S-Space College of Medicine/School of Medicine (의과대학/대학원) Anatomy (해부학전공) Journal Papers (저널논문_해부학전공)
Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines
- 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
- WILEY-BLACKWELL PUBLISHING, INC
- IMMUNOLOGY; Vol.128(3); 360-368
- 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.
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