Epstein-Barr Virus (EBV) is a tumor virus that causes lymphdmas and carcinomas in approximately 100,000 people each year. We have developed and applied genetic analyses of EBV's transforming genes with this grant's prior support focusing on EBV's latent membrane protein 1 (LMP1) in infected B- lymphocytes. These analyses identified a phenotype and cellular genes induced rapidly by LMPVs signaling. We propose to extend our genetic analysis to dissect further transforming functions of LMP1, Epstein-Barr Nuclear Antigen 1 (EBNA1), and EBV's microRNAs (miRNAs) by identifying phenotypes they induce and cellular genes they regulate. These viral transforming genes are all implicated in maintaining tumor phenotypes in some or all of EBV-associated tumors. Our proposed genetic analyses will help to elucidate how these viral transforming genes contribute to tumor maintenance. We shall also extend our genetic analyses of these viral genes to dissect their functions in infected epithelial cells. EBV causes more carcinomas than lymphomas, but studies in normal epithelial cells formerly were intractable. These cells are now amenable to infection allowing us to characterize EBV's transforming genes in them. EBV functions differently in B-lymphocytes and epithelial cells. We hypothesize that these viral transforming genes regulate different cellular genes in B-lymphocytes and epithelial cells to mediate EBV's different oncogenic contributions. The proposed genetic analysis of EBV's transforming genes will help to identify their^contributionsto maintaining EBV-associated lymphomas and carcinomas. An understanding of viral contributions to tumor maintenance will allow development of specific anti-viral, anti-tumor therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-B (03))
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Daschner, Phillip J
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Chiu, Ya-Fang; Sugden, Bill (2018) Plasmid Partitioning by Human Tumor Viruses. J Virol 92:
Albanese, Manuel; Tagawa, Takanobu; Buschle, Alexander et al. (2017) MicroRNAs of Epstein-Barr Virus Control Innate and Adaptive Antiviral Immunity. J Virol 91:
Chiu, Ya-Fang; Sugden, Arthur U; Fox, Kathryn et al. (2017) Kaposi's sarcoma-associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally. J Cell Biol 216:2745-2758
Albanese, Manuel; Tagawa, Takanobu; Bouvet, Mickaël et al. (2016) Epstein-Barr virus microRNAs reduce immune surveillance by virus-specific CD8+ T cells. Proc Natl Acad Sci U S A 113:E6467-E6475
Tagawa, Takanobu; Albanese, Manuel; Bouvet, Mickaël et al. (2016) Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing. J Exp Med 213:2065-80
Chiu, Ya-Fang; Sugden, Bill (2016) Epstein-Barr Virus: The Path from Latent to Productive Infection. Annu Rev Virol 3:359-372
Chakravorty, Adityarup; Sugden, Bill (2015) The AT-hook DNA binding ability of the Epstein Barr virus EBNA1 protein is necessary for the maintenance of viral genomes in latently infected cells. Virology 484:251-8
Hammerschmidt, Wolfgang (2015) The Epigenetic Life Cycle of Epstein-Barr Virus. Curr Top Microbiol Immunol 390:103-17
Steinbrück, Lisa; Gustems, Montse; Medele, Stephanie et al. (2015) K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus. J Virol 89:7248-61
Gustems, Montse; Woellmer, Anne; Rothbauer, Ulrich et al. (2014) c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res 42:3059-72

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