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University of California San Francisco Comprehensive Cancer Center and Department of Surgery, University of California, San Francisco 94143-0808 [R. R. R., J. M. A.]; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 [S. D., K. M.]; and McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706 [T. B., P. F. L.]
Human cervix cancer is caused by high-risk human papillomaviruses encoding E6 and E7 oncoproteins, each of which alter function of distinct targets regulating the cell cycle, apoptosis, and differentiation. Here we determined the molecular contribution of E6 or E7 to neoplastic progression and malignant growth in a transgenic mouse model of cervical carcinogenesis. E7 increased proliferation and centrosome copy number, and produced progression to multifocal microinvasive cervical cancers. E6 elevated centrosome copy number and eliminated detectable p53 protein, but did not produce neoplasia or cancer. E6 plus E7 additionally elevated centrosome copy number and created large, extensively invasive cancers. Centrosome copy number increases and p53 loss likely contributed to malignant growth; however, dysregulated proliferation and differentiation were required for carcinogenic progression.
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C. H. Storrs and S. J. Silverstein PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6 J. Virol., April 15, 2007; 81(8): 4080 - 4090. [Abstract] [Full Text] [PDF]
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 J P A Baak, A-J Kruse, S J Robboy, E A M Janssen, B van Diermen, and I Skaland Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular biomarkers J. Clin. Pathol., October 1, 2006; 59(10): 1017 - 1028. [Abstract] [Full Text] [PDF]
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K. Strati, H. C. Pitot, and P. F. Lambert Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model PNAS, September 19, 2006; 103(38): 14152 - 14157. [Abstract] [Full Text] [PDF]
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N. Gammoh, H. S. Grm, P. Massimi, and L. Banks Regulation of Human Papillomavirus Type 16 E7 Activity through Direct Protein Interaction with the E2 Transcriptional Activator J. Virol., February 15, 2006; 80(4): 1787 - 1797. [Abstract] [Full Text] [PDF]
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L.-H. Yih, Y.-Y. Tseng, Y.-C. Wu, and T.-C. Lee Induction of Centrosome Amplification during Arsenite-Induced Mitotic Arrest in CGL-2 Cells Cancer Res., February 15, 2006; 66(4): 2098 - 2106. [Abstract] [Full Text] [PDF]
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S. Balsitis, F. Dick, D. Lee, L. Farrell, R. K. Hyde, A. E. Griep, N. Dyson, and P. F. Lambert Examination of the pRb-Dependent and pRb-Independent Functions of E7 In Vivo J. Virol., September 1, 2005; 79(17): 11392 - 11402. [Abstract] [Full Text] [PDF]
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S. M. Genther Williams, G. L. Disbrow, R. Schlegel, D. Lee, D. W. Threadgill, and P. F. Lambert Requirement of Epidermal Growth Factor Receptor for Hyperplasia Induced by E5, a High-Risk Human Papillomavirus Oncogene Cancer Res., August 1, 2005; 65(15): 6534 - 6542. [Abstract] [Full Text] [PDF]
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T. Brake and P. F. Lambert Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model PNAS, February 15, 2005; 102(7): 2490 - 2495. [Abstract] [Full Text] [PDF]
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 K. Matsumoto, G. R. Leggatt, J. Zhong, X. Liu, R. L. de Kluyver, T. Peters, G. J. P. Fernando, A. Liem, P. F. Lambert, and I. H. Frazer Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors J Natl Cancer Inst, November 3, 2004; 96(21): 1611 - 1619. [Abstract] [Full Text] [PDF]
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K. Munger, A. Baldwin, K. M. Edwards, H. Hayakawa, C. L. Nguyen, M. Owens, M. Grace, and K. Huh Mechanisms of Human Papillomavirus-Induced Oncogenesis J. Virol., November 1, 2004; 78(21): 11451 - 11460. [Full Text] [PDF]
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K. Kawamura, H. Izumi, Z. Ma, R. Ikeda, M. Moriyama, T. Tanaka, T. Nojima, L. S. Levin, K. Fujikawa-Yamamoto, K. Suzuki, et al. Induction of Centrosome Amplification and Chromosome Instability in Human Bladder Cancer Cells by p53 Mutation and Cyclin E Overexpression Cancer Res., July 15, 2004; 64(14): 4800 - 4809. [Abstract] [Full Text] [PDF]
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 M. S. Longworth and L. A. Laimins Pathogenesis of Human Papillomaviruses in Differentiating Epithelia Microbiol. Mol. Biol. Rev., June 1, 2004; 68(2): 362 - 372. [Abstract] [Full Text] [PDF]
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 S. J. Balsitis, J. Sage, S. Duensing, K. Munger, T. Jacks, and P. F. Lambert Recapitulation of the Effects of the Human Papillomavirus Type 16 E7 Oncogene on Mouse Epithelium by Somatic Rb Deletion and Detection of pRb-Independent Effects of E7 In Vivo Mol. Cell. Biol., December 15, 2003; 23(24): 9094 - 9103. [Abstract] [Full Text] [PDF]
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T. Brake, J. P. Connor, D. G. Petereit, and P. F. Lambert Comparative Analysis of Cervical Cancer in Women and in a Human Papillomavirus-Transgenic Mouse Model: Identification of Minichromosome Maintenance Protein 7 as an Informative Biomarker for Human Cervical Cancer Cancer Res., December 1, 2003; 63(23): 8173 - 8180. [Abstract] [Full Text] [PDF]
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D. R. Lowy and M. L. Gillison A New Link Between Fanconi Anemia and Human Papillomavirus-Associated Malignancies J Natl Cancer Inst, November 19, 2003; 95(22): 1648 - 1650. [Full Text] [PDF]
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