|Genetics, Papillomavirus and Human Cancer|
|HEAD||Dr FAVRE Michel / firstname.lastname@example.org|
|MEMBERS||Dr DEMERET Caroline / Dr JACOB Yves / Dr SNIHURA Valeria / Dr VUILLIER Françoise/ NEVEU Grégory / ROLLOY Caroline / MULLER Mandy/ CASSONNET Patricia / PONS Christian / DELAIRE Marie-Claire / RIBIERRE Hélène
Human papillomaviruses (HPV) are the causative agents of different clinical types of skin warts and genital proliferations corresponding to the most common sexually transmitted infection. In addition, certain HPV induced carcinoma of the uterine cervix (HPV 16 and HPV18), the second woman cancer worldwide, and of the skin (HPV5) in patients suffering from epidermodysplasia verruciformis (EV). This genodermatosis results from mutations in either of two adjacent genes (EVER1and EVER2) that confer predisposition to infection with a specific group of viruses (beta-HPV), including HPV5. Our aims are to better characterize the functions of EVER1 and EVER2 proteins in normal and infected cells and to analyze the role of viral early proteins (E2, E6 and E7) in the HPV life cycle and in the malignant transformation associated with oncogenic HPV.
EVER protein functions.
It can be assumed that EVER genes control the expression of HPV genome in infected cells and/or trigger immune response for eradication of lesions. We have demonstrated that EVER1 and EVER2 form a complex in the endoplasmic reticulum with the zinc transporter ZnT-1. This complex is involved in the maintenance of cellular zinc homeostasis in keratinocytes and plays a central role in HPV-specific protective mechanisms as a negative regulator of some cellular transcription factors (c-Jun, c-Fos) needed for viral genome expression. Deregulation of cellular zinc balance emerges as an important step in the life cycle of not only cutaneous beta-HPV but also genital alpha-HPV. We have demonstrated that E5 protein disrupts the function of EVER/ZnT 1 complex, leading to the metabolic changes in keratinocytes strikingly similar as mutation in EVERgenes does. Our recent data suggest that beta-HPV are defective viruses expressed during epidermal repair processes and favor cell proliferation during wound healing. As far as the impact of EVER proteins on the control of immune response is concerned, we currently analyze the NFκB signaling pathway and the cytokine expression in cells obtained from EV patients and healthy individuals.
Role of early proteins in HPV life cycle and cell transformation
It is currently assumed that the pathogenesis of HPV results from complex viral and host factor relationships driven in particular by the interplay between the host proteome and the early viral proteins E5, E6 and E7 but also from deregulation of the viral early protein E2. Our goal is mainly focused on the characterization of viral protein activities specifically required to initiate and complete HPV life cycle (latency, replication, maturation) and to identify biological properties of early proteins associated with oncogenic potential. In order to determine their pathophysiological relevances and discriminate between tropism or pathogeny specific interactions, we have taken advantage of the extreme diversity of HPVs. We have develop a new comparative interactomics approach, based on the overlapping yeast two-hybrid (Y2H) interactome profiles of early viral proteins from 12 reference cutaneous and mucosal HPVs. In parallel, we have also undertaken a large-scale characterization by Mass Spectrometry analyses of HPVs-host interactions implicated in multiprotein complexes purified with tagged early viral proteins. By combining biostatistical analyses of these datasets and a new high-throughput protein-protein complementation assay (HT-PCA) performed in human cells it was possible to correlate specific virus-host interaction profiles with pathological traits. This provided a set of pathological markers that can be used both to evaluate the carcinogenic potential of HPVs but also to accelerate viral targets identification for drug design.
These approaches can provide new insights into genetic control of HPV infection as well as shed new light on viral strategies involved in skin and genital carcinogenesis.
Keywords: Viral carcinogenesis, human papillomavirus (HPV), epidermodysplasia verruciformis, predisposition genes, control of HPV infection, biological properties of early viral proteins, viral and human interactomes, yeast two-hybrid screening, protein-protein complementation assay, mass spectrometry
Mendoza J.A., Jacob Y., Cassonnet P., and Favre M (2006). The human papillomavirus type 5 E6 oncoprotein represses TGF-beta signaling pathway by binding to SMAD3. J. Virol. 80: 12420-12424
Lazarczyk M, Pons C, Mendoza JA, Cassonnet P, Jacob Y, and Favre M. (2008). Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses.J. Exp. Med.205:35-42
Thierry F and Demeret C. (2008). Direct activation of caspase 8 by the proapoptotic E2 protein of HPV18 independent of adaptor proteins. Cell. Death Diff.15:1356-1363.
Lazarczyk M and Favre M. (2008) . The role of Zn2+ ions in host-virus interactions. J. Virol.82:11486-11494.
Lazarczyk M, Cassonnet P, Pons C, Jacob Y, and Favre M. (2009). The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of HPV infections. Microbiol. Mol. Biol. Rev.73:348-370.
Activity Reports 2009 - Institut Pasteur
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