Published online before print August 7, 2008

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2008.080280v1 173/3/682    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krawczyk, E. Articles by Schlegel, R. Search for Related Content PubMed PubMed Citation Articles by Krawczyk, E. Articles by Schlegel, R.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080280

Accepted for publication May 20, 2008.

Article

Koilocytosis. A Cooperative Interaction between the Human Papillomavirus E5 and E6 Oncoproteins

Ewa Krawczyk^*, Frank A. Suprynowicz^*, Xuefeng Liu^*, Yuhai Dai^*, Dan P. Hartmann^*, John Hanover, and Richard Schlegel^*@

From the Department of Pathology,* Georgetown University Medical School, Washington, DC; and the Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

^@ To whom correspondence should be addressed. E-mail: schleger{at}georgetown.edu.

	Abstract

A long-recognized, pathognomonic feature of human papillomavirus (HPV) infection is the appearance of halo or koilocytotic cells in the differentiated layers of the squamous epithelium. These koilocytes are squamous epithelial cells that contain an acentric, hyperchromatic nucleus that is displaced by a large perinuclear vacuole. However, the genesis of the cytoplasmic vacuole has remained unclear, particularly because both HPV DNA replication and virion assembly occur exclusively in the nucleus. In clinical biopsies, koilocytosis is observed in both low- and high-risk HPV infections; therefore, in this study, we demonstrated that the E5 and E6 proteins from both low- and high-risk HPVs cooperate to induce koilocyte formation in human cervical cells in vitro, using both stable and transient assays. Both E5 and E6 also induce koilocytosis in human foreskin keratinocytes but not in primate COS cells. Deletion of the 20 C-terminal amino acids of E5 completely abrogates koilocytosis, whereas a 10-amino acid-deletion mutant retains 50% of its activity. Because the E6 protein from both the low- and high-risk HPVs is capable of potentiating koilocytosis with E5, it is apparent that the targeting of both p53 and PDZ proteins by E6 is not involved. Our data suggest new, cooperative functions for both the E5 and E6 proteins, hinting at additional targets and roles for these oncoproteins in the viral life cycle.

This article has been cited by other articles:

				S. Boulenouar, C. Weyn, M. Van Noppen, M. Moussa Ali, M. Favre, P. O. Delvenne, F. Bex, A. Noel, Y. Englert, and V. Fontaine Effects of HPV-16 E5, E6 and E7 proteins on survival, adhesion, migration and invasion of trophoblastic cells Carcinogenesis, March 1, 2010; 31(3): 473 - 480. [Abstract] [Full Text] [PDF]

				E. Krawczyk, F. A. Suprynowicz, S. R. Sudarshan, and R. Schlegel Membrane Orientation of the Human Papillomavirus Type 16 E5 Oncoprotein J. Virol., February 15, 2010; 84(4): 1696 - 1703. [Abstract] [Full Text] [PDF]

				S. Barbaresi, M. S. Cortese, J. Quinn, G. H. Ashrafi, S. V. Graham, and M. S. Campo Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain J. Gen. Virol., February 1, 2010; 91(2): 521 - 530. [Abstract] [Full Text] [PDF]

				R. Condjella, X. Liu, F. Suprynowicz, H. Yuan, S. Sudarshan, Y. Dai, and R. Schlegel The Canine Papillomavirus E5 Protein Signals from the Endoplasmic Reticulum J. Virol., December 15, 2009; 83(24): 12833 - 12841. [Abstract] [Full Text] [PDF]