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.
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.
|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|
|Lu, Jie; Jha, Hem C; Verma, Subhash C et al. (2014) Kaposi's sarcoma-associated herpesvirus-encoded LANA contributes to viral latent replication by activating phosphorylation of survivin. J Virol 88:4204-17|
|Jha, Hem C; A J, Mahadesh Prasad; Saha, Abhik et al. (2014) Epstein-Barr virus essential antigen EBNA3C attenuates H2AX expression. J Virol 88:3776-88|
|Sun, Zhiguo; Xiao, Bingyi; Jha, Hem Chandra et al. (2014) Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase Bub1. J Virol 88:7367-78|
|Banerjee, Shuvomoy; Lu, Jie; Cai, Qiliang et al. (2014) EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation. PLoS Pathog 10:e1004304|
|Banerjee, Shuvomoy; Lu, Jie; Cai, Qiliang et al. (2013) The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8. PLoS Pathog 9:e1003314|
|Saha, Abhik; Robertson, Erle S (2013) Impact of EBV essential nuclear protein EBNA-3C on B-cell proliferation and apoptosis. Future Microbiol 8:323-52|
|Jha, Hem Chandra; Lu, Jie; Saha, Abhik et al. (2013) EBNA3C-mediated regulation of aurora kinase B contributes to Epstein-Barr virus-induced B-cell proliferation through modulation of the activities of the retinoblastoma protein and apoptotic caspases. J Virol 87:12121-38|
|Verma, Subhash C; Cai, Qiliang; Kreider, Edward et al. (2013) Comprehensive analysis of LANA interacting proteins essential for viral genome tethering and persistence. PLoS One 8:e74662|
|Cai, Qiliang; Xiao, Bingyi; Si, Huaxin et al. (2012) Kaposi's sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation. PLoS Pathog 8:e1002566|
Showing the most recent 10 out of 23 publications