The E7 protein of the cottontail rabbit papillomavirus immortalizes normal rabbit keratinocytes and reduces pRb levels, while E6 cooperates in immortalization but neither degrades p53 nor binds E6AP.
Human papillomaviruses (HPVs) cause cervical cancer and are associated with the development of non-melanoma skin cancer. A suitable animal model for papillomavirus-associated skin carcinogenesis is the infection of domestic rabbits with the cottontail rabbit papillomavirus (CRPV). As the immortalizing activity of CRPV genes in the natural target cells remains unknown, we investigated the properties of CRPV E6 and E7 in rabbit keratinocytes (RK) and their influence on the cell cycle. Interestingly, CRPV E7 immortalized RK after a cellular crisis but showed no such activity in human keratinocytes. Co-expressed CRPV E6 prevented cellular crisis. The HPV16 or CRPV E7 protein reduced rabbit pRb levels thereby causing rabbit p19(ARF) induction and accumulation of p53 without affecting cellular proliferation. Both CRPV E6 proteins failed to degrade rabbit p53 in vitro or to bind E6AP; however, p53 was still inducible by mitomycin C. In summary, CRPV E7 immortalizes rabbit keratinocytes in a species-specific manner and E6 contributes to immortalization without directly affecting p53.
Ganzenmueller
Tina
T
Sektion Experimentelle Virologie, Universitaetsklinikum Tuebingen, 72076 Tuebingen, Germany.
Matthaei
Markus
M
Muench
Peter
P
Scheible
Michael
M
Iftner
Angelika
A
Hiller
Thomas
T
Leiprecht
Natalie
N
Probst
Sonja
S
Stubenrauch
Frank
F
Iftner
Thomas
T
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002472:Cell Transformation, Viral; D012777:Cottontail rabbit papillomavirus / Q000235:genetics / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D016685:Mitomycin / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011817:Rabbits; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C469554:E6 protein, Cottontail rabbit papillomavirus; C079183:E7 protein, cottontail rabbit papillomavirus; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases