This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horner, S. M.
Right arrow Articles by DiMaio, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horner, S. M.
Right arrow Articles by DiMaio, D.

 Previous Article  |  Next Article 

Journal of Virology, April 2004, p. 4063-4073, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4063-4073.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Repression of the Human Papillomavirus E6 Gene Initiates p53-Dependent, Telomerase-Independent Senescence and Apoptosis in HeLa Cervical Carcinoma Cells

Stacy M. Horner, Rosa Anna DeFilippis,{dagger} Laertes Manuelidis,{ddagger} and Daniel DiMaio1*

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510

Received 24 September 2003/ Accepted 12 December 2003

Cervical cancer cells express high-risk human papillomavirus (HPV) E6 and E7 proteins. When both HPV oncogenes are repressed in HeLa cervical carcinoma cells, the dormant p53 and retinoblastoma (Rb) tumor suppressor pathways are activated, and the cells undergo senescence in the absence of apoptosis. When the E6 gene is repressed in cells that continue to express an E7 gene, the p53 pathway, but not the Rb pathway, is activated, and both senescence and apoptosis are triggered. To determine the role of p53 signaling in senescence or apoptosis after repression of HPV oncogenes, we introduced a dominant-negative allele of p53 into HeLa cells. Dominant-negative p53 prevented senescence and apoptosis when E6 alone was repressed but did not inhibit senescence when both E6 and E7 were repressed. To determine whether reduced telomerase activity was involved in senescence or apoptosis after E6 repression, we generated HeLa cells stably expressing an exogenous hTERT gene, which encodes the catalytic subunit of telomerase. Although these cells contained markedly elevated telomerase activity and elongated telomeres, hTERT expression did not prevent senescence and apoptosis when E6 alone was repressed. These results demonstrate that when the Rb tumor suppressor pathway is inactivated by the E7 protein, E6 repression activates p53 signaling, which in turn is required for growth inhibition, senescence, and apoptosis. Thus, sustained inactivation of the p53 pathway by the E6 protein is required for maintenance of the proliferative phenotype of HeLa cervical carcinoma cells.

* Corresponding author. Mailing address: Department of Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. Phone: (203) 785-2684. Fax: (203) 785-6765. E-mail: daniel.dimaio{at}yale.edu.

{dagger} Present address: Department of Pathology, University of California at San Francisco, San Francisco, CA 94143.

{ddagger} Present address: Department of Dermatology, Medical University of South Carolina, Charleston, SC 29412.

Journal of Virology, April 2004, p. 4063-4073, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4063-4073.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rampias, T., Sasaki, C., Weinberger, P., Psyrri, A. (2009). E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells. JNCI J Natl Cancer Inst 101: 412-423 [Abstract] [Full Text]  
  • Lin, Z., Bazzaro, M., Wang, M.-C., Chan, K. C., Peng, S., Roden, R. B.S. (2009). Combination of Proteasome and HDAC Inhibitors for Uterine Cervical Cancer Treatment. Clin. Cancer Res. 15: 570-577 [Abstract] [Full Text]  
  • Nguyen, M. L., Kraft, R. M., Aubert, M., Goodwin, E., DiMaio, D., Blaho, J. A. (2007). p53 and hTERT Determine Sensitivity to Viral Apoptosis. J. Virol. 81: 12985-12995 [Abstract] [Full Text]  
  • Putral, L. N., Bywater, M. J., Gu, W., Saunders, N. A., Gabrielli, B. G., Leggatt, G. R., McMillan, N. A. J. (2005). RNA Interference against Human Papillomavirus Oncogenes in Cervical Cancer Cells Results in Increased Sensitivity to Cisplatin. Mol. Pharmacol. 68: 1311-1319 [Abstract] [Full Text]  
  • Behrend, L., Mohr, A., Dick, T., Zwacka, R. M. (2005). Manganese Superoxide Dismutase Induces p53-Dependent Senescence in Colorectal Cancer Cells. Mol. Cell. Biol. 25: 7758-7769 [Abstract] [Full Text]  
  • Zhang, H. M., Yuan, J., Cheung, P., Chau, D., Wong, B. W., McManus, B. M., Yang, D. (2005). Gamma Interferon-Inducible Protein 10 Induces HeLa Cell Apoptosis through a p53-Dependent Pathway Initiated by Suppression of Human Papillomavirus Type 18 E6 and E7 Expression. Mol. Cell. Biol. 25: 6247-6258 [Abstract] [Full Text]  
  • Bischof, O., Nacerddine, K., Dejean, A. (2005). Human Papillomavirus Oncoprotein E7 Targets the Promyelocytic Leukemia Protein and Circumvents Cellular Senescence via the Rb and p53 Tumor Suppressor Pathways. Mol. Cell. Biol. 25: 1013-1024 [Abstract] [Full Text]  
  • Mitra, S, Misra, C, Singh, R K, Panda, C K, Roychoudhury, S (2005). Association of specific genotype and haplotype of p53 gene with cervical cancer in India. J. Clin. Pathol. 58: 26-31 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»