The ubiquitous human Epstein-Barr virus (EBV) has been shown to be linked to a wide range of human cancers which include Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, adult T-cell lymphomas and lymphoproliferative diseases in immunocompromised patients. In vitro, EBV can efficiently transform human primary B-cells in vitro resulting in continual proliferation of the infected primary B-cells into transformed lymphoblastoid cell lines (LCLs). The nascently transformed B-lymphocytes by EBV are strictly latent in that a select set of genes are expressed, one of which is Epstein-Barr nuclear antigen (EBNA)3C. EBNA3C has been shown to be essential for B cell transformation in vitro by genetic analysis of the virus. Over the last decade the functions associated with EBNA3C has linked this essential molecule to regulation of viral and cellular transcription through interaction with the transcription repressor CSL, Nm23-H1, the tumor suppressor molecule Rb and other cell cycle regulatory factors which include Cyclin A and Cyclin D1. This proposal will investigate the interactions of the essential EBV nuclear antigen 3C and the cellular factors E2F and c-Myc involved in regulation of cell proliferation, cell cycle, transcription, and signaling involved in maintenance of cellular homeostasis. The specific amino acids of these cellular targets c-Myc and E2F interacting with 3C will be explored and the functional relationships examined in terms of B cell transformation and immortalization. The post-translational modifications of c-Myc and E2F important for activation of their regulatory functions will also be fully investigated. Simultaneously, we will generate site specific recombinant EBNA3C molecules that are knocked out for the specific interactions within the EBV genome to determine their role in primary B cell transformation.

Public Health Relevance

The ubiquitous gammaherpesvirus Epstein Barr virus is associated with a range of human cancers. At least 6 latent genes have been shown to be critical for cell transformation in vitro. Some of these antigens associate directly with cell cycle regulatory proteins and are also linked to the specific regulation of cellular events which include regulation of transcription, chromatin remodeling, cell proliferation and cell cycle regulation. This proposal will explore the role of one of the essential nuclear antigens EBNA3C in determining a more comprehensive model for the related functions of EBNA3C in regulation of the major cellular oncoproteins E2F and c-Myc through post-translation modification and cell cycle regulation leading to transformation of human B cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA137894-05
Application #
8390498
Study Section
Special Emphasis Panel (ZRG1-IDM-R (04))
Program Officer
Daschner, Phillip J
Project Start
2009-01-01
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$268,189
Indirect Cost
$97,910
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Jha, Hem Chandra; Banerjee, Shuvomoy; Robertson, Erle S (2016) The Role of Gammaherpesviruses in Cancer Pathogenesis. Pathogens 5:
Jha, Hem C; Pei, Yonggang; Robertson, Erle S (2016) Epstein-Barr Virus: Diseases Linked to Infection and Transformation. Front Microbiol 7:1602
Gandhi, Jaya; Gaur, Nivedita; Khera, Lohit et al. (2015) COX-2 induces lytic reactivation of EBV through PGE2 by modulating the EP receptor signaling pathway. Virology 484:1-14
Jha, Hem C; Yang, Karren; El-Naccache, Darine W et al. (2015) EBNA3C regulates p53 through induction of Aurora kinase B. Oncotarget 6:5788-803
Jha, Hem Chandra; Shukla, Sanket Kumar; Lu, Jie et al. (2015) Dissecting the contribution of EBNA3C domains important for EBV-induced B-cell growth and proliferation. Oncotarget 6:30115-29
Dzeng, Richard K; Jha, Hem Chandra; Lu, Jie et al. (2015) Small molecule growth inhibitors of human oncogenic gammaherpesvirus infected B-cells. Mol Oncol 9:365-76
Saha, Abhik; Jha, Hem C; Upadhyay, Santosh K et al. (2015) Epigenetic silencing of tumor suppressor genes during in vitro Epstein-Barr virus infection. Proc Natl Acad Sci U S A 112:E5199-207
Jha, Hem Chandra; Mehta, Devan; Lu, Jie et al. (2015) Gammaherpesvirus Infection of Human Neuronal Cells. MBio 6:e01844-15
Jha, Hem C; Lu, Jie; Verma, Subhash C et al. (2014) Kaposi's sarcoma-associated herpesvirus genome programming during the early stages of primary infection of peripheral blood mononuclear cells. MBio 5:

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