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.

  • Original Paper
  • Published:

Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β

Oncogene volume 22, pages 8394–8402 (2003)Cite this article

Abstract

Tumor suppressor p53 functions are downregulated in most cervical cancers, because the product of human papilloma virus (HPV) oncogene E6 binds to and inactivates p53 by promoting its degradation. p73, a p53 homologue, is similar to p53 in structure and function but yet not degraded by HPV E6 gene product. In this study, we have developed a replication-deficient recombinant adenovirus, which expresses p73β (Ad-p73). Infection of human cancer cells with Ad-p73 results in several fold increase of p73β levels as well as its known target genes like p21WAF1/CIP1. Ad-p73-infected cells showed reduced cellular DNA synthesis, arrest in G1 phase of cell cycle and induction of apoptosis. Ad-p73 inhibited the growth of cancer cells of different types. More importantly, Ad-p73 inhibited the growth of cell lines carrying HPV E6 gene, which was introduced by stable integration, more efficiently in comparison to an Ad-p53. Furthermore, Ad-p73 also inhibited the growth of HeLa cells, a cell line derived from cervical cancer, very efficiently. The ability of Ad-p73 to inhibit the growth of HPV E6-expressing cells and HeLa cells correlated with the stable expression of functional p73 in the presence of E6. These results suggest that Ad-p73 could be used as a potential gene therapy agent against cervical cancer.

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
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

HPV:

human papilloma virus

Brdu:

bromodeoxyuridine

References

  • Beer-Romero P, Glass S and Rolfe M . (1997). Oncogene, 14, 595–602.

  • Blagosklonny M and El-Deiry WS . (1996). Int. J. Cancer, 67, 386–392.

  • Brinton LA . (1992). Epidemiology of Cervical Cancer – Overview: The Epidemiology of Human Papillomavirus and Cervical Cancer, Munoz N, Bosch F, Shah KV and Meheus A (eds). Oxford University Press: Oxford, pp. 3–23.

    Google Scholar 

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW and Vogelstein B . (1998). Science, 282, 1497–1501.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WD, Kinzler KW and Vogelstein B . (1993). Cell, 75, 817–825.

  • Grenlee RT, Hill-Harmon MB, Murray T and Thun M . (2001). CA Cancer J. Clin., 51, 15–36.

  • Hamada K, Alemany R, Zhang WW, Hittelman WN, Lotan R, Roth JA and Mitchell MF . (1996). Cancer Res., 56, 3047–3054.

  • Haupt YR, Maya R, Kaza A and Oren M . (1997). Nature, 387, 296–299.

  • He TC, Zhou S, DaCosta LT, Yu J, Kinzler KW and Vogelstein B . (1998). Proc. Natl. Acad. Sci. USA, 95, 2509–2514.

  • Hollstein M, Sidransky D, Vogelstein B and Harris CC . (1991). Science, 253, 49–53.

  • Huh WK, Gomez-Navarro J, Arafat WO, Xiang J, Mahasreshti PJ, Alvarez RD, Barnes MN and Curiel DT . (2001). Gynecol. Oncol., 83, 370–377.

  • Jost CA, Marin MC and Kaelin WG . (1997). Nature, 389, 191–194.

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F and Caput D . (1997). Cell, 90, 809–819.

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ . (1998). Proc. Natl. Acad. Sci. USA, 5, 8292–8297.

  • Kubbutat MGH, Jones SN and Vousden K . (1997). Nature, 387, 299–303.

  • Lechner MA and Laminis LA . (1994). J. Virol., 68, 4262–4273.

  • Levine AJ . (1997). Cell, 88, 323–331.

  • Lungu O, Sun XW, Wright TCJ, Ferenczy A, Richart RM and Silverstein S . (1995). Obstet. Gynecol., 85, 337–342.

  • Marin MC, Jost CA, Irwin MS, DeCaprio JA, Caput D and Kaelin WG . (1998). Mol. Cell. Biol., 8, 6316–6324.

  • Oliner JD, Pientenpol JA, Thiagalingam S, Gyuris J, Kinzler KW and Vogelstein B . (1993). Nature, 362, 857–860.

  • Orlow I, LaRue H, Osman I, Lacombe L, Moore L, Rabbani F, Meyer F, Fradet Y and Cordon-Cardo C . (1999). Am. J. Pathol., 155, 105–113.

  • Prabhu NS, Blagosklonny M, Zeng YX, Wu GS, Waldman T and El-Deiry WS . (1996). Clin. Cancer Res., 2, 1221–1229.

  • Prabhu NS, Somasundaram K, Satyamoorthy K, Herlyn M and El-Deiry WS . (1998). Int. J. Oncol., 13, 5–9.

  • Qu W, Jiang G, Cruz Y, Chang CJ, Ho GY, Klein RS and Burk RD . (1997). J. Clin. Microbiol., 35, 1304–1310.

  • Rose PG and Eifel PJ . (2000). Combined Modality Treatment for Carcinoma of the Cervix: Cancer, Principles and Practice of Oncology, DeVita V, Hellman S and Rosenberg S (eds). Lippincott-Raven: Philadelphia, PA, pp. 14:1–14:10.

    Google Scholar 

  • Scheffner M, Munger K, Byrne JC and Howley PM . (1991). Proc. Natl. Acad. Sci. USA, 88, 5523–5527.

  • Somasundaram K and El-Deiry WS . (1997). Oncogene, 14, 1047–1105.

  • Somasundaram K, Jayaraman G, Williams T, Moran E, Frisch S and Thimmapaya B . (1996). Proc. Nat. Acad. Sci. USA, 93, 3088–3093.

  • Somasundaram K, MacLachlan TK, Burns TF, Sgagias M, Cowan KH, Weber BL and El-Deiry WS . (1999). Oncogene, 18, 6605–6614.

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G . (1998). EMBO J., 17, 5001–5014.

  • Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM, Matlashewski G and Banks L . (1998). Nature, 393, 229–234.

  • Takimoto R, MacLachlan TK, Dicker DT, Niitsu Y, Mori T and El-Deiry WS . (2002). Can. Biol. Ther., 1, 177–186.

  • Tsao YP, Huang SG, Chang JL, Hsieh JT, Pong RC and Chen SL . (1999). J. Virol., 78, 4983–4990.

  • Wu GS and El-Deiry WS . (1996). Clin. Cancer Res., 4, 623–633.

  • Yatabe N, Kyo S, Kondo S, Kanaya T, Wang Z, Maida Y, Takakura M, Nakamura M, Tanaka M and Inoue M . (2002). Cancer Gene Ther., 9, 624–630.

  • Zeng YX, Somasundaram K and El-Deiry WS . (1997). Nat. Genet., 15, 28–32.

  • Zhang Y, Xiong Y and Yarbrough WG . (1998). Cell, 92, 725–734.

Download references

Acknowledgements

This study was supported by a grant from Defence Research and Development Organization (DRDO), Government of India. SD is supported by a fellowship from Council for Scientific and Industrial Research (CSIR), Government of India.

Author information

Authors and Affiliations

  1. Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560 012, India

    Sanjeev Das & Kumaravel Somasundaram

  2. Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA

    Wafik S El-Deiry

Authors
  1. Sanjeev Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wafik S El-Deiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kumaravel Somasundaram
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kumaravel Somasundaram.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Das, S., El-Deiry, W. & Somasundaram, K. Efficient growth inhibition of HPV 16 E6-expressing cells by an adenovirus-expressing p53 homologue p73β. Oncogene 22, 8394–8402 (2003). https://doi.org/10.1038/sj.onc.1206908

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206908

Keywords

This article is cited by

Search

Advanced search

Quick links