E2A participates in a fine control of pre-mature B-cell apoptosis mediated by B-cell receptor signaling via transcriptional regulation of survivin, IAP2 and caspase-8 genes.
Antigen binding to the B-cell receptor (BCR) of pre-mature B lymphocytes induces their apoptotic cell death, but binding to the BCR of mature B lymphocytes triggers activation and proliferation. Binding to pre-mature B lymphocytes is thought not only to function as a mechanism to exclude B-cell clones that possess the ability to react with self-antigen, but also to act as a defense mechanism in auto-immune diseases. Cross-linking of BCR of pre-mature B-cell lines, including the chicken DT40 cell line, with anti-immunoglobulin IgG induces apoptotic cell death. Treatment with phorbol 12-myristate 13-acetate/ionomycin, which mimics BCR stimulation, is used to study intracellular signal transduction of B lymphocytes. Here, by analyzing the E2A-deficient DT40 cell line, E2A(-/-), we show that E2A deficiency prevents certain levels of apoptotic cell death mediated by BCR signaling. In addition, E2A deficiency-linked BCR signaling controls the mimicked pre-mature B-cell apoptosis by PMA/ionomycin through elevated survivin plus inhibitor of apoptosis 2 levels, and reduced caspase-3 and caspase-8 activities, resulting in increased amounts of ICAD (inhibitor of caspase-activated DNase), compared with those in the presence of E2A, followed by reduction of DNA fragmentation. These findings will contribute to the resolution of molecular mechanisms of negative selection of B cells and also auto-immune diseases.
Toyonaga
Kenji
K
Department of Medical Sciences, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan.
Kikuchi
Hidehiko
H
Yamashita
Koki
K
Nakayama
Masami
M
Chijiiwa
Kazuo
K
Nakayama
Tatsuo
T
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002645:Chickens; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D053181:Caspase 8; D051034:Inhibitor of Apoptosis Proteins; D015759:Ionomycin; D008869:Microtubule-Associated Proteins; D011947:Receptors, Antigen, B-Cell