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Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21^Cip1 in Cervical Carcinogenesis

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Requests for reprints: Paul F. Lambert, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Madison, WI 53706. Phone: 608-262-8533; Fax: 608-262-2824; E-mail: lambert{at}oncology.wisc.edu.

Key Words: HPV-16 E7 • p21 • cervical cancer

The E7 oncoprotein of the high-risk human papillomaviruses (HPV) is thought to contribute to cervical carcinogenesis at least in part by abrogating cell cycle regulation. E7 can dysregulate the cell cycle through its interaction with several cellular proteins including the retinoblastoma suppressor protein pRb, as well as the cyclin-dependent kinase inhibitor p21^Cip1. Inactivation of pRb in cervical epithelia is not sufficient to explain the ability of E7 to cause cervical cancers in transgenic mice. In the current study, we focused on the role of p21^Cip1 in cervical cancer. Cervical disease was significantly increased in p21^–/– mice compared with p21^+/+ mice, showing that p21^Cip1 can function as a tumor suppressor in this tissue. Importantly, the ability of E7 to induce cervical cancers was not significantly enhanced on the p21-null background, consistent with the hypothesis that the ability of E7 to inhibit p21^Cip1 contributes to its carcinogenic properties. Further supportive of this hypothesis, cervical carcinogenesis in mice expressing a mutant form of HPV-16 E7, E7^CVQ, which fails to inactivate p21^Cip1, was significantly reduced compared with that in K14E7^WT mice expressing wild-type HPV-16 E7. However, K14E7^CVQ mice still displayed heightened levels of cervical carcinogenesis compared with that in nontransgenic mice, indicating that activities of E7 besides its capacity to inactivate p21^Cip1 also contribute to cervical carcinogenesis. Taken together, we conclude that p21^Cip1 functions as a tumor suppressor in cervical carcinogenesis and that p21^Cip1 inactivation by HPV-16 E7 partially contributes to the contribution of E7 to cervical carcinogenesis. [Cancer Res 2009;69(14):5656–63]

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