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Departments of 1 Biochemistry and Biophysics, 2 Microbiology and Immunology, and 3 Pathology and Laboratory Medicine and 4 James P. Wilmot Cancer Center, University of Rochester, Rochester, New York
Requests for reprints: Dennis J. McCance, Department of Microbiology and Immunology, University of Rochester, 575 Elmwood Avenue, Rochester, NY 14642. Phone: 585-275-0101; Fax: 585-473-9573; E-mail: dennis_mccance{at}urmc.rochester.edu.
Human papillomaviruses (HPV) are small DNA tumor viruses causally associated with cervical cancer. The early gene product E7 from high-risk HPV is considered the major transforming protein expressed by the virus. Although many functions have been described for E7 in disrupting normal cellular processes, we describe in this study a new cellular target in primary human foreskin keratinocytes (HFK), the serine/threonine kinase AKT. Expression of HPV type 16 E7 in HFK caused inhibition of differentiation, hyperproliferation, and up-regulation of AKT activity in organotypic raft cultures. The ability of E7 to up-regulate AKT activity is dependent on its ability to bind to and inactivate the retinoblastoma (Rb) gene product family of proteins. Furthermore, we show that knocking down Rb alone, with short hairpin RNAs, was sufficient to up-regulate AKT activity in differentiated keratinocytes. Up-regulation of AKT activity and loss of Rb was also observed in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Together, these data provide evidence linking inactivation of Rb by E7 in the up-regulation of AKT activity during cervical cancer progression. (Cancer Res 2006; 66(11): 5555-9)
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  M. J. Lace, J. R. Anson, A. J. Klingelhutz, J. H. Lee, A. D. Bossler, T. H. Haugen, and L. P. Turek Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs J. Virol., November 15, 2009; 83(22): 11784 - 11794. [Abstract] [Full Text] [PDF]
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 S. Thaler, P. S. Hahnel, A. Schad, R. Dammann, and M. Schuler RASSF1A Mediates p21Cip1/Waf1-Dependent Cell Cycle Arrest and Senescence through Modulation of the Raf-MEK-ERK Pathway and Inhibition of Akt Cancer Res., March 1, 2009; 69(5): 1748 - 1757. [Abstract] [Full Text] [PDF]
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R. F.L. O'Shaughnessy, B. Akgul, A. Storey, H. Pfister, C. A. Harwood, and C. Byrne Cutaneous Human Papillomaviruses Down-regulate AKT1, whereas AKT2 Up-regulation and Activation Associates with Tumors Cancer Res., September 1, 2007; 67(17): 8207 - 8215. [Abstract] [Full Text] [PDF]
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 J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]
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