Human papillomavirus type 38 alters wild-type p53 activity to promote cell proliferation via the downregulation of integrin alpha 1 expression.

Maria Carmen Romero-Medina,Rosita Accardi,Assunta Venuti,Cesare Indiveri,Mariafrancesca Scalise,Purnima Gupta,Maria Grazia Ceraolo,Alexis Robitaille,Cecilia Sirand,Laura Pacini,Valerio Taverniti,Giusi Melita,Daniele Viarisio,Massimo Tommasino,Paul Francis Lambert

doi:10.1371/journal.ppat.1008792

Abstract

Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by different means strongly decreases the proliferation of HPV38 E6/E7 HKs. This p53 form is phosphorylated at S392 by the double-stranded RNA-dependent protein kinase PKR, which is highly activated by HPV38. PKR-mediated S392 p53 phosphorylation promotes the formation of a p53/DNMT1 complex, which inhibits expression of integrin alpha 1 (ITGA1), a repressor of epidermal growth factor receptor (EGFR) signaling. Ectopic expression of ITGA1 in HPV38 E6/E7 HKs promotes EGFR degradation, inhibition of cellular proliferation, and cellular death. Itga1 expression was also inhibited in the skin of HPV38 transgenic mice that have an elevated susceptibility to UV-induced skin carcinogenesis. In summary, these findings reveal the existence of a specific WT p53 form that displays pro-proliferation properties.

Highlights

Cellular transformation is intimately linked to alteration of pathways regulated by tumor suppressors, leading to reprogramming of cellular gene expression
This study shows that beta human papillomavirus type 38 (HPV38) can convert p53 functions from a tumor suppressor to an oncoprotein via the formation of a transcriptionally repressive complex, which in turn represses integrin alpha 1 (ITGA1) expression, promoting cellular proliferation and UV-induced skin carcinogenesis
Accumulation of p53 is induced by the viral proteins as previously shown (Fig 1C) [25].To evaluate whether the decrease in ITGA1 mRNA levels is a direct consequence of the viral gene expression and is not due to the immortalization of 38HK, we used as an experimental model primary human keratinocytes (HKs) expressing the human telomerase reverse transcriptase gene, which extends the life span of primary cells

Summary

Introduction

Cellular transformation is intimately linked to alteration of pathways regulated by tumor suppressors, leading to reprogramming of cellular gene expression. PRb negatively regulates cellular gene expression by interacting with several transcription factors, for example members of the E2F family, including E2F1–3 proliferation [3]. Upon exposure of quiescent cells to mitogenic signals, pRb is phosphorylated by cyclin-dependent kinase complexes, losing its ability to interact with E2Fs, which, in turn, are free to activate the expression of many genes that encode proteins with pro-proliferative functions [3]. In agreement with their negative role in cellular proliferation, loss of functional p53- and pRb-regulated pathways occurs in all cancer cells. E2F1 post-translational modifications, such as methylation, appear to influence its property of promoting cellular proliferation or apoptosis [7, 8]

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Results

Conclusion