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Journal of Virology, October 2002, p. 10559-10568, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10559-10568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells

Anna-Marija Helt,1,2 Jens Oliver Funk,1,{dagger} and Denise A. Galloway1,2*

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,1 Department of Microbiology, University of Washington, Seattle, Washington 981952

Received 25 April 2002/ Accepted 3 July 2002

The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and E7 {Delta}79-83 (deletion of positions 79 through 83) were further tested in several models of cell cycle arrest associated with elevated levels of p21. C-terminal mutations rendered E7 unable to induce S phase and endoreduplication in differentiated keratinocytes and rendered it less efficient in delaying senescence of human mammary epithelial cells. Interestingly, when cell cycle arrest was induced with a peptide form of p21, the E7 C-terminal mutants were deficient in overcoming arrest, whereas a mutant defective in Rb binding was competent in inhibiting G1 arrest. These results suggest that the inactivation of both p21 and Rb by E7 contributes to subversion of cell cycle control in normal human epithelia but that neither p21 nor Rb inactivation alone is sufficient.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Mail Stop C1-015, Seattle, WA 98109. Phone: (206) 667-4500. Fax: (206) 667-5815. E-mail: dgallowa{at}fhcrc.org.

{dagger} Present address: Laboratory of Molecular Tumor Biology, Department of Dermatology, University of Erlangen—Nuremberg, 91052 Erlangen, Germany.

Journal of Virology, October 2002, p. 10559-10568, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10559-10568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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