NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor.
Cross-linking of the B cell antigen receptor (BCR) with an anti-IgM antibody has been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells. However, the apoptotic mechanism triggered via BCR remains unknown. Here we reports a mechanism of BCR ligation-induced apoptosis involving protein phosphatase calcineurin and its specific substrate, transcriptional factor NF-AT. In response to BCR cross-linking, endogenous calcineurin was rapidly activated, and this facilitated nuclear translocation of NF-ATc2, a subtype of NF-AT members. Interestingly, nuclear-imported NF-ATc2 functioned pro-apoptotically in BL cells. The effect of NF-ATc2 was efficiently blocked with FK506, which prevented its nuclear translocation through inactivation of calcineurin. In addition, TR3 induction during BCR cross-linking was reduced by FK506 and the VIVIT peptide, which is a highly selective inhibitor for NF-AT. This strongly suggests that activation of NF-ATc2 by calcineurin is essential for TR3 recruitment, and that TR3 can be considered as a candidate for death effector in BCR-mediated apoptosis. Therefore, NF-ATc2 plays a crucial role in BCR-mediated apoptosis in type IBL, providing greater insight into unique BL characteristics through BCR signaling.
Kondo
Eisaku
E
Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. ekondo@md.okayama-u.ac.jp
Harashima
Akira
A
Takabatake
Takami
T
Takahashi
Hideo
H
Matsuo
Yoshinobu
Y
Yoshino
Tadashi
T
Orita
Kunzo
K
Akagi
Tadaatsu
T
D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D019703:Calcineurin; D002118:Calcium; D016559:Tacrolimus