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 Noya, F.
Right arrow Articles by Chow, L. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noya, F.
Right arrow Articles by Chow, L. T.

 Previous Article  |  Next Article 

Journal of Virology, July 2001, p. 6121-6134, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.6121-6134.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

p21cip1 Degradation in Differentiated Keratinocytes Is Abrogated by Costabilization with Cyclin E Induced by Human Papillomavirus E7

Francisco Noya, Wei-Ming Chien, Thomas R. Broker, and Louise T. Chow*

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

Received 2 April 2001/Accepted 9 April 2001

The human papillomavirus (HPV) E7 protein promotes S-phase reentry in a fraction of postmitotic, differentiated keratinocytes. Here we report that these cells contain an inherent mechanism that opposes E7-induced DNA replication. In organotypic raft cultures of primary human keratinocytes, neither cyclin E nor p21cip1 is detectable in situ. However, E7-transduced differentiated cells not in S phase accumulate abundant cyclin E and p21cip1. We show that normally p21cip1 protein is rapidly degraded by proteasomes. In the presence of E7 or E6/E7, p21cip1, cyclin E, and cyclin E2 proteins were all up-regulated. The accumulation of p21cip1 protein is a posttranscriptional event, and ectopic cyclin E expression was sufficient to trigger it. In constract, cdk2 and p27kip1 were abundant in normal differentiated cells and were not significantly affected by E7. Cyclin E, cdk2, and p21cip1 or p27kip1 formed complexes, and relatively little kinase activity was found associated with cyclin E or cdk2. In patient papillomas and E7 raft cultures, all p27kip1-positive cells were negative for bromodeoxyuridine (BrdU) incorporation, but only some also contained cyclin E and p21cip1. In contrast, all cyclin E-positive cells also contained p27kip1. When the expression of p21cip1 was reduced by rottlerin, a PKC delta  inhibitor, p27kip1- and BrdU-positive cells remained unchanged. These observations show that high levels of endogenous p27kip1 can prevent E7-induced S-phase reentry. This inhibition then leads to the stabilization of cyclin E and p21cip1. Since efficient initiation of viral DNA replication requires cyclin E and cdk2, its inhibition accounts for heterogeneous viral activities in productively infected lesions.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 510 McCallum Basic Health Sciences Bldg., 1918 University Blvd., Birmingham, AL 35294-0005. Phone: (205) 975-8300. Fax: (205) 975-6075. E-mail: ltchow{at}uab.edu.

Journal of Virology, July 2001, p. 6121-6134, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.6121-6134.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Wang, X., Wang, H.-K., McCoy, J. P., Banerjee, N. S., Rader, J. S., Broker, T. R., Meyers, C., Chow, L. T., Zheng, Z.-M. (2009). Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 15: 637-647 [Abstract] [Full Text]  
  • 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]  
  • Genovese, N. J., Banerjee, N. S., Broker, T. R., Chow, L. T. (2008). Casein Kinase II Motif-Dependent Phosphorylation of Human Papillomavirus E7 Protein Promotes p130 Degradation and S-Phase Induction in Differentiated Human Keratinocytes. J. Virol. 82: 4862-4873 [Abstract] [Full Text]  
  • Banerjee, N. S., Genovese, N. J., Noya, F., Chien, W.-M., Broker, T. R., Chow, L. T. (2006). Conditionally activated e7 proteins of high-risk and low-risk human papillomaviruses induce s phase in postmitotic, differentiated human keratinocytes.. J. Virol. 80: 6517-6524 [Abstract] [Full Text]  
  • Garner-Hamrick, P. A., Fostel, J. M., Chien, W.-M., Banerjee, N. S., Chow, L. T., Broker, T. R., Fisher, C. (2004). Global Effects of Human Papillomavirus Type 18 E6/E7 in an Organotypic Keratinocyte Culture System. J. Virol. 78: 9041-9050 [Abstract] [Full Text]  
  • Middleton, K., Peh, W., Southern, S., Griffin, H., Sotlar, K., Nakahara, T., El-Sherif, A., Morris, L., Seth, R., Hibma, M., Jenkins, D., Lambert, P., Coleman, N., Doorbar, J. (2003). Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers. J. Virol. 77: 10186-10201 [Abstract] [Full Text]  
  • Noya, F., Balague, C., Banerjee, N. S., Curiel, D. T., Broker, T. R., Chow, L. T. (2003). Activation of Adenovirus Early Promoters and Lytic Phase in Differentiated Strata of Organotypic Cultures of Human Keratinocytes. J. Virol. 77: 6533-6540 [Abstract] [Full Text]  
  • Fehrmann, F., Klumpp, D. J., Laimins, L. A. (2003). Human Papillomavirus Type 31 E5 Protein Supports Cell Cycle Progression and Activates Late Viral Functions upon Epithelial Differentiation. J. Virol. 77: 2819-2831 [Abstract] [Full Text]  
  • Noya, F., Chien, W.-M., Wu, X., Banerjee, N. S., Kappes, J. C., Broker, T. R., Chow, L. T. (2002). The Promoter of the Human Proliferating Cell Nuclear Antigen Gene Is Not Sufficient for Cell Cycle-dependent Regulation in Organotypic Cultures of Keratinocytes. J. Biol. Chem. 277: 17271-17280 [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]  
  • Balague, C., Noya, F., Alemany, R., Chow, L. T., Curiel, D. T. (2001). Human Papillomavirus E6E7-Mediated Adenovirus Cell Killing: Selectivity of Mutant Adenovirus Replication in Organotypic Cultures of Human Keratinocytes. J. Virol. 75: 7602-7611 [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»