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PARK, GA BIN,KIM, DAEJIN,PARK, SUNG JAE,LEE, HYUN-KYUNG,KIM, JI HYUN,KIM, YEONG SEOK,PARK, SAE-GWANG,CHOI, IN-HAK,YOON, SUNG HO,LEE, YOUN JAE,PAENG, SUNGHWA,HUR, DAE YOUNG UNKNOWN 2015 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.36 No.6
<P>Hepatitis C virus (HCV) E2 protein binds to CD81, which is a component of the B cell co-stimulatory complex. The E2-CD81 interaction leads to B cell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of B cell non-Hodgkin lymphoma (NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus (EBV) in the genesis of B lymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in B cells, we created an <I>in vitro</I> EBV-induced B cell transformation model. CD81 was gradually overexpressed during transformation by EBV. B cells isolated from HCV-positive patients grew more rapidly and clumped together earlier than B cells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting B cells with anti-CD81 monoclonal antibody (mAb) or HCV E2 accelerated the generation of lymphoblastoid cell lines (LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein (LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed B cells by anti-CD81 mAb or HCV E2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by B cells has differential effects on B cell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81.</P>
Park, Ga Bin,Kim, Yeong-Seok,Kim, Daejin,Kim, Seonghan,Lee, Hyun-Kyung,Cho, Dae-Ho,Lee, Wang Jae,Hur, Dae Young The American Association of Immunologists, Inc. 2013 JOURNAL OF IMMUNOLOGY Vol.191 No.12
<P>Melphalan (Mel) is widely used to treat patients with hematologic cancer, including multiple myeloma, but its mechanism of action in EBV-transformed B cells is poorly described. In this study, we demonstrate a novel mechanism by which transcriptionally active p73 (TAp73) induces translocation of X-linked inhibitor of apoptosis protein–associated factor 1 (XAF1) and xeroderma pigmentosum group A (XPA) during apoptosis caused by Mel treatment. We observed that Mel induced significant generation of reactive oxygen species (ROS) and subsequent apoptosis, as well as an early phosphorylation of p38 MAPK that preceded expression of the mitochondria membrane potential disruption–related molecules and the cleavage of caspases. In particular, Mel led to upregulation of TAp73, XAF1, and Puma and induced XPA nuclear import and translocation of Bax into mitochondria. Mel-induced apoptosis was inhibited by pretreatment with the ROS scavenger 4-amino-2,4-pyrrolidine-dicarboxylic acid (APDC) and the p38 MAPK inhibitor SB203580. We supposed that ROS generation might be the first event in Mel-induced apoptosis, because APDC blocked the increase in ROS, p38 MAPK, and TAp73, but SB203580 did not block ROS generation. Moreover, Mel elicited activation of ATR, and APDC inhibited phosphorylation of ATR but not SB203580. APDC and SB203580 completely blocked XPA and Bax translocation. We conclude that Mel promotes TAp73-mediated XAF1 and Puma expression via ROS generation and ATR/p38 MAPK pathway activation, thereby triggering apoptosis. Our results provide evidence of a novel alternate regulatory mechanism of TAp73 and reveal that Mel may be a therapeutic drug for curing EBV-related malignancies.</P>
Park, Ga Bin,Song, Hyunkeun,Kim, Yeong-Seok,Sung, Minjung,Ryu, Jeoung W.,Lee, Hyun-Kyung,Cho, Dae-Ho,Kim, Daejin,Lee, Wang J.,Hur, Dae Y. Blackwell Publishing Ltd 2009 Immunology Vol.128 No.3
<P>Summary</P><P>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.</P>
Park, Ga Bin,Chung, Yoon Hee,Kim, Daejin Spandidos Publications 2017 Oncology reports Vol.37 No.5
<P>The expression of different toll -like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK-OV-3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110 alpha, p110 beta and p110 delta) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, alpha-SMA, and TCF) in SK-OV-3 cells. The migratory activity and secretion of EMT-related cytokines of SK-OV-3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK-OV-3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p1101 beta isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110 delta isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS-treated SK-OV-3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer.</P>
Park, Ga Bin,Hur, Dae Young,Kim, Yeong Seok,Lee, Hyun-Kyung,Yang, Jae Wook,Kim, Daejin BlackWell Publishing Ltd 2015 Journal of cellular and molecular medicine Vol.19 No.5
<P>Toll-like receptor-3 (TLR3) and RNA helicase retinoic-acid-inducible protein-1 (RIG-I) serve as cytoplasmic sensors for viral RNA components. In this study, we investigated how the TLR3 and RIG-I signalling pathway was stimulated by viral infection to produce interleukin (IL)-32-mediated pro-inflammatory cytokines and type I interferon in the corneal epithelium using Epstein–Barr virus (EBV)-infected human cornea epithelial cells (HCECs/EBV) as a model of viral keratitis. Increased TLR3 and RIG-I that are responded to EBV-encoded RNA 1 and 2 (EBER1 and EBER2) induced the secretion of IL-32-mediated pro-inflammatory cytokines and IFN-β through up-regulation of TRIF/TRAF family proteins or RIP-1. TRIF silencing or TLR3 inhibitors more efficiently inhibited sequential phosphorylation of TAK1, TBK1, NF-κB and IRFs to produce pro-inflammatory cytokines and IFN-β than RIG-I-siRNA transfection in HCECs/EBV. Blockade of RIP-1, which connects the TLR3 and RIG-I pathways, significantly blocked the TLR3/TRIF-mediated and RIG-I-mediated pro-inflammatory cytokines and IFN-β production in HCECs/EBV. These findings demonstrate that TLR3/TRIF-dependent signalling pathway against viral RNA might be a main target to control inflammation and anti-viral responses in the ocular surface.</P>
Park, Ga-Bin,Kim, Yeong-Seok,Song, Hyun-Keun,Kim, Seong-Han,Park, Dong-Man,Lee, Wang-Jae,Hur, Dae-Young The Korean Association of Immunobiologists 2011 Immune Network Vol.11 No.6
Background: Epstein Barr virus (EBV) infected B cells are transformed into lymphoblastoid cell lines. Some researchers suggested some a few similarities between this process and carcinogenesis. We observed the expression of CD80 and CD86, co-stimulatory molecules on EBV-transformed B cells and changes of CD54 expression after stimulation of CD80 and CD86. Methods: CD80 and CD86 were stimulated using anti-CD80 and anti-CD86 monoclonal antibodies. To assess apoptosis and surface protein expression, flow cytometric analysis was performed. Intracellular signal molecules were evaluated by RT-PCR and immunoblot. Morphology and localization of proteins were examined using inverted or confocal microscope. Results: Cross-linking of CD80 and CD86 induced apoptosis and interfered with proliferation of EBV-transformed B cells, and dispersion of clumped cells. We also examined that their stimulation induced ROS accumulation and reduced CD54 expression. Interestingly, we observed that CD80 and CD86 diminished the expression of CD54 in different methods. Both CD80 and CD86 downregulated activation of focal adhesion kinase. CD80 stimulus inhibited CD54 expression through mainly RhoA inactivation, while CD86 down-regulated Ras and JNK phosphorylation. Conclusion: These results suggest that co-stimulatory CD80 and CD86 molecules, expressed EBV-transformed B cells, may play a role in apoptosis and cell adhesion.