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

doi:10.1128/JVI.75.16.7583-7591.2001

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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 thatexpress high-risk human papillomavirus (HPV) E7 proteins. Herewe show that pRB degradation is a direct activity of E7 and doesnot reflect a property of cell lines acquired during the selectionprocess for E7 expression. An amino-terminal domain of E7 thatdoes not directly contribute to pRB binding but is required fortransformation is also necessary for E7-mediated pRB degradation.Treatment with inhibitors of the 26S proteasome not only blocksE7-mediated pRB degradation but also causes the stabilizationof E7. Mutagenic analyses, however, reveal that the processesof proteasomal degradation of E7 and pRB are not linked processes.HPV type 16 E7 also targets the pRB-related proteins p107 andp130 for destabilization by a proteasome-dependent mechanism.Using the SAOS2 flat-cell assay as a biological indicator forpRB function, we demonstrate that pRB degradation, not solelybinding, is important for the E7-induced inactivation ofpRB.

^* Corresponding author. Mailing address: Department of Pathology and Center for Cancer Research, Harvard Medical School, ArmeniseResearch 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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