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Journal of Virology, September 2008, p. 8695-8705, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00579-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E7 Oncoprotein Associates with E2F6{triangledown}

Margaret E. McLaughlin-Drubin, Kyung-Won Huh,{dagger} and Karl Münger*

Infectious Diseases Division, The Channing Laboratory, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Received 14 March 2008/ Accepted 19 June 2008

The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.

* Corresponding author. Mailing address: The Channing Laboratory 861, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4282. Fax: (617) 525-4283. E-mail: kmunger{at}rics.bwh.harvard.edu

{triangledown} Published ahead of print on 25 June 2008.

{dagger} Present address: Department of Biochemistry and Molecular Biology, School of Medicine, Louisiana State University Health Science Center, New Orleans, LA.

Journal of Virology, September 2008, p. 8695-8705, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00579-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Shin, M.-K., Balsitis, S., Brake, T., Lambert, P. F. (2009). Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis. Cancer Res. 69: 5656-5663 [Abstract] [Full Text]  


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