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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070723-15
Application #
8014964
Study Section
Special Emphasis Panel (ZRG1-IDM-B (03))
Program Officer
Daschner, Phillip J
Project Start
1996-08-15
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
15
Fiscal Year
2011
Total Cost
$285,015
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Chiu, Ya-Fang; Sugden, Bill (2016) Epstein-Barr Virus: The Path from Latent to Productive Infection. Annu Rev Virol 3:359-372
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
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
Hammerschmidt, Wolfgang (2015) The Epigenetic Life Cycle of Epstein-Barr Virus. Curr Top Microbiol Immunol 390:103-17
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
Kuzembayeva, Malika; Hayes, Mitchell; Sugden, Bill (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61-5
Vereide, D T; Seto, E; Chiu, Y-F et al. (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258-64
Sugden, Bill (2014) Epstein-Barr virus: the path from association to causality for a ubiquitous human pathogen. PLoS Biol 12:e1001939
Shrestha, Prabha; Sugden, Bill (2014) Identification of properties of the Kaposi's sarcoma-associated herpesvirus latent origin of replication that are essential for the efficient establishment and maintenance of intact plasmids. J Virol 88:8490-503

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