Dissecting the Role of LMP1 Signalling in Epithelial Cells in Vivo

Charalambous, C. and Wilson, J.B. (2002) Dissecting the Role of LMP1 Signalling in Epithelial Cells in Vivo. Genes and Cancer 2002, Warwick, UK, 09-11 Dec 2002.

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Epstein-Barr virus (EBV) is a human herpesvirus that is associated with many malignancies and is classified by the World Health Organisation as a class I carcinogen. One of the genes that is factorial in its oncogenic property encodes the latent membrane protein 1 (LMP1). LMP1 activates several signalling pathways. LMP1 is expressed in nasopharyngeal carcinoma (NPC), an EBV associated tumour, that affects about 8% of Chinese, native Arctic and Mediterranean basin populations. In order to explore the consequences of expression of LMP1 in epithelial cells, we have developed lines of transgenic mice which express the protein in the epidermis (Wilson et al, Cell 1990, 61, 1315-1327). The mice develop epidermal hyperplasia as a result of excess proliferation and are sensitised to chemical carcinogenesis (Curran et al, Cancer Research 2001, 61, 6730-6738). The consequences of LMP1 signalling in epithelial cells in this mouse model, is being examined by several approaches. Array techniques will be used to examine gene upregulation/ downregulation of transgenic epidermis. Furthermore, specific candidate cellular genes will be explored individually. Papillomas collected from transgenic animals following chemical treatment will be sectioned and stained to deduce the effect of LMP1 on proliferation, apoptosis and senescence. A dominant negative mutant of LMP1 will be expressed in LMP1 positive and negative carcinoma cell lines in order to examine the outcome of loss of LMP1. Finally, by cross breeding transgenic mice other factors such as loss of the INK4a/ARF locus, that may play a role in NPC, will be investigated and the pathways will be dissected. To date, the transfected cell clones have been established. Progress in this work regarding the expression and effect of the dominant negative LMP1 in culture will be presented. Westerns performed on transgenic positive and control skin extracts showed that LMP1 leads to upregulation of TGFα in the epidermis of newborn pups. Whether increased TGFα expression leads to increased EGFR activation will be examined. Activation status of p38MAPK, which is implicated in the activation of TGFα, will also be examined. Transgenic cross breeding experiments have been set up. An LMP1(CAO)/INK4-/- line and an LMP1/INK4-/-/Ras line are being produced in order to examine cooperativity of these oncogenes and tumour suppressor genes in carcinogenesis.

Item Type:Conference or Workshop Item
Glasgow Author(s) Enlighten ID:Wilson, Professor Joanna
Authors: Charalambous, C., and Wilson, J.B.
Subjects:Q Science > QR Microbiology > QR355 Virology
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences

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