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Journal of Virology, August 2001, p. 7583-7591, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7583-7591.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7

Sonia L. Gonzalez,1,2 Matt Stremlau,3 Xi He,4 John R. Basile,2,5 and Karl Münger1,2,3,4,*

Program in Biological Sciences in Public Health, Harvard School of Public Health,1 Program in Biological and Biomedical Sciences,3 Virology Program,4 and Department of Pathology,2 Harvard Medical School, and Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine,5 Boston, Massachusetts 02115

Received 23 February 2001/Accepted 8 May 2001

The steady-state level and metabolic half-life of retinoblastoma tumor suppressor protein pRB are decreased in cells that express high-risk human papillomavirus (HPV) E7 proteins. Here we show that pRB degradation is a direct activity of E7 and does not reflect a property of cell lines acquired during the selection process for E7 expression. An amino-terminal domain of E7 that does not directly contribute to pRB binding but is required for transformation is also necessary for E7-mediated pRB degradation. Treatment with inhibitors of the 26S proteasome not only blocks E7-mediated pRB degradation but also causes the stabilization of E7. Mutagenic analyses, however, reveal that the processes of proteasomal degradation of E7 and pRB are not linked processes. HPV type 16 E7 also targets the pRB-related proteins p107 and p130 for destabilization by a proteasome-dependent mechanism. Using the SAOS2 flat-cell assay as a biological indicator for pRB function, we demonstrate that pRB degradation, not solely binding, is important for the E7-induced inactivation of pRB.

* Corresponding author. Mailing address: Department of Pathology and Center for Cancer Research, Harvard Medical School, Armenise Research Building D2/544A, 200 Longwood Ave., Boston, MA 02115-5701. Phone: (617) 432-2878. Fax: (617) 432-0426. E-mail: karl_munger{at}hms.harvard.edu.

Journal of Virology, August 2001, p. 7583-7591, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7583-7591.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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