EBNA1 Induces B-cells to Respond to IL-2 Survival Signals

Tsimbouri, P. , Drotar, M., Hill, E. and Wilson, J.B. (2004) EBNA1 Induces B-cells to Respond to IL-2 Survival Signals. 11th International EBV Symposium, Regensberg, Germany, 20-25 Sep 2004.

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Abstract

Whether EBNA-1 contributes to tumourigenesis by means other than its function in viral DNA propagation is controversial. In order to address this, we have explored the consequences of EBNA-1 expression in the B-cells of two independently derived lines of transgenic mice (Wilson et al., 1996, EMBO J., 15, p3117). With the aim of examining the direct effects of EBNA-1 expression and not secondary mutations occurring through tumourigenesis, our studies have been conducted using explanted transgenic lymphocytes prior to the development of any tumour pathology. Transgenic lymphocytes show enhanced proliferation compared to controls and prolonged survival when cultured in the presence of IL-2. Surviving cells are B-cells and continue to express EBNA-1. This phenotype is demonstrated by lymphocytes derived from both transgenic mouse lines, developed independently and with distinct transgene integration events. As such the properties of prolonged cell survival and enhanced growth cannot be due to insertion site effects and can only be attributed to the actions of EBNA-1. These properties are characteristic oncogenic activities and in this system are context dependant, upon IL-2 signalling, a cytokine normally produced by activated T-cells supporting both T- and B-cell immune responses. In order to explore the consequences upon tumour development of co-expression of EBNA-1 (inducing B-cell responsiveness to IL-2 as described above), LMP1 (a partial mimic of CD40 constitutive signalling) and LMP2A (mimicking B-cell receptor survival signals) a tritransgenic mouse crossbreed was developed. As previously reported, EµEBNA-1 mice develop B-cell tumours. Co-expression of EBNA-1 and LMP1 showed no impact upon the latency to tumour development while co-expression of EBNA-1 and LMP2A showed a slight inhibition in tumour development. However, co-expression of all three latent proteins significantly delayed the EBNA-1 induced tumour onset. Whether together the LMPs activate opposing mechanisms to EBNA-1 in B-cell development and differentiation will be discussed.

Item Type:Conference or Workshop Item
Status:Published
Refereed:No
Glasgow Author(s) Enlighten ID:Tsimbouri, Dr Monica and Wilson, Professor Joanna and Drotar, Mr Mark
Authors: Tsimbouri, P., Drotar, M., Hill, E., and Wilson, J.B.
Subjects:Q Science > QR Microbiology > QR355 Virology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Life Sciences
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