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The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner

Oncogene volume 26, pages 7386–7390 (2007)Cite this article

Abstract

Cyclin-dependent kinase inhibitor p27kip1 (p27) has recently been implicated as a positive regulator of cellular motility and is a marker of poor prognosis in several forms of cancer when localized to the cytoplasm. Cytoplasmic p27 exerts its effect on migration by binding to and inhibiting the activation of the small GTPase and cytoskeletal organizer RhoA, consequentially loosening cell substrate grip and enhancing movement. Using DNA damage as a p27 nuclear import signal, we found that the E7 oncoprotein from human papillomavirus type 16 (HPV-16), the etiological agent of cervical cancer, enhanced both the cytoplasmic retention of p27 and the migration of human foreskin keratinocytes (HFKs) in a phosphoinositide-3 kinase (PI3K)/Akt-dependent manner using a standard wound assay. Increased migration in E7-expressing HFKs correlated with an Akt-regulated downregulation of RhoA activity through p27 binding under conditions where a p27 nuclear import signal is given (that is, DNA damage). Under these conditions, inhibition of the downstream RhoA effector ROCK enhanced control cell migration, whereas relatively unaffecting E7-expressing cells, further implicating that the inhibitory effect of E7 on RhoA positively regulates migration. We believe that the E7 protein from HPV-16 can modulate the cytoplasmic localization of p27 and may in turn regulate tumor metastasis/aggressiveness through the PI3K/Akt pathway.

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Acknowledgements

We thank Craig Menges, Daksha Patel and Barry Thrash for critical review of this paper, Dirk Bohmann for the use of reagents and lab space, and Brian Ward for assistance with microscopy. National Institute of Allergy and Infectious Diseases Grant AI030798 (to DJ McCance). This publication was also made possible by Grant Number GM068411 from the Institutional Ruth L Kirschstein National Research Service Award and its views are the sole responsibility of the authors and not of the NIH.

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  1. D J McCance

    Present address: 3Current address: Center for Cancer Research and Cell Biology, Queens University, Belfast City Hospital, Belfast.,

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA

    S T Charette & D J McCance

  2. James P Wilmot Cancer Center, University of Rochester, Rochester, NY, USA

    D J McCance

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  1. S T Charette
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  2. D J McCance
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Correspondence to D J McCance.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Charette, S., McCance, D. The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner. Oncogene 26, 7386–7390 (2007). https://doi.org/10.1038/sj.onc.1210541

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