A role of Bcl6 in regulation of somatic hypermutation in the immunoglobulin gene

• Project/Area Number: 18390149
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: TOKUHISA Takeshi Chiba University, Graduate School of Medicine, Professor (20134364)
• Co-Investigator(Kenkyū-buntansha): HATANO Masahiko Chiba University, Graduate School of Medicine, Professor (20208523) ; ARIMA Masafumi Chiba University, Graduate School of Medicine, Lecturer (00202763) ; SAKAMOTO Akemi Chiba University, Graduate School of Medicine, Assistant Prof. (90359597) ; FUJIMURA Risa Chiba University, Biomedical Center, Assistant Prof. (30376363)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,720,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,920,000); Fiscal Year 2007: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2006: ¥8,400,000 (Direct Cost: ¥8,400,000)
• Keywords: immunology / target gene / cancer / genome / gene regulation

Research Abstract

Bcl6 is highly expressed in germinal center B cells and is essential for development of high affinity memory B cells. Bcl6 functions as a sequence specific transcriptional repressor by recruiting a histone deacetylase complex. However, a role for Bcl6 in induction of somatic hypermutation in germinal center B cells is not known. When we examined mutation frequencies in the Ig class-switch region and the c-myc region of IgG1 B cells derived from Bcl6-deficient mice, the frequencies in Bcl6-deficient IgG1 B cells were higher than those in wild type IgG1 B cells. These mutations were mainly generated by conversion of adenine to guanine. RNA-editing adenosine deaminase (ADAR) family converts adenosine of pre-mRNA into inosine, which is subsequently translated as guanosine, and ADAR1 mRNA among ADAR family was overexpressed in various cells from Bcl6-deficient mice. The promoter analysis revealed that ADAR1 is a molecular target of Bcl6. Furthermore, the exogenous ADAR1 increased frequency of point mutations from adenine to guanine in those regions of wild type IgG1 B cells. Since ADAR1 mRNA is detected in germinal center B cells in spite of high Bcl6 expression, ADAR1 may contribute adenine-targeted somatic hypermutation in germinal center B cells.

Research Products

• [Journal Article] A distinct role for lL-4 and lL-21 in their collaboration on proliferation and differentiation of activated B cells. (2008)
  • Author(s): Saito, et al.
  • Journal Title: Immunobiol. (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A distinct role for IL-4 and IL-21 in their collaboration on proliferation and differentiation of activated B cells (2008)
  • Author(s): Saito, T., Kitayama, D., Sakamoto, A., Tsuruoka, N., Arima, M., Hatano, M., Miyazaki, M., and Tokuhisa, T.
  • Journal Title: Immunobiol. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A role for Bcl6 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21 (2008)
  • Author(s): Kitayma, et. al.
  • Journal Title: Mol.Immunol 45 Pages: 1337-1345
  • Peer Reviewed
• [Journal Article] Identification of the consensus DNA sequence for Nczf-binding. (2007)
  • Author(s): Kitahashi, et al.
  • Journal Title: DNA and Cell Biol. 26 Pages: 395-401
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A role for Bc16 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21 (2007)
  • Author(s): Kitayama, et al.
  • Journal Title: Mol. Immunol. 45 Pages: 1337-1345
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bc16 protects apoptosis of naive B cells stimulated with IL-21. (2007)
  • Author(s): Tsuruoka, et al.
  • Journal Title: Immunol. Lett 110 Pages: 145-151
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bc16 is essential for the generation of long-term memory CD4^+ T cells. (2007)
  • Author(s): Ichii, et al.
  • Journal Title: Int. Immunol. 19 Pages: 427-433
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bcl6 is essential for the generation of long-term memory CD4^+ T cells (2007)
  • Author(s): Ichii, H., Sakamoto, A., Arima, M., Hatano, H., Kuroda, Y., and Tokuhisa, T.
  • Journal Title: Int. Immunol. 19 Pages: 427-433
  • NAID: 10020110313
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bc16 protects apoptosis of naive B cells stimulated with IL-21 (2007)
  • Author(s): Tsuruoka, N., Arima, M., Arguni, E., Saito, T., Kitayama, D., Sakamoto,A., Hatano, M., and Tokuhisa, T.
  • Journal Title: Immunol. Lett. 110 Pages: 145-151
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A role for Bc16 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21 (2007)
  • Author(s): Kitayama, D., Sakamoto, A., Arima, M., Hatano, M., Miyazaki, M., and Tokuhisa, T.
  • Journal Title: Mol. Immunol. 45 Pages: 1337-1345
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of the consensus DNA sequence for Nczf-binding (2007)
  • Author(s): Kitahashi, M., Sato, Y, Fujimura, L., Arima, M., Sakamoto, A., Yamamoto, S., Tokuhisa, T., and Hatano, H.
  • Journal Title: DNA and Cell Biol. 26 Pages: 395-401
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bcl6 is essential for the generation of long-term memory CD4^+ T cells (2007)
  • Author(s): Ichii, et. al.
  • Journal Title: Int.Immunol 19 Pages: 427-433
  • Peer Reviewed
• [Journal Article] Bcl6 protects apoptosis of naive B cells stimulated with IL-21 (2007)
  • Author(s): Tsuruoka, et. al.
  • Journal Title: Immunol.Lett 110 Pages: 145-151
  • Peer Reviewed
• [Journal Article] Overexpression of Nd1, a novel Kelch family protein, in the heart of transgenic mice protects against doxorubicin-induced cardiomyopathy. (2006)
  • Author(s): Matsudo, et al.
  • Journal Title: Transgenic Research 15 Pages: 573-581
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bc16 controls Granzyme B expression in effector CD8 T cells. (2006)
  • Author(s): Yoshida, et al.
  • Journal Title: Eur. J. Immunol. 36 Pages: 3146-3156
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of the Nd1 gene is down-regulated by doxorubicin at post-transcriptional level (2006)
  • Author(s): Takamori, Y., et al.
  • Journal Title: Int. J. Mol. Med. 18 Pages: 963-967
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Lung-specific expression of IL-25 enhances allergic airway inflammati on by amplifying a Th2 cell-dependent pathway. (2006)
  • Author(s): Tamachi, T., et al.
  • Journal Title: J. Allergy Clin. Immunol. 118 Pages: 606-614
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] JunD/AP-1 and STAT3 are the major enhancer molecules for high Bc16 expression in germinal center B cells. (2006)
  • Author(s): Arguni, E., et al.
  • Journal Title: Int. Immunol. 18 Pages: 1079-1089
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of Clastl in differentiation of cerebellar granule cells. (2006)
  • Author(s): Maeda, Y., et al.
  • Journal Title: Brain Res. 1104 Pages: 18-26
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] JunD/AP-1 and STAT3 are the major enhancer molecules for high Bc16 expression in germinal center B cells (2006)
  • Author(s): Arguni, E., Arima, M., Tsuruoka, N., Sakamoto, A., Hatano, M., and Tokuhisa, T.
  • Journal Title: Int. Immunol. 18 Pages: 1079-1089
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lung-specific expression of IL-25 enhances allergic airway inflammation by amplifying a Th2 cell-dependent pathway (2006)
  • Author(s): Tamachi, T., Maezawa, Y., Ikeda, K., Kagami, S., Hatano, M., Seto, Y., Suto, A., Suzuki, K., Watanabe, N., Saito, Y., Tokuhisa, T., Iwamoto, I., and Nakajima, H.
  • Journal Title: J. Allergy Clin. Immunol. 118 Pages: 606-614
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bc16 controls Granzyme B expression in effector CD8 T cells (2006)
  • Author(s): Yoshida, K., Sakamoto, A., Yamashita, K., Arguni, E., Horigome, S., Arima, M., Hatano, M., Seki, N., Ichikawa, T., and Tokuhisa, T.
  • Journal Title: Eur. J. Immunol. 36 Pages: 3146-3156
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the Ndl gene is down-regulated by doxorubicin at post-transcriptional level (2006)
  • Author(s): Takamori, Y., Matsudo, Y., Fujimura, L., Kang, M., Harada, Y, Moriya, H., Tokuhisa, T., and Hatano, M.
  • Journal Title: Int. J. Mol. Med. 18 Pages: 963-967
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of Clastl in differentiation of cerebellar granule cells (2006)
  • Author(s): Maeda, Y, Fujimura, L., O-Wang, J., Hatano, M., Sakamoto,A., Arima, M., Ebara, M., Ino, H., Yamashita, T., Saisho, H., and Tokuhisa, T.
  • Journal Title: Brain Res. 1104 Pages: 18-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of Ndl, a novel Kelch family protein, in the heart of transgenic mice protects against doxorubicin-induced cardiomyopathy (2006)
  • Author(s): Matsudo, Y., Takamori, Y., Sasagawa, K., Fujimura, L., Komuro, I., Tokuhisa, T., and Hatano, M.
  • Journal Title: Transgenic Research 15 Pages: 573-581
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bc16 controls Granzyme B expression in effector CD8 T cells. (2006)
  • Author(s): Yoshida, K., et al.
  • Journal Title: Eur. J. Immunol. 36 Pages: 3146-3156
• [Journal Article] Expression of the Ndl gene is down-regulated by doxorubicin at post-transcriptional level. (2006)
  • Author(s): Takamori, Y., et al.
  • Journal Title: Int. J. Mol. Med. 18 Pages: 963-967
• [Journal Article] Lung-specific expression of IL-25 enhances allergic airway inflammation by amplifying a Th2 cell-dependent pathway. (2006)
  • Author(s): Tamachi, T., et al.
  • Journal Title: J. Allergy Clin. Immunol. 118 Pages: 606-614
• [Journal Article] Role of Clast1 in differentiation of cerebellar of granule cells. (2006)
  • Author(s): Maeda, Y., et al.
  • Journal Title: Brain Res. 1104 Pages: 18-26
• [Journal Article] Role of DNA polymerase theta in tolerance of endogenous and exogenous DNA damage in mouse B cells. (2006)
  • Author(s): Ukai, A., et al.
  • Journal Title: Genes Cells 11 Pages: 111-121
• [Presentation] A Role for Bc16 in B Cells Activated with Sequential Stimulation of IL-4 and IL-21 (2008)
  • Author(s): 徳久剛史、他
  • Organizer: 第36回日本免疫学会
  • Place of Presentation: 大阪
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Bc16 protects apoptosis of naive B cells stimulated withIL-21 (2007)
  • Author(s): 鶴岡 信栄, 他
  • Organizer: 第37回日本免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-20
• [Presentation] Bc16 protects apoptosis of naive B cells stimulated with IL-21 (2007)
  • Author(s): 鶴岡信栄、他
  • Organizer: 第37回日本免疫学会
  • Place of Presentation: 東京
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Bc16 protects apoptosis of naive B cells stimulated with IL-21 (2007)
  • Author(s): Tsuruoka, N., Tokuhisa, T., et. al.
  • Organizer: 37h Japanese Society for Immunology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A Role for Bcl6 in B Cells Activated with Sequential Stimulation of IL-4 and IL-21 (2006)
  • Author(s): Tokuhisa, T., Kitayama, D., Tsuruoka, N., Saito, T., Sakamoto,A., Arima, M., and Hatano, M.
  • Organizer: 36th Japanese Society for Immunology
  • Place of Presentation: Osaka
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/
• [Remarks]
  • URL: http://www.m.chiba-u.ac.jp/class/devgen/