Cutaneous papillomavirus E6 proteins must interact with p300 and block p53-mediated apoptosis for cellular immortalization and tumorigenesis.
The binding of the papillomavirus E6 protein to E6AP and the induction of p53 degradation are common features of high-risk genital human papillomaviruses (HPV); cutaneous HPVs, on the other hand, lack these capacities. Nevertheless, several cutaneous HPV types of the beta-genus, such as HPV38 are associated with tumor formation when combined with genetic predisposition, immunosuppression, or UV exposure. In an animal model system, the cottontail rabbit papillomavirus (CRPV) rapidly induces skin cancer without additional cofactors, and CRPVE6 and E7 immortalize rabbit keratinocytes in vitro. However, CRPVE6 neither interacts with E6AP and p53 nor does it induce p53 degradation. In this study, we show that the interaction of CRPVE6, or HPV38E6, with the histone acetyltransferase p300 is crucial to inhibit the ability of p53 to induce apoptosis. Strikingly, E6 mutants deficient for p300 binding are incapable of preventing p53 acetylation, p53-dependent transcription, and apoptosis induction. Moreover, E6 mutants deficient for p300 binding cannot contribute to HPV38-induced immortalization of human keratinocytes or CRPV-induced tumor formation. Our findings highlight changes in the p53 acetylation status mediated by the viral E6 protein as a crucial requirement in the ability of high-risk cutaneous papillomaviruses to immortalize primary keratinocytes and induce tumors. Cancer Res; 70(17); 6913-24. (c)2010 AACR.
Muench
Peter
P
Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tuebingen, Tuebingen, Germany.
Probst
Sonja
S
Schuetz
Johanna
J
Leiprecht
Natalie
N
Busch
Martin
M
Wesselborg
Sebastian
S
Stubenrauch
Frank
F
Iftner
Thomas
T
D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002461:Cell Line, Transformed; D012777:Cottontail rabbit papillomavirus; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011817:Rabbits; D012878:Skin Neoplasms / Q000378:metabolism / Q000821:virology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C469554:E6 protein, Cottontail rabbit papillomavirus; C079183:E7 protein, cottontail rabbit papillomavirus; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein