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Journal of Virology, May 2001, p. 4150-4157, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4150-4157.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Papillomavirus Type 6b Virus-Like Particles Are Able To Activate the Ras-MAP Kinase Pathway and Induce Cell Proliferation

Elizabeth Payne,1 Mark R. Bowles,1 Alistair Don,1 John F. Hancock,2 and Nigel A. J. McMillan1,*

Molecular Virology Laboratory, Centre for Immunology and Cancer Research, P.A. Hospital,1 and Queensland Cancer Fund Laboratory of Experimental Oncology, Department of Pathology,2 University of Queensland, Brisbane, Australia

Received 8 November 2000/Accepted 1 February 2001

The initial step in viral infection is the attachment of the virus to the host cell via an interaction with its receptor. We have previously shown that a receptor for human papillomavirus is the alpha 6 integrin. The alpha 6 integrin is involved in the attachment of epithelial cells with the basement membrane, but recent evidence suggests that ligation of many integrins results in intracellular signaling events that influence cell proliferation. Here we present evidence that exposure of A431 human epithelial cells to human papillomavirus type 6b L1 virus-like particles (VLPs) results in a dose-dependent increase in cell proliferation, as measured by bromodeoxyuridine incorporation. This proliferation is lost if VLPs are first denatured or incubated with a monoclonal antibody against L1 protein. The MEK1 inhibitor PB98059 inhibits the VLP-mediated increase in cell proliferation, suggesting involvement of the Ras-MAP kinase pathway. Indeed, VLP binding results in rapid phosphorylation of the beta 4 integrin upon tyrosine residues and subsequent recruitment of the adapter protein Shc to beta 4. Within 30 min, the activation of Ras, Raf, and Erk2 was observed. Finally, the upregulation of c-myc mRNA was observed at 60 min. These data indicate that human papillomavirus type 6b is able to signal cells via the Ras-MAP kinase pathway to induce cell proliferation. We hypothesize that such a mechanism would allow papillomaviruses to infect hosts more successfully by increasing the potential pool of cells they are able to infect via the initiation of proliferation in resting keratinocyte stem and suprabasal cells.

* Corresponding author. Mailing address: Molecular Virology Laboratory, CICR, P.A. Hospital, University of Queensland, Brisbane, Queensland 4102, Australia. Phone: 617 3240 5392. Fax: 617 3240 5946. E-mail: nmcmillan{at}cicr.pa.uq.edu.au.

Journal of Virology, May 2001, p. 4150-4157, Vol. 75, No. 9
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.9.4150-4157.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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