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.
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.
|Anders, Penny; Bhende, Prasanna M; Foote, Michael et al. (2015) Dual inhibition of phosphatidylinositol 3-kinase/mammalian target of rapamycin and mitogen activated protein kinase pathways in non-Hodgkin lymphoma. Leuk Lymphoma 56:263-6|
|Giffin, Louise; Damania, Blossom (2014) KSHV: pathways to tumorigenesis and persistent infection. Adv Virus Res 88:111-59|
|Hosseinipour, Mina C; Sweet, Kristen M; Xiong, Jie et al. (2014) Viral profiling identifies multiple subtypes of Kaposi's sarcoma. MBio 5:e01633-14|
|Kumar, Ravindra; Whitehurst, Christopher B; Pagano, Joseph S (2014) The Rad6/18 ubiquitin complex interacts with the Epstein-Barr virus deubiquitinating enzyme, BPLF1, and contributes to virus infectivity. J Virol 88:6411-22|
|Ozgur, Sezgin; Griffith, Jack (2014) Interaction of Kaposi's sarcoma-associated herpesvirus ORF6 protein with single-stranded DNA. J Virol 88:8687-95|
|Marquitz, Aron R; Mathur, Anuja; Chugh, Pauline E et al. (2014) Expression profile of microRNAs in Epstein-Barr virus-infected AGS gastric carcinoma cells. J Virol 88:1389-93|
|Bentz, Gretchen L; Bheda-Malge, Anjali; Wang, Ling et al. (2014) KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation. Virology 448:293-302|
|Aga, M; Bentz, G L; Raffa, S et al. (2014) Exosomal HIF1? supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene 33:4613-22|
|Yang, Dongmei; Chen, Wuguo; Xiong, Jie et al. (2014) Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma. Proc Natl Acad Sci U S A 111:E4762-8|
|Chen, Stefanie Hartman; Plank, Jody L; Willcox, Smaranda et al. (2014) Top3? is required during the convergent migration step of double Holliday junction dissolution. PLoS One 9:e83582|
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