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Journal of Virology, February 2003, p. 2195-2206, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.2195-2206.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The E6 and E7 Proteins of the Cutaneous Human Papillomavirus Type 38 Display Transforming Properties

Sandra Caldeira,1,{dagger} Ingeborg Zehbe,1 Rosita Accardi,1 Ilaria Malanchi,1 Wen Dong,1 Marianna Giarrè,1,{ddagger} Ethel-Michele de Villiers,1 Raffaele Filotico,2 Petra Boukamp,3 and Massimo Tommasino1*

Angewandte Tumorvirologie,1 Genetik der Hautcarcinogenese, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany,3 Istituto di Dermatologia, Facoltà di Medicina, Università di Bari, Bari, Italy2

Received 2 August 2002/ Accepted 1 November 2002

Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces loss of G1/S transition control, a key event in carcinogenesis. In contrast, HPV10 and HPV20 E7 proteins do not display these in vitro transforming activities. We also show that the two early proteins E6 and E7 of HPV38 are sufficient to corrupt the cell cycle and senescence programs in primary cells, inducing active and long-lasting proliferation of primary human keratinocytes, the natural host cells. Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carcinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens (P < 0.001).

* Corresponding author. Present address: Unit of Infection and Cancer, International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France. Phone: 33 472738191. Fax: 33 472738442. E-mail: tommasino{at}iarc.fr.

{dagger} Present address: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.

{ddagger} Present address: Laboratory of Clinical Chemistry, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.

Journal of Virology, February 2003, p. 2195-2206, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.2195-2206.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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