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Journal of Virology, December 2004, p. 13769-13778, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13769-13778.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E6 Promotes Retinoblastoma Protein Phosphorylation and Cell Cycle Progression

Ilaria Malanchi,1,{dagger} Rosita Accardi,1 Frank Diehl,2 Anouk Smet,1 Elliot Androphy,3 Jörg Hoheisel,2 and Massimo Tommasino1*

Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, Lyon, France,1 Unit of Function Genome Analysis, Deutches Krebsforschungszentrum, Heidelberg, Germany,2 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts3

Received 28 April 2004/ Accepted 3 August 2004

We show that E6 proteins from benign human papillomavirus type 1 (HPV1) and oncogenic HPV16 have the ability to alter the regulation of the G1/S transition of the cell cycle in primary human fibroblasts. Overexpression of both viral proteins induces cellular proliferation, retinoblastoma (pRb) phosphorylation, and accumulation of products of genes that are negatively regulated by pRb, such as p16INK4a, CDC2, E2F-1, and cyclin A. Hyperphosphorylated forms of pRb are present in E6-expressing cells even in the presence of ectopic levels of p16INK4a. The E6 proteins strongly increased the cyclin A/cyclin-dependent kinase 2 (CDK2) activity, which is involved in pRb phosphorylation. In addition, mRNA and protein levels of the CDK2 inhibitor p21WAF1/CIP1 were strongly down-regulated in cells expressing E6 proteins. The down-regulation of the p21WAF1/CIP1 gene appears to be independent of p53 inactivation, since HPV1 E6 and an HPV16 E6 mutant unable to target p53 were fully competent in decreasing p21WAF1/CIP1 levels. E6 from HPV1 and HPV16 also enabled cells to overcome the G1 arrest imposed by oncogenic ras. Immunofluorescence staining of cells coexpressing ras and E6 from either HPV16 or HPV1 revealed that antiproliferative (p16INK4a) and proliferative (Ki67) markers were coexpressed in the same cells. Together, these data underline a novel activity of E6 that is not mediated by inactivation of p53.

* Corresponding author. Mailing address: Infections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69372 Lyon cedex 08, France. Phone: 33 4 72738191. Fax: 33 4 72738442. E-mail: tommasino{at}iarc.fr.

{dagger} Present address: Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland.

Journal of Virology, December 2004, p. 13769-13778, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13769-13778.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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