The viral proteins, latent membrane protein 1 (LMP1) and latent membrane protein 2 (LMP2), are expressed in many of the malignancies associated with EBV. The immunoglobulin heavy chain promoter/enhancer (Ig- LMPI) transgenic mice develop clonal B-cell lymphomas that can be passaged xenografts in SCID mice. The growth characteristics in vitro and lymphoma development of these mice, the lg-LMP2 mice, and doubly transgenic lg-LMP1/LMP2 mice have been determined. To evaluate the effects of LMP1 on epithelial cell growth, we have produced transgenic mice that express LMP1 under the control of the keratin 14 (K14) promoter. In classical tumor initiation and promotion analyses, LMP1 functions as a tumor promoter with a possible role in tumor progression. K14-LMP2 transgenic mice do not have enhanced papilloma or carcinoma development, however, carcinoma development is increased in the K14-LMP1/LMP2 double transgenic mice.
Our specific aims are:
Aim 1) The transgenic LMP1 + lymphocytes, LMP1 + lymphomas, LMP2 transgenic lymphocytes, and LMP1/LMP2+ lymphomas will be further characterized : A). Analyze the activated form of c-rel in the LMP1+ lymphomas using immunoprecipitation and proteomics to identify its binding partners. B.) Identify c-rel and STAT3 regulated genes in the lymphomas using chromatin immunoprecipitation and deep sequencing. C.) Assess the effects of inhibition of specific activated pathways including NFkB, Akt, Stat3, and in collaboration with Dr. Pagano, UCHL1, on activation of specific transcription factors and on growth and metastasis in vivo. D.) Confirm potential targets identified by microarray analysis using targeted arrays in the Virogenomics Core and determine the effects of inhibition of NFkB, Akt, Stat3, and Erk on the activation of specific genes within these pathways.
Aim 2) Determine the effects of LMP1 and LMP2 on mouse cellular miRNA expression using the Virogenomics Core. Assess the effects of expression of the cellular miRNAs on the growth of transgenic cells.
Aim 3) Characterize the K14 LMP1 and LMP2 squamous cell carcinomas: A.) Determine the effects on cellular expression using 2-D fluorescence difference gel electrophoresis and mass spectrometry and mRNA expression arrays. Identify effects of the viral genes on specific cellular regulatory pathways using expression microarray analyses. B.) Test the hypothesis that LMP1 and LMP2 will transform K14 mutant ras transgenic mice and induce carcinoma development.
The Epstein Barr virus is an important human pathogen that is a causative factor in the development of many cancers. Two of the viral proteins have major effects on cell growth. This study will analyze transgenic mice that express these proteins and develop lymphoma and carcinoma. The study of these tumors will identify how these proteins control cell growth and test potential, novel therapies in vivo in the transgenic mice.
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