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.

SV40 infection induces telomerase activity in human mesothelial cells

Abstract

Mesotheliomas are malignant tumors of the pleural and peritoneal membranes which are often associated with asbestos exposure and with Simian virus 40 (SV40) infection. Telomerase activity is repressed in somatic cells and tissues but is activated in immortal and malignant cells. We evaluated telomerase activity in seven primary malignant mesothelioma biopsies and matched lung specimens and 20 mesothelioma cell lines and eight corresponding primary tumor cultures. All the tumor biopsies, and nearly all primary cell mesothelioma cultures and cell lines were telomerase positive. The findings in cell lines paralleled those observed in primary cultures in cases where paired samples were available. Next, we found that SV40, a DNA tumor virus present in 50% of mesothelioma biopsies in the USA, induced telomerase activity in primary human mesothelial cells, but not in primary fibroblasts. Telomerase activity became detectable as early as 72 h following wild-type (strain 776) SV40 infection, and a clear DNA ladder was detectable 1 week after infection. The amount of telomerase activity increased during passage in cell culture and appeared to parallel increases in the cellular amounts of the SV40 large T-antigen. Thus, SV40 infection leads to telomerase activity before the infected mesothelial cells become transformed and immortalized. SV40 infection of human fibroblasts did not cause detectable telomerase activity. We also determined that the SV40 small t-antigen (tag) plays an important role in inducing telomerase activity because this activity was undetectable or minimal in mesothelial cells infected and/or transformed by SV40 tag mutants. Asbestos alone did not induce telomerase activity, and asbestos did not influence telomerase activity in mesothelial cells infected with SV40. Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Abbreviations

SV40:

Simian virus 40

Tag:

SV40 large tumor antigen

tag:

SV40 small tumor antigen

HM:

primary human mesothelial cells

HF:

primary human fibroblasts

MM:

malignant mesothelioma

M.O.I.:

multiplicity of infection

TRAP:

telomeric repeat amplification protocol

References

  • Ali SK, De Caprio JA . 2001 Sem. Cancer Biol. 11: 15–21

  • Bocchetta M, Di Resta I, Powers A, Fresco R, Tosolini A, Testa JR, Pass HI, Rizzo P, Carbone M . 2000 Proc. Natl. Acad. Sci. USA 97: 10214–10218

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE . 1998 Science 279: 349–352

  • Broccoli D, Young JW, de Lange T . 1995 Proc. Natl. Acad. Sci. USA 92: 9082–9086

  • Broccoli D, Godley LA, Donehower LA, Varmus HE, de Lange T . 1996 Mol. Cell. Biol. 16: 3765–3772

  • Bryan TM, Reddel RR . 1994 Crit. Rev. Onco 5: 331–357

  • Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR . 1995 EMBO J. 14: 4240–4248

  • Cacciotti P, Libener R, Betta P, Martini F, Porta C, Procopio A, Strizzi L, Penengo L, Tognon M, Mutti L, Gaudino G . 2001 Proc. Natl. Acad. Sci. USA 98: 12032–12037

  • Carbone M, Pompetti F, Cicala C, Nguyen K, Dixon K, Dixon K . 1991 Molecular Basis of Human Cancer Nicolini C (ed) New York: Plenum Press pp 195–206

    Book  Google Scholar 

  • Carbone M, Rizzo P, Grimley PM, Procopio A, Mew DJ, Shridar V, de Bartolomeis A, Esposito V, Giuliano MT, Steinberg SM, Levine SM, Giordano A, Pass HI . 1997 Nat. Med. 3: 908–912

  • Carbone M, Kratzke RA, Testa JR . 2002 Semin. Oncol. in press

  • Chong L, van Steensel B, Broccoli D, Erdjument-Bromage H, Hanish J, Tempst P, de Lange T . 1995 Science 270: 1663–1667

  • Counter CM, Botelho FM, Wang P, Harley CB, Bacchetti S . 1994 J. Virol. 68: 3410–3414

  • De Luca A, Baldo A, Esposito V, Howard C, Bagella L, Rizzo P, Caputi M, Pass HI, Giordano GG, Baldi F, Carbone M, Giordano A . 1997 Nat. Med. 3: 913–916

  • Dunham MA, Neumann AA, Fasching CL, Reddel RR . 2000 Nat. Genet. 26: 447–450

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA . 1999a Nature 400: 464–468

  • Hahn W, SA S, Brooks M, York S, Eaton E, Kurachi A, Beijersbergen R, Knoll J, Meyerson M, Weinberg R . 1999b Nat. Med. 5: 1164–1170

  • Jasani B, Cristaudo A, Emri SA, Gazdar AF, Gibbs A, Krynska B, Miller C, Mutti L, Radu C, Tognon M, Procopio A . 2001 Semin. Cancer Biol. 11: 49–61

  • Kang SS, Kwon T, Kwon DY, Do S . 1999 J. Biol. Chem. 274: 13085–13090

  • Ke Y, Reddel RR, Gerwin BI, Reddel HK, Somers ANA, McMenamin AM, LaVeck MA, Sthel RA, Lechnier JF, Harris CC . 1989 Am. J. Pathol. 134: 979–991

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW . 1994 Science 266: 2011–2015

  • Klein B, Pastink A, Odijik H, Westerveld A, van der Eb AJ . 1990 Exp. Cell Res. 191: 256–262

  • Klein G . 2001 Proc. Natl. Acad. Sci. USA 97: 9830–9831

  • Klein G, Powers A, Croce CA . 2002 Oncogene 21: 1141–1149

  • Krynska B, Del Valle L, Croul S, Gordon J, Katsetos CD, Carbone M, Giordano A, Khalili K . 1999 Proc. Natl. Acad. Sci. USA 96: 11519–11524

  • Luderus ME, van Steensel B, Chong L, Sibon OC, Cremers FF, de Lange T . 1996 J. Cell. Biol. 135: 867–881

  • Ozer LH, Banga SS, Dasgupta T, Houghton JM, Hubbard K, Jha KH, Kim SH, Lenahan M, Pang Z, Pardinas JR, Ptsalis PC . 1996 Exp. Gerontol. 31: 303–310

  • Pipas JM, Levine AJ . 2001 Sem. Cancer Biol. 11: 23–30

  • Rizzo P, Di Resta I, Matker CM, Zhang A, Mutti L, Kast WM, Pass HI, Carbone M . 1998 Monaldi Arch. Chest Dis. 53: 202–210

  • Rundell K, Parakati R . 2001 Sem. Cancer Biol. 11: 5–13

  • Sager R . 1984 Cancer Cells 2: 487–493

  • Schrump DS, Waheed I . 2001 Sem. Cancer Biol. 11: 73–80

  • Shay JW, Wright WE . 1989 Exp. Cell Res. 184: 109–118

  • Shay JW, van der Haegen BA, Ying Y, Wright WE . 1993 Exp. Cell Res. 209: 45–52

  • Shay JW, Wright WE . 1996 Trends Genet. 12: 129–131

  • Shay JW, Zou Y, Hiyama E, Wright WE . 2001 Hum. Mol. Genet. 10: 677–685

  • Stewart SA, Weinberg RA . 2000 Semin. Cancer Biol. 10: 399–406

  • Testa SR, Carbone M, Hirvonen A, Khalili K, Krynska B, Linnainmaa K, Pooley FD, Rizzo P, Rusch V, Xiao GH . 1998 Cancer Res. 58: 4505–4509

  • Testa JR, Pass HI, Carbone M . 2001 Cancer: Principles and Practice of Oncology. DeVita Jr VT, Hellman S, Rosenberg SA. (eds) 6th edn Philadelphia: Lippincott Williams & Wilkins pp 1937–1943

    Google Scholar 

  • Testa JR, Giordano A . 2001 Sem. Cancer Biol. 11: 31–38

  • van Steensel B, de Lange T . 1997 Nature 385: 740–743

  • Vaziri H, Benchimol S . 1998 Curr. Biol. 8: 279–282

  • Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW . 1996 Dev. Genet. 18: 173–179

  • Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR . 1999 Cancer Res. 59: 4175–4179

  • Yu J, Boyapati A, Rundell K . 2002 Virology 230: 132–138

  • Zhang X, Mar V, Zhou W, Harrington L, Robinson M . 1999 Genes Dev. 13: 2388–2399

Download references

Acknowledgements

We are grateful to Dr Kathleen Rundell for the critical reading of this manuscript. This work was supported by grants: ACS 8632 through a generous donation from Mr Dean Butchkovitz, by a grant from the Charlotte Geyer Foundation and by the Riviera Country Club, Illinois (to M Carbone); and by grants NCI CA-45745 and CA-06927, a gift from the Local #14 Mesothelioma Fund of the International Association of Heat and Frost Insulators & Asbestos Workers in memory of Hank Vaughan and Alice Haas, and an appropriation from the Commonwealth of Pennsylvania (to JR Testa).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michele Carbone.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Foddis, R., De Rienzo, A., Broccoli, D. et al. SV40 infection induces telomerase activity in human mesothelial cells. Oncogene 21, 1434–1442 (2002). https://doi.org/10.1038/sj.onc.1205203

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205203

Keywords

  • SV40
  • telomerase
  • asbestos
  • mesothelioma

Further reading

Search

Quick links