title: 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.
abstract: Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that is implicated in several human malignancies, including Burkitt's lymphoma (BL), posttransplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma (NPC), and AIDS-associated lymphomas. Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential EBV latent antigens, can induce mammalian cell cycle progression through its interaction with cell cycle regulators. Aurora kinase B (AK-B) is important for cell division, and deregulation of AK-B is associated with aneuploidy, incomplete mitotic exit, and cell death. Our present study shows that EBNA3C contributes to upregulation of AK-B transcript levels by enhancing the activity of its promoter. Further, EBNA3C also increased the stability of the AK-B protein, and the presence of EBNA3C leads to reduced ubiquitination of AK-B. Importantly, EBNA3C in association with wild-type AK-B but not with its kinase-dead mutant led to enhanced cell proliferation, and AK-B knockdown can induce nuclear blebbing and cell death. This phenomenon was rescued in the presence of EBNA3C. Knockdown of AK-B resulted in activation of caspase 3 and caspase 9, along with poly(ADP-ribose) polymerase 1 (PARP1) cleavage, which is known to be an important contributor to apoptotic signaling. Importantly, EBNA3C failed to stabilize the kinase-dead mutant of AK-B compared to wild-type AK-B, which suggests a role for the kinase domain in AK-B stabilization and downstream phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). This study demonstrates the functional relevance of AK-B kinase activity in EBNA3C-regulated B-cell proliferation and apoptosis.
authors.affiliation: Department of Microbiology and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hem Chandra
authors.initials: HC
authors.lastname: Jha
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Abhik
authors.initials: A
authors.lastname: Saha
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
authors.forename: Shuvomoy
authors.initials: S
authors.lastname: Banerjee
authors.forename: Mahadesh A J
authors.initials: MA
authors.lastname: Prasad
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D015153:Blotting, Western; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054875:Ubiquitination
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D064107:Aurora Kinase B; D020169:Caspases