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 Thomas, J. T.
Right arrow Articles by Laimins, L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thomas, J. T.
Right arrow Articles by Laimins, L. A.

 Previous Article  |  Next Article 

J Virol, February 1998, p. 1131-1137, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Human Papillomavirus Oncoproteins E6 and E7 Independently Abrogate the Mitotic Spindle Checkpoint

Jennifer T. Thomas and Laimonis A. Laimins*

Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611

Received 25 July 1997/Accepted 10 November 1997

The E6 and E7 genes of the high-risk human papillomavirus (HPV) types encode oncoproteins, and both act by interfering with the activity of cellular tumor suppressor proteins. E7 proteins act by associating with members of the retinoblastoma family, while E6 increases the turnover of p53. p53 has been implicated as a regulator of both the G1/S cell cycle checkpoint and the mitotic spindle checkpoint. When fibroblasts from p53 knockout mice are treated with the spindle inhibitor nocodazole, a rereplication of DNA occurs without transit through mitosis. We investigated whether E6 or E7 could induce a similar loss of mitotic checkpoint activity in human keratinocytes. Recombinant retroviruses expressing high-risk E6 alone, E7 alone, and E6 in combination with E7 were used to infect normal human foreskin keratinocytes (HFKs). Established cell lines were treated with nocodazole, stained with propidium iodide, and analyzed for DNA content by flow cytometry. Cells infected with high-risk E6 were found to continue to replicate DNA and accumulated an octaploid (8N) population. Surprisingly, expression of E7 alone was also able to bypass this checkpoint. Cells expressing E7 alone exhibited increased levels of p53, while those expressing E6 had significantly reduced levels. The p53 present in the E7 cells was active, as increased levels of p21 were observed. This suggested that E7 bypassed the mitotic checkpoint by a p53-independent mechanism. The levels of MDM2, a cellular oncoprotein also implicated in control of the mitotic checkpoint, were significantly elevated in the E7 cells compared to the normal HFKs. In E6-expressing cells, the levels of MDM2 were undetectable. It is possible that abrogation of Rb function by E7 or increased expression of MDM2 contributes to the loss of mitotic spindle checkpoint control in the E7 cells. These findings suggest mechanisms by which both HPV oncoproteins contribute to genomic instability at the mitotic checkpoint.

* Corresponding author. Mailing address: Department of Microbiology-Immunology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611. Phone: (312) 503-0648. Fax: (312) 503-0649. E-mail: lal{at}merle.acns.nwu.edu.




This article has been cited by other articles:

  • Nobre, R. J., Herraez-Hernandez, E., Fei, J.-W., Langbein, L., Kaden, S., Grone, H.-J., de Villiers, E.-M. (2009). E7 Oncoprotein of Novel Human Papillomavirus Type 108 Lacking the E6 Gene Induces Dysplasia in Organotypic Keratinocyte Cultures. J. Virol. 83: 2907-2916 [Abstract] [Full Text]  
  • Heilman, S. A., Nordberg, J. J., Liu, Y., Sluder, G., Chen, J. J. (2009). Abrogation of the Postmitotic Checkpoint Contributes to Polyploidization in Human Papillomavirus E7-Expressing Cells. J. Virol. 83: 2756-2764 [Abstract] [Full Text]  
  • Nguyen, C. L., Munger, K. (2009). Human Papillomavirus E7 Protein Deregulates Mitosis via an Association with Nuclear Mitotic Apparatus Protein 1. J. Virol. 83: 1700-1707 [Abstract] [Full Text]  
  • Nguyen, C. L., McLaughlin-Drubin, M. E., Munger, K. (2008). Delocalization of the Microtubule Motor Dynein from Mitotic Spindles by the Human Papillomavirus E7 Oncoprotein Is Not Sufficient for Induction of Multipolar Mitoses. Cancer Res. 68: 8715-8722 [Abstract] [Full Text]  
  • Hebner, C., Beglin, M., Laimins, L. A. (2007). Human Papillomavirus E6 Proteins Mediate Resistance to Interferon-Induced Growth Arrest through Inhibition of p53 Acetylation. J. Virol. 81: 12740-12747 [Abstract] [Full Text]  
  • Liu, Y., Heilman, S. A., Illanes, D., Sluder, G., Chen, J. J. (2007). p53-Independent Abrogation of a Postmitotic Checkpoint Contributes to Human Papillomavirus E6-Induced Polyploidy. Cancer Res. 67: 2603-2610 [Abstract] [Full Text]  
  • Vinokurova, S., Wentzensen, N., Einenkel, J., Klaes, R., Ziegert, C., Melsheimer, P., Sartor, H., Horn, L.-C., Hockel, M., von Knebel Doeberitz, M. (2005). Clonal History of Papillomavirus-Induced Dysplasia in the Female Lower Genital Tract. JNCI J Natl Cancer Inst 97: 1816-1821 [Abstract] [Full Text]  
  • Cho, N H, Kang, S, Hong, S, Jeong, G B, Choi, I W, Choi, H J, Choi, H K (2005). Multinucleation of koilocytes is in fact multilobation and is related to aberration of the G2 checkpoint. J. Clin. Pathol. 58: 576-582 [Abstract] [Full Text]  
  • Brake, T., Lambert, P. F. (2005). Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc. Natl. Acad. Sci. USA 102: 2490-2495 [Abstract] [Full Text]  
  • Munger, K., Baldwin, A., Edwards, K. M., Hayakawa, H., Nguyen, C. L., Owens, M., Grace, M., Huh, K. (2004). Mechanisms of Human Papillomavirus-Induced Oncogenesis. J. Virol. 78: 11451-11460 [Full Text]  
  • Patel, D., Incassati, A., Wang, N., McCance, D. J. (2004). Human Papillomavirus Type 16 E6 and E7 Cause Polyploidy in Human Keratinocytes and Up-Regulation of G2-M-Phase Proteins. Cancer Res. 64: 1299-1306 [Abstract] [Full Text]  
  • Cotsiki, M., Lock, R. L., Cheng, Y., Williams, G. L., Zhao, J., Perera, D., Freire, R., Entwistle, A., Golemis, E. A., Roberts, T. M., Jat, P. S., Gjoerup, O. V. (2004). Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1. Proc. Natl. Acad. Sci. USA 101: 947-952 [Abstract] [Full Text]  
  • Duensing, S., Munger, K. (2002). The Human Papillomavirus Type 16 E6 and E7 Oncoproteins Independently Induce Numerical and Structural Chromosome Instability. Cancer Res. 62: 7075-7082 [Abstract] [Full Text]  
  • Nakahara, T., Nishimura, A., Tanaka, M., Ueno, T., Ishimoto, A., Sakai, H. (2002). Modulation of the Cell Division Cycle by Human Papillomavirus Type 18 E4. J. Virol. 76: 10914-10920 [Abstract] [Full Text]  
  • Chien, W.-M., Noya, F., Benedict-Hamilton, H. M., Broker, T. R., Chow, L. T. (2002). Alternative Fates of Keratinocytes Transduced by Human Papillomavirus Type 18 E7 during Squamous Differentiation. J. Virol. 76: 2964-2972 [Abstract] [Full Text]  
  • Gaillard, S., Fahrbach, K. M., Parkati, R., Rundell, K. (2001). Overexpression of Simian Virus 40 Small-T Antigen Blocks Centrosome Function and Mitotic Progression in Human Fibroblasts. J. Virol. 75: 9799-9807 [Abstract] [Full Text]  
  • Duensing, S., Duensing, A., Flores, E. R., Do, A., Lambert, P. F., Munger, K. (2001). Centrosome Abnormalities and Genomic Instability by Episomal Expression of Human Papillomavirus Type 16 in Raft Cultures of Human Keratinocytes. J. Virol. 75: 7712-7716 [Abstract] [Full Text]  
  • Oh, S. T., Kyo, S., Laimins, L. A. (2001). Telomerase Activation by Human Papillomavirus Type 16 E6 Protein: Induction of Human Telomerase Reverse Transcriptase Expression through Myc and GC-Rich Sp1 Binding Sites. J. Virol. 75: 5559-5566 [Abstract] [Full Text]  
  • Duensing, S., Lee, L. Y., Duensing, A., Basile, J., Piboonniyom, S.-o., Gonzalez, S., Crum, C. P., Münger, K. (2000). The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc. Natl. Acad. Sci. USA 10.1073/pnas.170093297v1 [Abstract] [Full Text]  
  • Flores, E. R., Allen-Hoffmann, B. L., Lee, D., Lambert, P. F. (2000). The Human Papillomavirus Type 16 E7 Oncogene Is Required for the Productive Stage of the Viral Life Cycle. J. Virol. 74: 6622-6631 [Abstract] [Full Text]  
  • Zheng, L., Chen, Y., Riley, D. J., Chen, P.-L., Lee, W.-H. (2000). Retinoblastoma Protein Enhances the Fidelity of Chromosome Segregation Mediated by hsHec1p. Mol. Cell. Biol. 20: 3529-3537 [Abstract] [Full Text]  
  • Chang, Y. E., Laimins, L. A. (2000). Microarray Analysis Identifies Interferon-Inducible Genes and Stat-1 as Major Transcriptional Targets of Human Papillomavirus Type 31. J. Virol. 74: 4174-4182 [Abstract] [Full Text]  
  • Crish, J. F., Bone, F., Balasubramanian, S., Zaim, T. M., Wagner, T., Yun, J., Rorke, E. A., Eckert, R. L. (2000). Suprabasal expression of the human papillomavirus type 16 oncoproteins in mouse epidermis alters expression of cell cycle regulatory proteins. Carcinogenesis 21: 1031-1037 [Abstract] [Full Text]  
  • Ogston, P., Raj, K., Beard, P. (2000). Productive Replication of Adeno-Associated Virus Can Occur in Human Papillomavirus Type 16 (HPV-16) Episome-Containing Keratinocytes and Is Augmented by the HPV-16 E2 Protein. J. Virol. 74: 3494-3504 [Abstract] [Full Text]  
  • Seavey, S. E., Holubar, M., Saucedo, L. J., Perry, M. E. (1999). The E7 Oncoprotein of Human Papillomavirus Type 16 Stabilizes p53 through a Mechanism Independent of p19ARF. J. Virol. 73: 7590-7598 [Abstract] [Full Text]  
  • Harrington, E. A., Bruce, J. L., Harlow, E., Dyson, N. (1998). pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc. Natl. Acad. Sci. USA 95: 11945-11950 [Abstract] [Full Text]  
  • Geraghty, R. J., Krummenacher, C., Cohen, G. H., Eisenberg, R. J., Spear, P. G. (1998). Entry of Alphaherpesviruses Mediated by Poliovirus Receptor-Related Protein 1 and Poliovirus Receptor. Science 280: 1618-1620 [Abstract] [Full Text]  
  • Liu, Y., Hong, Y., Androphy, E. J., Chen, J. J. (2000). Rb-independent Induction of Apoptosis by Bovine Papillomavirus Type 1 E7 in Response to Tumor Necrosis Factor alpha. J. Biol. Chem. 275: 30894-30900 [Abstract] [Full Text]  
  • Duensing, S., Lee, L. Y., Duensing, A., Basile, J., Piboonniyom, S.-o., Gonzalez, S., Crum, C. P., Munger, K. (2000). The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc. Natl. Acad. Sci. USA 97: 10002-10007 [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»