Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues including the epidermis and epithelial linings of the upper respiratory system and anogenital tract. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with greater than 95% of cervical carcinomas. Two genes of the high-risk anogenital human papillomaviruses (HPV), E6 and E7, are implicated in cervical carcinogenesis owing to their selective and continued expression in those cancers. E6 and E7 proteins possess multiple biochemical activities including but not limited to their capacities to inactivate tumor suppressor genes p53 and pRB, respectively. We and others have demonstrated that the inactivation of p53 and pRB cannot account completely for E6 and E7's transforming potential in tissue culture and tumorigenic properties in animal models. The goals of this application are to identify the cellular targets of E6 and E7 that contribute to their oncogenic function. We shall use transgenic mouse models in which the E6 and E7 genes of the high risk HPV most commonly associated with human cervical cancer, HPV-16, are directed in their expression to stratified squamous epithelia. These mouse models permit us to evaluate acute and long-term effects of E6 and E7 expression on mouse tissue including tumorigenesis in the epidermis and cervix. The availability of mouse strains that have been altered in specific cellular genes provide us a compelling approach to defining the cellular targets of E6 and E7 that contribute to HPV-associated cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Virology Study Section (VR)
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Read-Connole, Elizabeth Lee
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Spurgeon, Megan E; Chung, Sang-Hyuk; Lambert, Paul F (2014) Recurrence of cervical cancer in mice after selective estrogen receptor modulator therapy. Am J Pathol 184:530-40
Park, J W; Shin, M-K; Lambert, P F (2014) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. Oncogene 33:3383-91
Park, Jung Wook; Shin, Myeong-Kyun; Pitot, Henry C et al. (2013) High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins. PLoS One 8:e75056
Spurgeon, Megan E; Lambert, Paul F (2013) Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435:118-30
Johannsen, Eric; Lambert, Paul F (2013) Epigenetics of human papillomaviruses. Virology 445:205-12
Yamben, Idella F; Rachel, Rivka A; Shatadal, Shalini et al. (2013) Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse. Dev Biol 384:41-52
Michael, Stella; Lambert, Paul F; Strati, Katerina (2013) The HPV16 oncogenes cause aberrant stem cell mobilization. Virology 443:218-25
Shin, Myeong-Kyun; Sage, Julien; Lambert, Paul F (2012) Inactivating all three rb family pocket proteins is insufficient to initiate cervical cancer. Cancer Res 72:5418-27
Bonilla-Delgado, José; Bulut, Gülay; Liu, Xuefeng et al. (2012) The E6 oncoprotein from HPV16 enhances the canonical Wnt/?-catenin pathway in skin epidermis in vivo. Mol Cancer Res 10:250-8
Ibarra Sierra, E; Diaz Chavez, J; Cortes-Malagon, E M et al. (2012) Differential gene expression between skin and cervix induced by the E7 oncoprotein in a transgenic mouse model. Virology 433:337-45

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