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Interleukin‐2 induces NF‐κB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells
Author(s) -
Chan KaKui,
Shen Lijun,
Au WingYan,
Yuen HiuFung,
Wong KaiYau,
Guo Tianhuan,
Wong Michelle LY,
Shimizu Norio,
Tsuchiyama Junjiro,
Kwong YokLam,
Liang Raymond HS,
Srivastava Gopesh
Publication year - 2010
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2699
Subject(s) - bcl10 , protein kinase b , cancer research , biology , pi3k/akt/mtor pathway , nf κb , microbiology and biotechnology , signal transduction , lymphoma , immunology
Deregulation of nuclear factor (NF)‐κB signalling is common in cancers and is essential for tumourigenesis. Constitutive NF‐κB activation in extranodal natural killer (NK)‐cell lymphoma, nasal type (ENKL) is known to be associated with aberrant nuclear translocation of BCL10. Here we investigated the mechanisms leading to NF‐κB activation and BCL10 nuclear localization in ENKLs. Given that ENKLs are dependent on T‐cell‐derived interleukin‐2 (IL2) for cytotoxicity and proliferation, we investigated whether IL2 modulates NF‐κB activation and BCL10 subcellular localization in ENKLs. In the present study, IL2‐activated NK lymphoma cells were found to induce NF‐κB activation via the PI3K/Akt pathway, leading to an increase in the entry of G 2 /M phase and concomitant transcription of NF‐κB‐responsive genes. We also found that BCL10, a key mediator of NF‐κB signalling, participates in the cytokine receptor‐induced activation of NF‐κB. Knockdown of BCL10 expression resulted in deficient NF‐κB signalling, whereas Akt activation was unaffected. Our results suggest that BCL10 plays a role downstream of Akt in the IL2‐triggered NF‐κB signalling pathway. Moreover, the addition of IL2 to NK cells led to aberrant nuclear translocation of BCL10, which is a pathological feature of ENKLs. We further show that BCL10 can bind to BCL3, a transcriptional co‐activator and nuclear protein. Up‐regulation of BCL3 expression was observed in response to IL2. Similar to BCL10, the expression and nuclear translocation of BCL3 were induced by IL2 in an Akt‐dependent manner. The nuclear translocation of BCL10 was also dependent on BCL3 because silencing BCL3 by RNA interference abrogated this translocation. We identified a critical role for BCL10 in the cytokine receptor‐induced NF‐κB signalling pathway, which is essential for NK cell activation. We also revealed the underlying mechanism that controls BCL10 nuclear translocation in NK cells. Our findings provide insight into a molecular network within the NF‐κB signalling pathway that promotes the pathogenesis of NK cell lymphomas. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.