title: EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation.
abstract: Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers.
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Shuvomoy
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Molecular Medical Virology (Ministries of Education and Health), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hem Chandra
authors.initials: HC
authors.lastname: Jha
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D002472:Cell Transformation, Viral / Q000502:physiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: C498774:EBNA-3C, epstein-barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D051573:Proto-Oncogene Proteins c-pim-1