title: Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation.
abstract: EBV, an oncogenic human herpesvirus, can transform primary B lymphocytes into immortalized lymphoblastoid cell lines (LCLs) through multiple regulatory mechanisms. However, the involvement of protein tyrosine kinases in the infinite proliferation of B cells is not clear. In this study, we performed kinase display assays to investigate this subject and identified a specific cellular target, Recepteur d'Origine Nantais (RON) tyrosine kinase, expressed in LCLs but not in primary B cells. Furthermore, we found that latent membrane protein 1 (LMP1), an important EBV oncogenic protein, enhanced RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-κB binding to the RON promoter. RON knockdown decreased the proliferation of LCLs, and transfection with RON compensated for the growth inhibition caused by knockdown of LMP1. Immunohistochemical analysis revealed a correlation between LMP1 and RON expression in biopsies from posttransplantation lymphoproliferative disorder (PTLD), suggesting that LMP1-induced RON expression not only is essential for the growth of LCLs but also may contribute to the pathogenesis of EBV-associated PTLD. Our study is the first to reveal the impact of RON on the proliferation of transformed B cells and to suggest that RON may be a novel therapeutic target for EBV-associated lymphoproliferative diseases.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chou
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Lin
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.forename: Te-Huei
authors.initials: TH
authors.lastname: Yeh
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Weng
authors.forename: Jiun-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Tsai
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004790:Enzyme Induction; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014763:Viral Matrix Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases