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Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines

Cited 19 time in Web of Science Cited 21 time in Scopus
Authors
Park, Ga Bin; Song, Hyunkeun; Kim, Yeong-Seok; Sung, Minjung; Lee, Hyun-Kyung; Kim, Daejin; Hur, Dae Y.; Lee, Wang J.; Cho, Dae-Ho; Ryu, Jeoung W.
Issue Date
2009-11
Publisher
WILEY-BLACKWELL PUBLISHING, INC
Citation
IMMUNOLOGY; Vol.128(3); 360-368
Keywords
apoptosisEpstein-Barr viruscostimulationcell cyclecancerB7-H4B cells
Abstract
B7-H4 is a recently discovered B7 family member that has inhibitory effects on T-cell immunity. However, the reverse signalling mechanism of the B7-H4-expressing cells remains unclear. Previous work has shown that B7-H4 expression was enhanced on B cells following Epstein-Barr virus (EBV) infection, and engagement of cell-surface-expressed B7-H4 induces cell death of EBV-transformed B cells. Here we found that B7-H4 was constitutively expressed on EBV-positive lymphoma cells, Raji and IM-9 cells, but was not expressed on EBV-negative lymphoma cells (Ramos). Engagement of B7-H4 significantly reduced cell growth of Raji and IM-9 cells and resulted in cell cycle arrest at G0-G1 phase in a dose- and time-dependent manner. To clarify the mechanism of cell cycle arrest via activation of B7-H4, cell cycle regulatory factors were examined by reverse transcription-polymerase chain reaction and immunoblotting. We found that B7-H4 triggered down-regulation of CDK4/6 and up-regulation of p21 expression at both protein and RNA levels. Furthermore, CDK2 and cyclin E/D expression was down-regulated by B7-H4 triggering. Additionally, the down-regulation of phospho-AKT and phospho-cyclin E were clearly detected in B7-H4-activated Raji cells, but the phosphorylation of p53 was constitutively maintained. These results indicate that B7-H4-mediated signalling on EBV-positive B-cell lymphoma cells modulates the cell cycle through down-regulation of the AKT pathway. Consequently, B7-H4 may be a new potential target for use in EBV-positive lymphoma therapy.
ISSN
0019-2805
Language
English
URI
http://hdl.handle.net/10371/78674
DOI
https://doi.org/10.1111/j.1365-2567.2009.03111.x
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College of Medicine/School of Medicine (의과대학/대학원)Anatomy (해부학전공)Journal Papers (저널논문_해부학전공)
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