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 Stewart, D.
Right arrow Articles by Matlashewski, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stewart, D.
Right arrow Articles by Matlashewski, G.

 Previous Article  |  Next Article 

Journal of Virology, July 2005, p. 8773-8783, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8773-8783.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Involvement of Nuclear Export in Human Papillomavirus Type 18 E6-Mediated Ubiquitination and Degradation of p53

Deborah Stewart,1,2 Anirban Ghosh,1 and Greg Matlashewski1*

Department of Microbiology and Immunology, McGill University, Montreal, Canada,1 Institute of Parasitology, McGill University, Montreal, Canada2

Received 1 November 2004/ Accepted 15 March 2005

The E6 protein from high-risk human papillomaviruses (HPVs) targets the p53 tumor suppressor for degradation by the proteasome pathway. This ability contributes to the oncogenic potential of these viruses. However, several aspects concerning the mechanism of E6-mediated p53 degradation at the cellular level remain to be clarified. This study therefore examined the role of cell localization and ubiquitination in the E6-mediated degradation of p53. As demonstrated within, following coexpression both p53 and high-risk HPV type 18 (HPV-18) E6 (18E6) shuttle from the nucleus to the cytoplasm. Mutation of the C-terminal nuclear export signal (NES) of p53 or treatment with leptomycin B inhibited the 18E6-mediated nuclear export of p53. Impairment of nuclear export resulted in only a partial reduction in 18E6-mediated degradation, suggesting that both nuclear and cytoplasmic proteasomes can target p53 for degradation. This was also consistent with the observation that 18E6 mediated the accumulation of polyubiquitinated p53 in the nucleus. In comparison, a p53 isoform that localizes predominantly to the cytoplasm was not targeted for degradation by 18E6 in vivo but could be degraded in vitro, arguing that nuclear p53 is the target for E6-mediated degradation. This study supports a model in which (i) E6 mediates the accumulation of polyubiquitinated p53 in the nucleus, (ii) E6 is coexported with p53 from the nucleus to the cytoplasm via a CRM1 nuclear export mechanism involving the C-terminal NES of p53, and (iii) E6-mediated p53 degradation can be mediated by both nuclear and cytoplasmic proteasomes.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, McGill University, 3775 University Street, Room 511, Montreal, Quebec, Canada H3A 2B4. Phone: (514) 398-3914. Fax: (514) 398-7052. E-mail: greg.matlashewski{at}mcgill.ca.

Journal of Virology, July 2005, p. 8773-8783, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8773-8783.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ghosh, A., Kuppusamy, H., Pilarski, L. M. (2009). Aberrant Splice Variants of HAS1 (Hyaluronan Synthase 1) Multimerize with and Modulate Normally Spliced HAS1 Protein: A POTENTIAL MECHANISM PROMOTING HUMAN CANCER. J. Biol. Chem. 284: 18840-18850 [Abstract] [Full Text]  
  • He, F., Syed, S. M., Hameed, A. S. S., Kwang, J. (2009). Viral ubiquitin ligase WSSV222 is required for efficient white spot syndrome virus replication in shrimp. J. Gen. Virol. 90: 1483-1490 [Abstract] [Full Text]  
  • Hiller, T., Poppelreuther, S., Stubenrauch, F., Iftner, T. (2006). Comparative Analysis of 19 Genital Human Papillomavirus Types with Regard to p53 Degradation, Immortalization, Phylogeny, and Epidemiologic Risk Classification.. Cancer Epidemiol. Biomarkers Prev. 15: 1262-1267 [Abstract] [Full Text]  
  • Utama, B., Shen, Y. H., Mitchell, B. M., Makagiansar, I. T., Gan, Y., Muthuswamy, R., Duraisamy, S., Martin, D., Wang, X., Zhang, M.-X., Wang, J., Wang, J., Vercellotti, G. M., Gu, W., Li Wang, X. (2006). Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells. J. Cell Sci. 119: 2457-2467 [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»