Regulation of cell death by cell cycling

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 13043013
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TSUBATA Takeshi Tokyo Medical and Dental University, Laboratory of Immunolog, School of Biomedical Science, Professor, 疾患生命科学研究部, 教授 (80197756)
• Project Period (FY): 2001 – 2005
• Keywords: Cell death / c-Myc / Reactive oxygen species / CDK inhibitor / lymphocyte

Research Abstract

Cellular defects that perturb cell cycle progression induce checkpoint-mediated cell cycle arrest, and the defect in this arrest causes cell death. However, checkpoint-independent cell cycle arrest is known to either induce or block cell death. In this study, we addressed mechanisms for cell cycling-mediated regulation of cell death and its biological significance. By using B lymphoma line that undergoes efficient apoptosis upon cell cycle arrest, we established the experimental system in which gene fragments regulating cell cycle arrest-induced apoptosis are enriched We isolated the c-myc gene as a regulator of cell cycle arrestinduced cell death. We further demonstrated that cell cycle arrest induces apoptosis in cells expressing a high level of c-myc, but induces survival in c-myclo cells. This result suggests that cMyc determines whether cell cycling regulates cell death positively or negatively. Further, we isolated genes involved in RNA metabolism such as SMN as regulators of cell cycling-regulated cell death. B lymphocytes undergo cell death upon antigen stimulation, and the antigen-induced cell death is abrogated by CD40 signaling for generating immune responses. We demonstrated that CD40mediated cell survival requires cell cycling, suggesting that regulation of cell death by cell cycling play a crucial role in the immune system. Further, we demonstrated that ROS is generated upon induction of cell death by cell cycle arrest or antigen stimulation, and plays a crucial role in the cell death.

Research Products

• [Journal Article] B cell sbnormality and systemic lupus crythematosus. (2007)
  • Author(s): Tsubata, T.
  • Journal Title: APLAR J. Rheum. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Augmentation of signaling therough BCR containing lgE but not that containing IgA due to lack of CD22-mediated signal regulation. (2007)
  • Author(s): Sato, M., Adachi, T., Tsubata, T.
  • Journal Title: J. immunol. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] B cell abnormality and systemic lupus erythematosus. (2007)
  • Author(s): Tsubata, T.
  • Journal Title: APLAR J. Rheum. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of signaling through BCR containing IgE but not that containing IgA due to lack of CD22-mediated signal regulation. (2007)
  • Author(s): Sato, M., Adachi, T., Tsubata, T.
  • Journal Title: J. immunol. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The tumor suppressor p53 is not required for antigen receptor-mediated apoptosis of B lymphoeytes. (2006)
  • Author(s): Devi, S.S., Hagiyama, H., Adachi, T., Miyasaka, N., Tsubata, T.
  • Journal Title: Signal Transduction 6 Pages: 54-61
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bispeeifie antibodies against modified protein and DNA with oxidized lipids. (2006)
  • Author(s): Akagawa, M., Ito, S., Toyoda, K., Ishii, Y., Tatuda, E., Shibata, T., Kawai, Y., Ishino, K., Kishi, Y., Adachi, T>, Tsubata, T., Takasaki, Y., Hattori, N., Matsuda, T., Uchida, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA. 103 Pages: 6160-6165
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The tumor suppressor p53 is not required for antigen receptor-mediated apoptosis of B lymphocytes. (2006)
  • Author(s): Devi, S.S., Hagiyama, H., Adachi, T., Miyasaka, N., Tsubata, T.
  • Journal Title: Signal Transduction 6 Pages: 54-61
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bispecific antibodies against modified protein and DNA with oxidized lipids. (2006)
  • Author(s): Akagawa, M., Ito, S., Toyoda, K., Ishii, Y., Tatsuda, E., Shibata, T., Kawai, Y., Ishino, K., Kishi, Y., Adachi, T., Tsubata, T., Takasaki, Y., Hattori, N., Matsuda, T., Uchida, K.
  • Journal Title: Proc. Natl Acad. Sci. USA. 103 Pages: 6160-5
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] B cell abnormality and autoimmune diserders. (2005)
  • Author(s): Tsubata, T.
  • Journal Title: Autoimmunity 38 Pages: 331-337
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] B cell abnormality and autoimmune disorders. (2005)
  • Author(s): Tsubata, T.
  • Journal Title: Autoimmunity 38 Pages: 331-337
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extopie CD40 ligand expression on B cells trigger intestinal inflammation. (2004)
  • Author(s): Kawamura, T., Kanai, T., Dohi, T., Urushihara, K., Totsuka, T., Iiyama, R., Taneda, C., Yamazaki, M., Nakamura, T., Higuchi, T., Aiba, Y., Tsubata, T., Watanabe, M.
  • Journal Title: J. Immunol. 172 Pages: 6388-6397
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular interactions regulate BCR signal inhibition by CD22 and CD72. (2004)
  • Author(s): Nitsehke, L., Tsubata, T.
  • Journal Title: Trends Immunol. 25 Pages: 543-550
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ectopic CD40 ligand expression on B cells trigger intestinal inflammation. (2004)
  • Author(s): Kawamura, T., Kanai, T., Dohi, T., Uraushihara, K., Totsuka, T., Iiyama, R., Taneda, C., Yamazaki, M., Nakamura, T., Higuchi, T., Aiba, Y., Tsubata, T., Watanabe, M.
  • Journal Title: J. Immunol. 172 Pages: 6388-6397
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular interactions regulate BCR signal inhibition by CD22 and CD72. (2004)
  • Author(s): Nitschke, L., Tsubata, T.
  • Journal Title: Trends Immunol. 25 Pages: 543-550
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Critical roles of Pten in B cell homeostasis and immunoglobulin elass switch recombination. (2003)
  • Author(s): Suzuki, A., Kaisho, T., Ohishi, M., Tsukio-Yamaguchi, M., Tsubata, T., Koni, P.A., Sasaki, T., Mak, T.M., Nakano, T.
  • Journal Title: J. Exp. Med. 197 Pages: 657-667
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory co-receptors activated by antigens but not by antiimmunoglobulinheavy chain antibodies install requirement of co-stimulation through CD40 for survival and proliferaration of B cells. (2003)
  • Author(s): Hokazono, Y., Adachi, T., Wabl, M., Tada, N., Amagasa, T., Tsubata, T.
  • Journal Title: J. Immunol. 171 Pages: 261-269
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of cell cycle progression in survaival signaling through CD40 in B lymphecyte line WEIII-231. (2003)
  • Author(s): Hirai, H, Adachi, T., Tsubata, T.
  • Journal Title: Cell. Death. Differ 11 Pages: 261-269
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. (2003)
  • Author(s): Suzuki, A., Kaisho, T., Ohishi, M., Tsukio-Yamaguchi, M., Tsubata, T., Koni, P.A., Sasaki, T., Mak, T.W., Nakano, T.
  • Journal Title: J.Exp.Med 197 Pages: 657-667
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory co-receptors activated by antigens but not by anti immunoglobulin heavy chain antibodies install requirement of co-stimulation through CD40 for survival and proliferation of B cells. (2003)
  • Author(s): Hokazono, Y., Adachi, T., Wabl, M., Tada, N., Amagasa, T., Tsubata' T.
  • Journal Title: J. Immunol. 171 Pages: 261-269
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of cell cycle progression in survaival signaling through CD40 inB lymphocyte line WEHI-231. (2003)
  • Author(s): Hirai, H., Adachi, T., Tsubata, T.
  • Journal Title: CelLDeath.Differ 11 Pages: 261-269
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cutting Edge : Ectopie expression of CD40 ligand on B cells induces lupus-loke autoimmune sisease. (2002)
  • Author(s): Higuchi, T., Aiba, Y., Nomura, T., Matsuda, J., Mochida, K., Suzuki, M., Kikutani, H., Honjo, T.., Nishioka, K., Tsubata, T.
  • Journal Title: J. Immunol 168 Pages: 9-12
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A distinet signaling pathway used by the IgG-containing B cell antigen receptor. (2002)
  • Author(s): Wakabayashi C., Adachi, T., Wienands, J., Tsubata, T.
  • Journal Title: Science. 298 Pages: 2392-2395
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cutting Edge : Ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. (2002)
  • Author(s): Higuchi, T., Aiba, Y., Nomura, T., Matsuda, J., Mochida, K., Suzuki, M., Kikutani, H., Honjo, T., Nishioka, K.
  • Journal Title: J. Immunol 168 Pages: 9-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A distinct signaling pathway used by the IgG-containing B cell antigen receptor. (2002)
  • Author(s): Wakabayashi, C., Adachi, T., Wienands, J., Tsubata, T.
  • Journal Title: Science. 298 Pages: 2392-2395
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T cell-specific loss of Pten leads to defects in central and perilheral tolerance. (2001)
  • Author(s): Suzuki, A, Tsukio-Yamaguchi M., Ohteki, T, Sasaki, T., Kaisho, T., Kimura, Y., Yoshida, R., Wakeham, A., Higuchi, T., Fukumoto, M., Tsubata, T., Ohashi, P., Koyasu, S., Penninger, J.M., Nkano, T., Mak, T.W.
  • Journal Title: Immunity 14 Pages: 523-534
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. (2001)
  • Author(s): Adachi, T, Wenands, J, Wakabayashi, C, Yakura, H., Reth, M., Tsubata, T.
  • Journal Title: J. Biol. Chem. 276 Pages: 26648-26655
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular mechanisms for apoptosis induced by signaling through the B cell antigen receptor. (2001)
  • Author(s): Tsubata, T.
  • Journal Title: Int. Rev. Immunol. 20 Pages: 791-803
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] T cell-specific loss of Pten leads to defects in central and peripheral tolerance. (2001)
  • Author(s): Suzuki, A., Tsukio-Yamaguchi, M., Ohteki, T., Sasaki, T., Kaisho, T., Kimura, Y., Yoshida, R., Wakeham, A., Higuchi, T., Fukumoto, M., Tsubata, T., Ohashi, P., Koyasu, S., Penninger, J.M., Nakano, T., Mak, T.W.
  • Journal Title: Immunity 14 Pages: 523-534
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. (2001)
  • Author(s): Adachi, T., Wienands, J., Wakabayashi, C., Yakura, H., Reth, M., Tsubata, T.
  • Journal Title: J. BioL Chem 276 Pages: 26648-26655
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular mechanisms for apoptosis induced by signaling through the B cell antigen receptor. (2001)
  • Author(s): Tsubata, T.
  • Journal Title: Int. Rev. Immunol 20 Pages: 791-803
  • Description: 「研究成果報告書概要(欧文)」より