Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation

Ya Ching Chou, Sue Jane Lin, Jean Lu, Te Huei Yeh, Chi Long Chen, Pei Lun Weng, Jiun Han Lin, Ming Yao, Ching Hwa Tsai

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18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1340-1349
Number of pages10
JournalBlood
Volume118
Issue number5
DOIs
Publication statusPublished - Aug 4 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Chou, Y. C., Lin, S. J., Lu, J., Yeh, T. H., Chen, C. L., Weng, P. L., Lin, J. H., Yao, M., & Tsai, C. H. (2011). Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation. Blood, 118(5), 1340-1349. https://doi.org/10.1182/blood-2011-02-335448