oncogene 6, 1673–1676 (1991).

    CAS  PubMed  Google Scholar 

  27. Frost, J.A. et al. Simian virus 40 small t antigen cooperates with mitogen activated kinases to stimulate AP-1 activity. Mol. Cell. Biol. 14, 6244–6252 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Heintz, N.H., Janssen, Y.M. & Mossman, B.T. Persistent induction of c-fos and c-jun protooncogene expression by asbestos. Proc. Natl. Acad. Sci. USA 90, 3299–3304 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cicala, C. et al. SV40 small t deletion mutants preferentially transform mononuclear phagocytes and B-lymphocytes in vivo. Virology 190, 475–479 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Cicala, C. et al. Simian virus 40 small-t antigen stimulates viral DNA replication in permissive monkey cells. J. Virol. 68, 3138–3144 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Michieli, P. et al. Induction of Wafl/Cipl by a p53-independent pathway. Cancer Res. 54, 3391–3395 (1994).

    CAS  PubMed  Google Scholar 

  32. Ewald, D. et al. Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen. Science 273, 1384–1386 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Moorwood, K., Price, T.N.C. & Mayne, L.V. Mutation of p53 is not a prerequisite for immortalization of human fibroblasts by SV40 T antigen. Exp. Cell Res. 223, 308–313 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Banga, S.S. et al. SEN6, a locus for SV40 mediated immortalization of human cells, maps to 6q26–27. Oncogene 14, 313–321 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Maroulakaou, I.G., Anver, M., Garrett, L. & Green, J.E. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3 (1) simian virus 40 large tumor antigen fusion gene. Proc. Natl. Acad. Sci. USA 91, 11236–11240 (1994).

    Article  Google Scholar 

  36. Reddel, R.R., Malan-Shibley, L., Gerwin, B.I., Metcalf, R.A. & Harris, C.C. Tumorigenicity of human mesothelial cell line transfected with EJ-ras oncogene. J Natl. Cancer Inst. 81, 945–948 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Appel, J.D., Fasy, T.M., Kohtz, D.S. & Johnson, E.M. Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA. Proc. Natl. Acad. Sci. USA 85, 7670–7674 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dubes, G.R. Asbestos mediates viral DNA transformation of mouse cells to produce multilayered foci (abstract). Proc. Am. Assoc. Cancer Res. 34, 185 (1993).

  39. Marsella, J.M., Liu, B.L., Vaslet, C.A. & Agnes, B.K. Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Environ. Health Perspect. (in the press).

  40. Pompetti, F. et al. Oncogene alterations in primary, recurrent, and metastatic human bone tumors. J. Cell. Biochem. 63, 37–50 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Lehman, T.A. et al. p53 mutations, ras mutations and p53-heat-shock protein complexes in human lung carcinoma cell lines. Cancer Res. 51, 4090–4096 (1991).

    CAS  PubMed  Google Scholar 

  42. de Bartolomeis, A. et al. Dopaminergic and peptidergic mRNA levels in juvenile rat brain after prenatal cocaine treatment. Brain Res. Mol. Brain. Res. 21, 312–332 (1994).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardinal Bemardin Cancer Center, Cancer Immunology Program, Department of Pathology, Loyola University Chicago, Room 205, 2160 South First Avenue, Maywood, Illinois, 60153, USA

    Michele Carbone & Paola Rizzo

  2. Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland, 20889, USA

    Philip M. Grimley

  3. Laboratorio di Fisiopatologia Molecolare, University ofChieti, Chieti, 66013, Italy

    Antonio Procopio & Maria Teresa Giuliano

  4. Aerodigestive Program, Karmanos Cancer Institute, Detroit, Michigan, 48201, USA

    Daphne J.Y. Mew, Viji Shridhar & Harvey I. Pass

  5. Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Maryland, 20892, USA

    Andrea De Bartolomeis

  6. Deptartment of Pathology, Anatomy & Cell Biology and Sbarro Institute for Cancer Research, Jefferson Medical College, Philadelphia, Pennsylvania, 19107, USA

    Vincenzo Esposito & Antonio Giordano

  7. Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, 20892, USA

    Seth M. Steinberg

  8. Section on DNA Replication, Repair, and Mutagenesis, National Institute of Child Health and Human Development, Bethesda, Maryland, 20892, USA

    Arthur S. Levine

Authors
  1. Michele Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip M. Grimley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Procopio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daphne J.Y. Mew
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Viji Shridhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrea De Bartolomeis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vincenzo Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Teresa Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seth M. Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Arthur S. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Antonio Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Harvey I. Pass
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carbone, M., Rizzo, P., Grimley, P. et al. Simian virus-40 large-T antigen binds p53 in human mesotheliomas. Nat Med 3, 908–912 (1997). https://doi.org/10.1038/nm0897-908

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0897-908

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing