Kenji Toyonaga

Publications (3)11.13 Total impact

• Article: Lacking of Aiolos accelerates pre-mature B cell apoptosis mediated by BCR signaling through elevation in cytochrome c release.

  Hidehiko Kikuchi, Koki Yamashita, Masami Nakayama, Kenji Toyonaga, Isao Tsuneyoshi, Mayumi Takasaki, Tatsuo Nakayama
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  ABSTRACT: Antigen binding to B cell receptor (BCR) of pre-mature B lymphocytes leads to their apoptosis, while binding to BCR of mature B lymphocytes induces their activation and proliferation. The former binding is believed to be a mechanism so as to exclude B cell clones leading to protection from auto-immune diseases. Cross-linking of BCR of pre-mature B cells, including chicken DT40 cells, with anti-immunoglobulin antibody induces their apoptosis. The PMA/ionomycin treatments, which mimic BCR stimulation, are used to study intracellular signal transduction of B lymphocytes. Here, by analyzing the Aiolos-deficient DT40 cell line, Aiolos(-/-), we reveal that the lack of Aiolos accelerates apoptosis of DT40 cells mediated by BCR signaling. Moreover, the Aiolos-deficiency and BCR signaling cooperatively control this apoptosis through dramatically elevated cytochrome c release from mitochondria to cytosol and elevated caspase (caspase-3, 8 and 9) activities, resulting in drastically diminished amounts of ICAD followed by increased DNA fragmentation. Re-expression study reveals that the shorter isoform of Aiolos (Aio-2) controls PMA/ionomycin-mediated apoptosis via up-regulation and down-regulation of the PKCdelta and bak genes, respectively. These findings could be a powerful trigger to resolve molecular mechanisms of negative selection of B lymphocytes and also auto-immune diseases.
  Biochimica et Biophysica Acta 06/2009; 1793(7):1304-14. · 4.66 Impact Factor
• Article: 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.

  Kenji Toyonaga, Hidehiko Kikuchi, Koki Yamashita, Masami Nakayama, Kazuo Chijiiwa, Tatsuo Nakayama
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  ABSTRACT: 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.
  FEBS Journal 02/2009; 276(5):1418-28. · 3.79 Impact Factor
• Article: HDAC2 controls IgM H- and L-chain gene expressions via EBF1, Pax5, Ikaros, Aiolos and E2A gene expressions.

  Masami Nakayama, Hiroyuki Suzuki, Nahoko Yamamoto-Nagamatsu, Hirak Kumar Barman, Hidehiko Kikuchi, Yasunari Takami, Kenji Toyonaga, Koki Yamashita, Tatsuo Nakayama
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  ABSTRACT: We previously reported that histone deacetylase-2 (HDAC2) controls the amount of IgM H-chain at the steps of transcription of its gene and alternative processing of its pre-mRNA in DT40 cells. Here, we showed not only that the HDAC2-deficiency caused repressions of gene expressions for HDAC7, EBF1, Pax5, Aiolos and Ikaros, and elevations of gene expressions for HDAC4, HDAC5, PCAF and E2A, but also that it caused altered acetylation levels of several Lys residues of core histones. Using gene targeting techniques, we generated three homozygous DT40 mutants: EBF1(-/-), Aiolos(-/-) and E2A(-/-), devoid of EBF1, Aiolos and E2A genes, respectively. Semiquantitative RT-PCR analysis of the resultant mutants revealed not only that EBF1 and Aiolos down-regulate expressions of IgM H- and L-chain genes, but also that E2A up-regulates expressions of these two genes. These results, together with others, indicate that HDAC2 controls indirectly expressions of IgM H- and L-chain genes through opposite transcriptional regulations of EBF1, Pax5, Aiolos plus Ikaros and E2A genes.
  Genes to Cells 04/2007; 12(3):359-73. · 2.68 Impact Factor