P-2: LANA-1 mediated negative regulation of gene expression

Johns Hopkins University, Baltimore MD

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Abstract

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