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Journal of Virology, August 2001, p. 7583-7591, Vol. 75, No. 16
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.
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
*
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.
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