Research Papers:

Human papillomavirus type 18 E5 oncogene supports cell cycle progression and impairs epithelial differentiation by modulating growth factor receptor signalling during the virus life cycle

Christopher W. Wasson, Ethan L. Morgan, Marietta Müller, Rebecca L. Ross, Margaret Hartley, Sally Roberts and Andrew Macdonald _

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Oncotarget. 2017; 8:103581-103600. https://doi.org/10.18632/oncotarget.21658

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Christopher W. Wasson1, Ethan L. Morgan1, Marietta Müller1, Rebecca L. Ross1, Margaret Hartley2, Sally Roberts2,* and Andrew Macdonald1,*

1School of Molecular and Cellular Biology, Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK

2Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

*These authors have contributed equally to this work

Correspondence to:

Andrew Macdonald, email: [email protected]

Keywords: HPV, E5, proliferation, EGFR, differentiation

Received: July 26, 2017     Accepted: August 16, 2017     Published: October 06, 2017


Deregulation of proliferation and differentiation-dependent signalling pathways is a hallmark of human papillomavirus (HPV) infection. Although the manipulation of these pathways by E6 and E7 has been extensively studied, controversies surround the role of the E5 oncoprotein during a productive virus life cycle. By integrating primary keratinocytes harbouring wild type or E5 knockout HPV18 genomes with pharmacological and gain/loss of function models, this study aimed to provide molecular information about the role of E5 in epithelial proliferation and differentiation. We show that E5 contributes to cell cycle progression and unscheduled host DNA synthesis in differentiating keratinocytes. E5 function correlates with increased EGFR activation in differentiating cells and blockade of this pathway impairs differentiation-dependent cell cycle progression of HPV18 containing cells. Our findings provide a functional requirement of enhanced EGFR signalling for suprabasal cellular DNA synthesis during the virus life cycle. They also reveal an unrecognised contribution of E5 towards the impaired keratinocyte differentiation observed during a productive HPV infection. E5 suppresses a signalling axis consisting of the keratinocyte growth factor receptor (KGFR) pathway. Inhibition of this pathway compensates for the loss of E5 in knockout cells and re-instates the delay in differentiation. The negative regulation of KGFR involves suppression by the EGFR pathway. Thus our data reveal an unappreciated role for E5-mediated EGFR signalling in orchestrating the balance between proliferation and differentiation in suprabasal cells.

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