Genetics, Paillomavirus and Human Cancer


  HEADDr FAVRE Michel / mfavre@pasteur.fr
  MEMBERSDr DEMERET Caroline / Dr JACOB Yves / Dr MENDOZA José / NEVEU Grégory
ROLLOY Caroline / Dr VUILLIER Françoise


  Annual Report

Certain human papillomaviruses are the causative agents of the carcinoma of the uterine cervix (HPV16 and HPV18), the second woman cancer worldwide, and of the skin carcinoma (HPV5) developing in epidermodysplasia verruciformis (EV). This genodermatosis results from an abnormal susceptibility to a specific group of related HPV (EV HPV), including HPV5. We have demonstrated that mutations in either of two genes (EVER1 and EVER2) with unknown functions confer the sensitivity to EV HPV. It can be assumed that they play a role in the permissivity of keratinocytes to EV HPV or in the triggering of immune responses for elimination of lesions. Our aim is to characterize the functions of EVER1 and EVER2 proteins in normal and infected cells and to analyze the role of viral E6 and E7 proteins in the malignant transformation associated with oncogenic HPV.

EVER protein function(s)

We have demonstrated interactions between EVER1, EVER2 and the zinc transporter ZnT-1. The three proteins located in the endoplasmic reticulum influence intracellular localization of free zinc and down regulate expression of transcription factors induced by zinc (MTF-1) and cytokines (c-jun, elk). We currently study the impact of mutations in EVER1 and EVER2 on the pattern of expression of cytokines in lymphoblastoid cell lines and keratinocytes obtained from patients and healthy relatives. To get some insight into the control of EV HPV infection, we investigate whether EVER and ZnT-1 proteins interact with viral E6 and E7 oncoproteins or interfere with signaling pathways altered by the oncogenic HPV. We also analyze in keratinocytes the impact of EVER mutations on the transcription of the early viral genes (E1, E2, E6, and E7) and on late steps of the viral life cycle (DNA replication, virion production).

Interactome networks of early proteins of low risk and high risk HPV

Our aim is to unravel the strategies developed by HPV to replicate and transform infected keratinocytes. To this end, we have performed the cloning and expression of E6 and E7 open reading frame of twelve cutaneous and mucous HPV with low risk and high risk for the development of skin or genital carcinomas. Using a high-throughput yeast two-hybrid screening we have identified 1,460 interactions between viral E6 and cell proteins. These interactions are currently analyzed and validated in mammalian cells. Bioinformatics approaches will allow us to integrate these viral interactomes into the global cellular protein networks. Studies are in progress to analyze consequences of inhibition of the TGF-β1 signaling pathway by HPV5 E6 oncoprotein on the viral life cycle and malignant conversion of keratinocytes. This program is part of the Infection Mapping Project (I-MAP) between INSERM (IFR 128 Biosciences Lyon-Gerland) and Pasteur Institute (Unité de Génomique Virale and our unit).

These studies should allow a better understanding of the viral strategies involved in skin and genital carcinogenesis and to define new approaches for the treatment of these infections that are widespread in the general population.



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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