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:

Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis

Oncogene volume 24, pages 5069–5078 (2005)Cite this article

Abstract

Inhibition of apoptosis plays an important role in the cellular immortalization and transformation induced by E6 and E7 oncoproteins of human papillomavirus (HPV). Here, we report that the transcription of the inhibitor of apoptosis gene, cellular inhibitor of apoptosis protein 2, (c-IAP2), is significantly upregulated in HPV16 E6/E7-immortalized human oral keratinocytes (HOK16E6E7). Overexpression of E6/E7 from the high-risk HPV16 or 18, but not from the low-risk HPV6, activated c-IAP2 promoter. E6 from HPV16 and 18 played a major role in the activation. In addition, the induction of c-IAP2 transcription required nuclear factor-κB activity. Overexpression of c-IAP2 in normal human oral keratinocyte conferred resistance to tumor necrosis factor-α (TNF-α)/cycloheximide (CHX)-induced apoptosis, suggesting the increased c-IAP2 expression in HOK16E6E7 may protect the cells from TNF-α-mediated cell death. Moreover, depletion of endogenous c-IAP2 using RNA interference in HOK16E6E7 induced apoptosis, indicating that c-IAP2 is necessary for HPV16 E6/E7-induced resistance to apoptosis and cell survival. Of note, high levels of c-IAP2 transcription were found in several HPV16- or HPV18-positive cancer cells, and depletion of c-IAP2 caused cell death in HPV18-positive HeLa cells. Thus, upregulation of c-IAP2 by E6 and E7 may confer resistance to apoptosis that is necessary for sustained growth of some HPV16- and HPV18-positive cancer cells.

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

Similar content being viewed by others

References

  • An DS, Xie Y, Mao SH, Morizono K, Kung SK and Chen IS . (2003). Hum. Gene Ther., 14, 1207–1212.

  • Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH and Ballard DW . (1997). Proc. Natl. Acad. Sci. USA., 94, 10057–10062.

  • Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC . (1998). EMBO J., 17, 2215–2223.

  • Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H and Marynen P . (1999). Blood, 93, 3601–3609.

  • Duffy CL, Phillips SL and Klingelhutz AJ . (2003). Virology, 314, 196–205.

  • Ferreira CG, van der Valk P, Span SW, Jonker JM, Postmus PE, Kruyt FA and Giaccone G . (2001). Ann. Oncol., 12, 799–805.

  • Filippova M, Song H, Connolly JL, Dermody TS and Duerksen-Hughes PJ . (2002). J. Biol. Chem., 277, 21730–21739.

  • Finzer P, Aguilar-Lemarroy A and Rosl F . (2002). Cancer Lett., 188, 15–24.

  • Foster SA, Demers GW, Etscheid BG and Galloway DA . (1994). J Virol., 68, 5698–5705.

  • Gross-Mesilaty S, Reinstein E, Bercovich B, Tobias KE, Schwartz AL, Kahana C and Ciechanover A . (1998). Proc. Natl. Acad. Sci. USA., 95, 8058–8063.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Havard L, Delvenne P, Frare P, Boniver J and Giannini SL . (2002). Virology, 298, 271–285.

  • Hong SY, Yoon WH, Park JH, Kang SG, Ahn JH and Lee TH . (2000). J. Biol. Chem., 275, 18022–18028.

  • Hosokawa Y, Suzuki H, Suzuki Y, Takahashi R and Seto M . (2004). Cancer Res., 64, 3452–3457.

  • Hu S and Yang X . (2004). J. Biol. Chem., 278, 10055–10060.

  • Huang H, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD and Hunter T . (2000). J. Biol. Chem., 275, 26661–26664.

  • Hui EK, Yap EM, An DS, Chen IS and Nayak DP . (2004). J. Gen. Virol., 85, 1877–1884.

  • Jewett A, Wang MY, Teruel A, Poupak Z, Bostanian Z and Park NH . (2003). Hum. Immunol., 64, 505–520.

  • Jiang M and Milner J . (2002). Oncogene, 21, 6041–6048.

  • Jones DL, Thompson DA and Munger K . (1997). Virology, 239, 97–107.

  • Karin M, Cao Y, Greten FR and Li ZW . (2002). Nat. Rev. Cancer, 2, 301–310.

  • Kawagoe J, Ohmichi M, Takahashi T, Ohshima C, Mabuchi S, Takahashi K, Igarashi H, Mori-Abe A, Saitoh M, Du B, Ohta T, Kimura A, Kyo S, Inoue M and Kurachi H . (2003). J. Biol. Chem., 278, 43363–43372.

  • Li X, Yang Y and Ashwell JD . (2002). Nature, 416, 345–347.

  • Mantovani F and Banks L . (2001). Oncogene, 20, 7874–7887.

  • Miller AD and Rosman GJ . (1989). Biotechniques, 7, 980–988.

  • Min BM, Woo KM, Lee G and Park NH . (1999). Exp. Cell Res., 249, 377–385.

  • Mota F, Rayment N, Chong S, Singer A and Chain B . (1999). Clin. Exp. Immunol., 116, 33–40.

  • Munger K and Howley PM . (2002). Virus Res., 89, 213–228.

  • Nachmias B, Ashhab Y and Ben-Yehuda D . (2004). Semin. Cancer Biol., 14, 231–243.

  • Nees M, Geoghegan JM, Hyman T, Frank S, Miller L and Woodworth CD . (2001). J. Virol., 75, 4283–4296.

  • Nishihara H, Hwang M, Kizaka-Kondoh S, Eckmann L and Insel PA . (2004). J. Biol. Chem., 279, 26176–26183.

  • Nishitani J, Chen Z, Qin M, Liu F, Chen H, Nelson SF and Liu X . (2002). Cell. Mol. Biol., 48, 331–341.

  • Park SM, Yoon JB and Lee TH . (2004). FEBS Lett., 566, 151–156.

  • Rothe M, Pan MG, Henzel WJ, Ayres TM and Goeddel DV . (1995). Cell, 83, 1243–1252.

  • Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC . (1997). EMBO J., 16, 6914–6925.

  • Salvesen GS and Duckett CS . (2002). Nat. Rev. Mol. Cell Biol., 3, 401–410.

  • Sinha-Datta U, Horikawa I, Michishita E, Datta A, Sigler-Nicot JC, Brown M, Kazanji M, Barrett JC and Nicot C . (2004). Blood, 104, 2523–2531.

  • Spitkovsky D, Hehner SP, Hofmann TG, Moller A and Schmitz ML . (2002). J. Biol. Chem., 277, 25576–25582.

  • Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR and Lipp J . (1998). J. Exp. Med., 188, 211–216.

  • Stoppler H, Stoppler MC, Johnson E, Simbulan-Rosenthal CM, Smulson ME, Iyer S, Rosenthal DS and Schlegel R . (1998). Oncogene, 17, 1207–1214.

  • Thomas M and Banks L . (1998). Oncogene, 17, 2943–2954.

  • Thompson DA, Zacny V, Belinsky GS, Classon M, Jones DL, Schlegel R and Munger K . (2001). Oncogene, 20, 3629–3640.

  • Uren AG, Pakusch M, Hawkins CJ, Puls KL and Vaux DL . (1996). Proc. Natl. Acad. Sci. USA, 93, 4974–4978.

  • Webster JC, Huber RM, Hanson RL, Collier PM, Haws TF, Mills JK, Burn TC and Allegretto EA . (2002). Endocrinology, 143, 3866–3874.

  • Yang QH, Church-Hajduk R, Ren J, Newton ML and Du C . (2003). Genes Dev., 17, 1487–1496.

  • Yang QH and Du C . (2004). J. Biol. Chem., 279, 16963–16970.

  • Yin L, Hubbard AK and Giardina C . (2000). J. Biol. Chem., 275, 36671–36675.

  • Yuan H, Xie YM and Chen IS . (2003). J. Virol., 77, 2063–2070.

  • Zhang HG, Wang J, Yang X, Hsu HC and Mountz JD . (2004). Oncogene, 23, 2009–2015.

  • zur Hausen H . (1999). Eur. J. Cancer, 35, 1878–1885.

Download references

Acknowledgements

We are grateful to Denise A Galloway (Fred Hutchinson Cancer Research Center, Seattle, WA, USA), Shimin Hu (University of Pennsylvania), Ki-Hyuk Shin (UCLA), Anahid Jewett (UCLA), Shih-Ming Huang (Tri-Service General Hospital, Taipei, Taiwan), Tae H Lee (Yonsei University, South Korea) for providing important reagents. We also thank Dr Marcel A Baluda (UCLA) for critical discussion and review of this paper. This work was supported by NIH/NIDCR K23 Grant DE00430 and Research Grant from the Research Center in Minority Institutions (NIH/RCMI G12-RR03026-15).

Author information

Authors and Affiliations

  1. Department of Oral & Maxillofacial Surgery, Charles R Drew University of Medicine & Science, Los Angeles, 90059, CA, USA

    Huidong Yuan, Fenghua Fu, Jiaying Zhuo, Wei Wang & Xuan Liu

  2. Department of Otolaryngology, Charles R Drew University of Medicine & Science, Los Angeles, 90059, CA, USA

    Junko Nishitani

  3. Departments of Medicine and Microbiology, Immunology and Molecular Genetics, UCLA AIDS Institute, Los Angeles, 90095, CA, USA

    Dong Sung An & Irvin S Y Chen

Authors
  1. Huidong Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fenghua Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaying Zhuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junko Nishitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong Sung An
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irvin S Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xuan Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, H., Fu, F., Zhuo, J. et al. Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis. Oncogene 24, 5069–5078 (2005). https://doi.org/10.1038/sj.onc.1208691

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208691

Keywords

This article is cited by

Search

Advanced search

Quick links