Regulation of cell death by cell cycling

通过细胞周期调节细胞死亡

• 批准号: 13043013
• 负责人: TSUBATA Takeshi
• 金额: $ 67.97万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13043013/
• 关键词: Cell death; c-Myc; Reactive oxygen species; CDK inhibitor; lymphocyte; アポトーシス; 細胞周期回転; 活性酸素; p38MAPK; ApoE; Serf2; CD40; PDIP1; siRNA; p27kip1; 分化; 肝細胞; Ras

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.

扰乱细胞周期进程的细胞缺陷会诱导检查点介导的细胞周期停滞，而这种停滞的缺陷会导致细胞死亡。然而，已知不依赖于检查点的细胞周期停滞可以诱导或阻止细胞死亡。在这项研究中，我们探讨了细胞周期介导的细胞死亡调节机制及其生物学意义。通过使用在细胞周期停滞时经历有效凋亡的B淋巴瘤系，我们建立了富集调节细胞周期停滞诱导的细胞凋亡的基因片段的实验系统。我们分离了c-myc基因作为细胞周期停滞诱导的细胞死亡的调节因子。我们进一步证明，细胞周期停滞会诱导表达高水平 c-myc 的细胞凋亡，但会诱导 c-myclo 细胞存活。这一结果表明，cMyc 决定细胞周期是否积极或消极地调节细胞死亡。此外，我们分离了参与 RNA 代谢的基因，例如 SMN，作为细胞周期调节的细胞死亡的调节因子。 B 淋巴细胞在抗原刺激下经历细胞死亡，并且抗原诱导的细胞死亡被 CD40 信号传导消除以产生免疫反应。我们证明 CD40 介导的细胞存活需要细胞周期，这表明细胞周期对细胞死亡的调节在免疫系统中发挥着至关重要的作用。此外，我们证明ROS是在细胞周期停滞或抗原刺激诱导细胞死亡时产生的，并且在细胞死亡中发挥着至关重要的作用。

项目成果

Critical roles of Pten in B cell homeostasis and immunoglobulin elass switch recombination.

Pten 在 B 细胞稳态和免疫球蛋白弹性开关重组中的关键作用。

• 发表时间: 2003
• 期刊: J. Exp. Med. 197
• 作者: Suzuki;A.;Kaisho;T.;Ohishi;M.;Tsukio-Yamaguchi;M.;Tsubata;T.;Koni;P.A.;Sasaki;T.;Mak;T.M.;Nakano;T.
• 通讯作者: T.

A distinet signaling pathway used by the IgG-containing B cell antigen receptor.

包含 IgG 的 B 细胞抗原受体使用的独特信号传导途径。

• 发表时间: 2002
• 期刊: Science. 298
• 作者: Wakabayashi C.;Adachi;T.;Wienands;J.;Tsubata;T.
• 通讯作者: T.

Hokazono, Y., Adachi, T., Wabl, M., Tada, N., Amagasa, T., Tsubata T.: "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 o

Hokazono，Y.，Adachi，T.，Wabl，M.，Tada，N.，Amagasa，T.，Tsubata T.：“由抗原激活的抑制性共受体，但不由抗免疫球蛋白重链抗体激活，需要共-

Higuchi T: "Cutting Edge : Ectopic expression of CD4O ligand on B cells induces lupus-likeautoimmune disease"J.Immunol. 168. 9-12 (2002)

Higuchi T：“前沿：B 细胞上 CD4O 配体的异位表达会诱发狼疮样自身免疫性疾病”J.Immunol。

Suzuki A: "T-cell specific loss of PTEN leads to defects in central and peripheral tolerance"Immunity. 14. 523-534 (2001)

Suzuki A：“T 细胞特异性 PTEN 缺失导致中枢和外周耐受性缺陷”免疫。