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Journal of Virology, September 2007, p. 9737-9747, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00881-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Cullin 2 Ubiquitin Ligase Complex, Which Contributes to Degradation of the Retinoblastoma Tumor Suppressor{triangledown}

KyungWon Huh,1 Xiaobo Zhou,1 Hiroyuki Hayakawa,1 Je-Yoel Cho,2 Towia A. Libermann,3 Jianping Jin,4 J. Wade Harper,4 and Karl Munger1*

The Channing Laboratory, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115,1 Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu 700-422, South Korea,2 Beth Israel Deaconess Medical Center Genomics Center and Bioinformatics Core, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,3 Department of Pathology, Harvard Medical School, Boston, Massachusetts 021154

Received 24 April 2007/ Accepted 20 June 2007

Human papillomavirus type 16 (HPV16) and other high-risk HPVs are etiologically linked to the development of cervical carcinomas and contribute to a number of other tumors of the anogenital tract, as well as oral cancers. The high-risk HPV E6 and E7 oncoproteins are consistently expressed in cervical cancer cells and are necessary for the induction and maintenance of the transformed phenotype. An important aspect of HPV16 E7's oncogenic activities is destabilization of the retinoblastoma tumor suppressor (pRB) through a ubiquitin/proteasome-dependent mechanism, although the exact molecular mechanism is unknown. Here, we report that HPV16 E7 is associated with an enzymatically active cullin 2 ubiquitin ligase complex and that the HPV16 E7/pRB complex contains cullin 2. Depletion of cullin 2 by RNA interference causes increased steady-state levels and stability of pRB in HPV16 E7-expressing cells, and ectopic expression of HPV16 E7 and the cullin 2 complex leads to pRB ubiquitination in vivo. Hence, we propose that the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells.

* Corresponding author. Mailing address: The Channing Laboratory 861, Brigham and Women's Hospital, 181 Longwood Avenue, 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 3 July 2007.

Journal of Virology, September 2007, p. 9737-9747, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00881-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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