The Oncogenic Activity of the Latent Membrane Protein of EBV in Transgenic Mice

[摘要] There is an ever increasing list of disease states which have been shown to have an association with EBV latent infection. In particular research has focused on the latent membrane protein (LMP-1). Study of this gene has largely been restricted to B-cells in vitro due to the inability to infect epithelial cells with EBV in vitro. This has resulted in little information concerning the effects of LMP-1 in an epithelial environment. As a consequence, the role of LMP-1 in nasopharyngeal carcinoma (NPC), with which EBV is most closely associated, is poorly understood. Creation of transgenic mice where LMP-1 is directed to the epithelial cell compartment has therefore achieved two important goals. LMP-1 can now be studied in an epithelial cell in vivo whilst the mice provide the first step in a model for the disease state of NPC. In this study the mechanism of action of LMP-1 in the PyLMP-1 line 53 of transgenic mice has been investigated. In addition, a study on the progression of the transgenic LMP-1 induced hyperplastic phenotype to carcinoma has been conducted. Firstly, using immunohistochemical techniques, the hyperplastic epidermal phenotype of the PyLMP-1 mice previously reported is shown to result from a 2-3 fold increase in the rate of cellular proliferation whilst differentiation continues unimpeded in the transgenic skin. Secondly, the mouse skin model of multi-stage carcinogenesis is utilised to show that LMP-1 does not act as an initiator of carcinogenesis nor does it affect the conversion to a more malignant tumour. However, LMP-1 does function to increase both the rate and number of lesions forming during chemical tumour promotion, and more importantly LMP-1 acts as a weak or second stage promoter on it's own. This finding has significant implications for NPC. Thirdly, by cross-breeding PyLMP-1 line 53 with other lines of transgenic or knockout mice it is shown that LMP-1 does not co-operate with activated Ra-ras or loss of p53 function in tumour progression. However, the combination of the PyLMP-1 transgene and K10-TGF?1 transgene results in embryonic lethality. Lastly, the EmuLMP-1 line 39 transgenic mice which express LMP-1 in the B-cell compartment at very low levels have been studied for a 24 month period and shown to succumb to a long latency lymphoma.

[发布机构] University:University of Glasgow

[关键词] Molecular biology, Genetics, Virology