Abstract

The program continues its focus on the human oncogenic herpesvirus, Epstein-Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus (KSHV) to identify the critical mechanisms by which these agents induce cancer and deregulate cell growth. To identify the mechanisms responsible for the oncogenic properties of these agents, the projects will characterize the basic molecular properties of viral proteins and their interactions with cellular proteins. In Project 1, Dr. Jack Griffith will continue his studies of the HSV recombinase complex consisting of ICP8 and UL12, and will apply the imaging skills that he has developed to analyze the structure of EBV and KSHV proteins and the association of KSHV proteins with DNA. Project 2 continues the study by Dr, Joseph Pagano on a novel deubiquitinase, UCHL1, whose expression is induced by EBV. This project will characterize the properties of this protein and in collaboration with Drs. Raab-Traub and Dittmer, determine its anti-growth properties in the mouse models that they have developed in Projects 4 and 5. Dr. Damania in Project 3 will develop systems to determine how KSHV induces angiogenesis, cell survival and migration. Drs. Raab-Traub and Dittmer in Projects 4 and 5 will develop and characterize the pathways that are essential for transformation and oncogenesis in transgenic murine models. The effects of EBV and KSHV on cellular miRNAs in the transgenic cancers will also be determined in both projects. A new core is requested, the Virogenomics Core, that will provide gene expression array support for all 5 projects on this program, profiling of the cellular miRNAs, and bioinformatic services for expression arrays and ChlP-Seq approaches.

Public Health Relevance

Epstein-Barr Virus and Kaposi Sarcoma Herpesvirus are linked to multiple human cancers. This proposal will study the viral proteins that are expressed in the cancers and that we have shown change the growth properties of cells inducing malignant properties. These experiments will identify how these proteins interact with cellular proteins to change their function. The requirement for these properties and the potential therapeutic benefit from blocking their functions will be tested in laboratory and animal models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA019014-34
Application #
8504907
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Daschner, Phillip J
Project Start
1997-05-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
34
Fiscal Year
2013
Total Cost
$1,722,119
Indirect Cost
$552,680

  Institution

Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Bigi, Rachele; Landis, Justin T; An, Hyowon et al. (2018) Epstein-Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 115:E11379-E11387
El-Mallawany, Nader Kim; Villiera, Jimmy; Kamiyango, William et al. (2018) Endemic Kaposi sarcoma in HIV-negative children and adolescents: an evaluation of overlapping and distinct clinical features in comparison with HIV-related disease. Infect Agent Cancer 13:33
Kobayashi, E; Aga, M; Kondo, S et al. (2018) C-Terminal Farnesylation of UCH-L1 Plays a Role in Transport of Epstein-Barr Virus Primary Oncoprotein LMP1 to Exosomes. mSphere 3:
Hopcraft, Sharon E; Pattenden, Samantha G; James, Lindsey I et al. (2018) Chromatin remodeling controls Kaposi's sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog 14:e1007267
Sin, Sang-Hoon; Eason, Anthony B; Bigi, Rachele et al. (2018) Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections. J Virol 92:
Zhang, Yugen; Dittmer, Dirk P; Mieczkowski, Piotr A et al. (2018) RIG-I Detects Kaposi's Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner. MBio 9:
Anders, Penny M; Montgomery, Nathan D; Montgomery, Stephanie A et al. (2018) Human herpesvirus-encoded kinase induces B cell lymphomas in vivo. J Clin Invest 128:2519-2534
Ciesielski, Grzegorz L; Nadalutti, Cristina A; Oliveira, Marcos T et al. (2018) Structural rearrangements in the mitochondrial genome of Drosophila melanogaster induced by elevated levels of the replicative DNA helicase. Nucleic Acids Res 46:3034-3046
Gurung, Sunam; Preno, Alisha N; Dubaut, Jamie P et al. (2018) Translational Model of Zika Virus Disease in Baboons. J Virol :
McNamara, Ryan P; Costantini, Lindsey M; Myers, T Alix et al. (2018) Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses. MBio 9:

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