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.

  • Molecular and Cellular Pathology
  • Published:

E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia

British Journal of Cancer volume 86, pages 263–268 (2002)Cite this article

Abstract

In common with other E2F1 responsive genes such as p14ARF and B-myb, the promoter of p73 is shown to be positively regulated in cell lines and primary human keratinocytes by E7 proteins from oncogenic human papillomavirus (HPV) types 16, 18, 31 and 33, but not HPV 6. Mutational analysis revealed that transactivation of the p73 promoter by HPV 16E7 requires association with pRb. Expression of p73 in normal cervical epithelium is confined to the basal and supra-basal layers. In contrast, expression in neoplastic lesions is detected throughout the epithelium and increases with grade of neoplasia, being maximal in squamous cell cancers (SCC). Deregulation of expression of the N-terminal splice variant p73Δ2 was observed in a significant proportion of cancers, but not in normal epithelium. The frequent over-expression of p73Δ2, which has recognized transdominant properties, in malignant and pre-malignant lesions suggests a role in the oncogenic process in cervical epithelium.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Bates S, Phillips AC, Clarke PA, Stott F, Peters G, Ludwig RL, Vousden KH (1998) p14ARF links the tumour suppressors RB and p53. Nature 395: 124–125

    Article  CAS  Google Scholar 

  • Chi S-G, Chang S-G, Lee S-J, Lee C-H, Kim JI, Park J-H (1999) Elevated and biallelic expression of p73 is associated with progression of human bladder cancer. Cancer Res 59: 2791–2793

    CAS  PubMed  Google Scholar 

  • Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5′CpG methylation. Cancer Res 59: 3352–3356

    CAS  PubMed  Google Scholar 

  • De Laurenzi V, Rossi A, Terrinoni A, Barcoroli D, Levrero M, Costanzo A, Knight RA, Guerrieri P, Melino G (2000) p63 and p73 transactivate differentiation gene promoters in human keratinocytes. Biochem Biophys Res Commun 273: 342–346

    Article  CAS  Google Scholar 

  • De Laurenzi V, Costanzo A, Barcaroli D, Terrinoni A, Falco M, Annicchiarico-Petruzzelli M, Levrero M, Melino GJ (1998) Two new splice variants, gamma and delta, with different transcriptional activity. J Exp Med 188: 1763–1768

    Article  CAS  Google Scholar 

  • Ding Y, Inoue T, Kamiyama J, Tamura Y, Ohtani-Fujita N, Igata E, Sakai T (1999) Molecular cloning and functional characterization of the upstream promoter region of the human p73 gene. DNA Res 6: 347–351

    Article  CAS  Google Scholar 

  • Edmonds C, Vousden KH (1989) A point mutational analysis of human papillomavirus type 16 E7 protein. J Virol 63: 2650–2656

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fillippovich I, Sorokina N, Gatei M, Haupt Y, Hobson K, Moallem E, Spring K, Mould M, McGuckin MA, Lavin MF, Khanna KK (2001) Transactivation-deficient p73α (p73Delta exon 2) inhibits apoptosis and competes with p53. Oncogene 20: 514–522

    Article  CAS  Google Scholar 

  • Gazzeri S, Della Valle V, Chaussade L, Brambilla C, Larsen CJ, Brambilla E (1998) The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 58: 3926–3931

    CAS  PubMed  Google Scholar 

  • Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J 8: 3905–3910

    Article  CAS  Google Scholar 

  • Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin Jr WG (2000) Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 407: 645–648

    Article  CAS  Google Scholar 

  • Jost CA, Marin MC, Kaelin Jr WG (1997) p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 389: 191–194

    Article  CAS  Google Scholar 

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, DuMont X, Ferrara P, McKeon F, Caput D (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90: 809–819

    Article  CAS  Google Scholar 

  • Lam E, Lam EW, Morris JD, Davies R, Crook T, Watson RJ, Vousden KH (1994) HPV16 E7 oncoprotein deregulates B-myb expression: correlation with targeting of p107/E2F complexes. EMBO J 13: 871–878

    Article  CAS  Google Scholar 

  • Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF (2000) A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature 407: 642–645

    Article  CAS  Google Scholar 

  • Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley P (1989) Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 8: 4099–4105

    Article  CAS  Google Scholar 

  • Ng S-W, Yiu GK, Liu Y, Huang L-W, Palnati M, Jun SH, Berkowitz RS, Mok SC (2000) Analysis of p73 in human borderline and invasive ovarian tumor. Oncogene 19: 1885–1890

    Article  CAS  Google Scholar 

  • Storey A, Pim D, Murray A, Osborn K, Banks L, Crawford L (1989) Comparison of the in vitro transforming activities of human papillomavirus types. EMBO J 7: 1815–1820

    Article  Google Scholar 

  • Troncone G, Martinez JC, Palombini L, De Rosa G, Mugica C, Rodriguez JA, Zeppa P, Di Vizio D, Lucariello A, Piris MA (1998) Immunohistochemical expression of mdm2 and p21Waf1 in invasive cervical cancer: correlation with p53 protein and high risk HPV infection. J Clin Pathol 51: 754–760

    Article  CAS  Google Scholar 

  • Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189: 1–3

    Article  Google Scholar 

  • Zaika AI, Kovalev S, Marchenko ND, Moll UM (1999) Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res 59: 3257–3263

    CAS  PubMed  Google Scholar 

  • Zaika A, Irwin M, Sansome C, Moll UM (2001) Oncogenes induce and activate endogenous p73 protein. J Biol Chem 276: 11310–11316

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are very grateful to Professor Ute Moll for providing pE1A, and to Dr William Kaelin for the anti-p73 antibody.

Author information

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, St Mary's Hospital Medical School, Norfolk Place, London, W2 1PG, UK

    L A Brooks, A Sullivan, J O'Nions, P J Farrell & T Crook

  2. University Department of Pathology, Glasgow University, Western Infirmary, Glasgow, UK

    A Bell, B Dunne & B Gusterson

  3. Department of Gynaecological Oncology, University of Sheffield, Northern General Hospital, Sheffield, S5 7AU, UK

    J A Tidy

  4. Department of Histopathology, St Mary's Hospital Medical School, Norfolk Place, London, W2, UK

    D J Evans

  5. Department of Pathology, University College Hospital, London, WC1, UK

    P Osin

  6. ABL Basic Research Program, NCI-Fredrick Cancer Research and Development Center, Fredrick, Maryland, 21702-1201, MD, USA

    K H Vousden

  7. Centre for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, E1 2AT, UK

    A Storey

  8. UO Oncologia Medica, Azienda Ospedaliera S. Croce e Carle, Via Coppino 26, Cuneo, 12100, Italy

    M Gasco

  9. Department of Preventitive Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    T Sakai

Authors
  1. L A Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J O'Nions
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Dunne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J A Tidy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D J Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Osin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K H Vousden
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B Gusterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P J Farrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Storey
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Gasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T Crook
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Crook.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brooks, L., Sullivan, A., O'Nions, J. et al. E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia. Br J Cancer 86, 263–268 (2002). https://doi.org/10.1038/sj.bjc.6600033

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bjc.6600033

Keywords

This article is cited by

Search

Advanced search

Quick links