Skip Navigation LinksHome > July/August 2014 - Volume 37 - Issue 6 > Ligation of CD47 Induces G1 Arrest in EBV-transformed B Cell...
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Journal of Immunotherapy:
doi: 10.1097/CJI.0000000000000042
Basic Studies

Ligation of CD47 Induces G1 Arrest in EBV-transformed B Cells Through ROS Generation, p38 MAPK/JNK Activation, and Tap73 Upregulation

Park, Ga Bin*; Bang, Si Ra; Lee, Hyun-Kyung; Kim, Daejin*; Kim, Seonghan*; Kim, Jin Kyoung§; Kim, Yeong Seok*; Hur, Dae Young*

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Abstract

CD47 is expressed in normal activated cells as well as in several tumors. It also has been implicated as having antiangiogenic and antimetastatic properties, but its roles in Epstein-Barr virus (EBV)-transformed B cells are still not fully understood. Herein, we report that EBV infection induced CD47 surface expression on B cells, and CD47 ligation with anti-CD47 mAb (B6H12) reduced cell proliferation and induced G1 arrest. CD47-induced G1 arrest was mediated through increased cyclin-dependent kinase inhibitors (CDKi) and a simultaneously decreased CDK/cyclins, and p38 MAPK/JNK activation preceded binding of CDKi-CDK. Moreover, reactive oxygen species (ROS) generation and upregulation of both TAp73 and ER stress sensor proteins were detected after CD47 ligation, and p38 inhibitor SB203580 and JNK inhibitor SP600125 blocked upregulation of TAp73 and cell cycle arrest. We investigated whether ROS generation is the initial event of CD47-mediated G1 arrest because ROS scavenger NAC effectively abrogated the majority of CD47-mediated responses but SB203580 and SP600125 did not block ROS production. Taken together, we concluded that CD47 ligation on EBV-transformed B cells led to G1 arrest by ROS generation and, subsequently, there was p38 MAPK/JNK pathway activation, ER stress triggering, and TAp73 upregulation. Our findings provide data supporting CD47 as a feasible target for EBV-associated tumor therapy.

Copyright © 2014 by Lippincott Williams & Wilkins

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