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Inhibition of Epidermal Growth Factor Receptor (EGFR) expression by human cytomegalovirus correlates with an increase in the expression and binding of Wilms' Tumour 1 protein to the EGFR promoter

University of Cambridge

¹ E-mail: js{at}mole.bio.cam.ac.uk

Infection with human cytomegalovirus (HCMV) modulates the expression of a number of cellular receptors and is known to inhibit expression of the epidermal growth factor receptor (EGFR); a cell surface receptor which can promote cell proliferation through a cascade of intracellular signaling events. We have examined the mechanisms by which HCMV mediates down-regulation of EGFR expression and show that virus infection results in the profound up-regulation of Wilms' Tumor 1 (WT1) protein, a transcription factor associated with the negative regulation of a number of growth factors and growth factor receptors – including EGFR. Moreover, chromatin immunoprecipitation experiments also show that HCMV infection results in increased binding of WT1 to the EGFR promoter. Finally, we show that depleting the cell of WT1 using siRNA abrogates virus-mediated down-regulation of EGFR.Taken together, our observations suggest that HCMV-mediated repression of EGFR expression results from a virus-mediated increase in cellular WT1, a known pleotropic regulator of mitogenesis, apoptosis and differentiation.

Received 15 December 2008; accepted 24 March 2009.