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Identification of a novel activity of human papillomavirus type 16 E6 protein in deregulating the G1/S transition

Oncogene volume 21, pages 5665–5672 (2002)Cite this article

Abstract

In this study we show that E6 of human papillomavirus has the ability to deregulate the cell cycle G1/S transition. In rodent immortalized fibroblasts (NIH3T3) serum deprivation or over-expression of the cyclin-dependent kinase inhibitors, p16INK4a or p27KIP1, leads to G1 cell cycle arrest. HPV16 E6 overcomes the antiproliferative signals, gaining the ability to drive serum-deprived and p16INK4a or p27KIP1 over-expressing cells into S phase. E6 protein from the benign HPV type 1 displays a similar activity to HPV16 E6 to deregulate the G1/S transition. Thus, this activity appears to be conserved between E6 proteins from non-oncogenic and oncogenic HPV types. Furthermore, we show that HPV16 E6 is not able to circumvent a G1 arrest imposed by pRb mutant in which all CDK phosphorylation sites have been mutated. These data indicate that the viral protein acts upstream of pRb and its mechanism in promoting cell cycle progression is dependent on pRb phosphorylation. In summary, this study describes a novel biological function of HPV E6 and shows that the S phase entry, required for viral DNA replication, is not exclusively controlled by E7, but that E6 also is involved in this event.

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References

  • Alevizopoulos K, Vlach J, Hennecke S, Amati B . 1997 EMBO J. 16: 5322–5333

  • Alunni-Fabbroni M, Littlewood T, Deleu L, Caldeira S, Giarre M, Dell'Orco M, Tommasino M . 2000 Oncogene 19: 2277–2285

  • Botz J, Zerfass-Thome K, Spitkovsky D, Delius H, Vogt B, Eilers M, Hatzigeorgiou A, Jansen-Dürr P . 1996 Mol. Cell. Biol. 16: 3401–3409

  • Boyer SN, Wazer DE, Band V . 1996 Cancer Research 56: 4620–4624

  • Caldeira S, de Villiers EM, Tommasino M . 2000 Oncogene 19: 821–826

  • Ciccolini F, Di Pasquale G, Carlotti F, Crawford L, Tommasino M . 1994 Oncogene 9: 2342–2348

  • Dyson N, Howley PM, Munger K, Harlow E . 1989 Science 243: 934–937

  • Elbel M, Carl S, Spaderna S, Iftner T . 1997 Virology 239: 132–149

  • Gage JR, Meyers C, Wettstein FO . 1990 J. Virol. 64: 723–730

  • Giarrè M, Caldeira S, Malanchi I, Ciccolini F, Leão MJ, Tommasino M . 2001 J. Virol. 75: 4705–4712

  • Jones DL, Munger K . 1997 J. Virol. 71: 2905–2912

  • Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI, Bartek J . 1997 Genes Dev. 11: 1479–1492

  • Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J . 1995 Nature 375: 503–506

  • Mann DJ, Jones NC . 1996 Curr. Biol. 6: 474–483

  • Martin LG, Demers GW, Galloway DA . 1998 J. Virol. 72: 975–985

  • Morgenstern JP, Land H . 1990 Nucleic Acids Res. 18: 3587–3596

  • Morris EJ, Dyson NJ . 2001 Adv. Cancer Res. 82: 1–54

  • Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM . 1989 EMBO J. 8: 4099–4105

  • Pear WS, Nolan GP, Scott ML, Baltimore D . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396

  • Schmitt A, Harry JB, Rapp B, Wettstein FO, Iftner T . 1994 Journal of Virology 68: 7051–7059

  • Schulze A, Zerfaß K, Spitkovsky D, Berges J, Middendorp S, Jansen-Dürr P, Henglein B . 1995 Proc. Natl. Acad. Sci. USA 92: 11264–11268

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . 1997 Cell 88: 593–602

  • Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512

  • Thomas M, Pim D, Banks L . 1999 Oncogene 18: 7690–7700

  • Tommasino M, Jansen-Dürr P . 1997 E7 protein. ‘Human papillomaviruses in human cancer: the role of E6 and E7 oncoproteins’ Austin, USA: R.G. Landes Company

    Book  Google Scholar 

  • Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B . 1996 EMBO J. 15: 6595–6604

  • Zerfass K, Schulze A, Spitkovsky D, Friedman V, Henglein B, Jansen-Dürr P . 1995 J. Virol. 69: 6389–6399

  • Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz J, Jansen-Dürr P . 1996 Oncogene 13: 2323–2330

  • zur Hausen H . 2000 J. Natl. Cancer Instit. 92: 690–698

  • Zwerschke W, Jansen-Durr P . 2000 Adv. Cancer Res. 78: 1–29

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Acknowledgements

We are grateful to Professors Harald zur Hausen and Lutz Gissmann for their continuous support and interest in our work. We would also like to thank all the members of our laboratory for their co-operation, Drs Bruno Amati, Jiri Bartek, Michele Pagano and Gordon Peters for antibodies or DNA constructs, Drs Werner Rittgen and Lutz Edler for statistical analysis and Dr Leonie Ringrose for critical reading of the manuscript. S Caldeira was supported by a PRAXIS XXI doctoral fellowship (Sub Programa Ciencia e Tecnologia do 2° Quadro Comunitario de Apoio).

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Author notes

  1. Marianna Alunni-Fabbroni

    Present address: Center for Cancer Biology, University of Rochester Medical Center, Rochester, 14642, New York, NY, USA

Authors and Affiliations

  1. Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, INF 242, Heidelberg, D-69120, Germany

    Ilaria Malanchi, Sandra Caldeira, Maja Krützfeldt, Marianna Giarre, Marianna Alunni-Fabbroni & Massimo Tommasino

  2. Centre for Cell and Molecular Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK

    Maja Krützfeldt

  3. Laboratory of Clinical Chemistry, Lausanne University Hospital (CHUV), Lausanne, CH-1011, Switzerland

    Marianna Giarre

Authors
  1. Ilaria Malanchi
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Correspondence to Massimo Tommasino.

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Malanchi, I., Caldeira, S., Krützfeldt, M. et al. Identification of a novel activity of human papillomavirus type 16 E6 protein in deregulating the G1/S transition. Oncogene 21, 5665–5672 (2002). https://doi.org/10.1038/sj.onc.1205617

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