The Kaposi's sarcoma associated herpesvirus, KSHV, is associated with the malignancies Kaposi's sarcoma, primary effusion lymphoma and Castleman's disease. These cancers have an increased incidence in patients with AIDS. The KSHV latency associated nuclear antigen LANA/LANA1 is expressed in all KSHV infected cells and in the associated cancers. LANA is a multi-functional protein that is essential for replication and maintenance of episomal KSHV genomes and also has transcriptional regulatory properties. LANA is known to activate expression of cellular genes through upregulation of E2F and through the Wnt/ beta-catenin pathway. However, when tethered to DNA as a Gal4-fusion, LANA is also capable of repressing transcription and gene array studies also report LANA-mediated transcriptional repression. The ways in which LANA might repress gene expression are not understood nor are the full range of cell gene targets known. Transcriptional silencing is likely to contribute to maintenance of KSHV latency and to the development of KSHV associated malignancies and hence it is proposed to investigate this aspect of LANA's function. The experimental focus will be on genes identified in gene array analyses as being repressed. The contribution to repression of the LANA interacting proteins MeCP2, and sp100-HMG will be evaluated. We have previously demonstrated a role for these proteins in tethering LANA to cell chromosomes and now propose that these proteins might have a dual function in LANA-mediated repression. In addition the contribution of newly identified interactions between LANA and DNA methyl transferases and LANA and transcription factors will be investigated. The individual aims will address: (i) The contribution of histone deacetylases and DNA methyl transferases to the repression of moderately versus strongly repressed promoters, (ii) Investigation of the role of MeCP2 and sp100-HMG in repression, (iii) Examination of transcription factor interactions in LANA mediated repression (iv) Evaluation of LANA-mediated repression in clinical specimens.
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