Analysis of molecular mechanism of signal transduction pathway via cytokine receptors by bioprobes

生物探针分析细胞因子受体信号转导途径的分子机制

• 批准号: 15380069
• 负责人: KATAOKA Takao
• 金额: $ 7.55万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15380069/
• 关键词: Cytotoxic T lymphocyte; Epoxycyclohexenone; RKTS-33; Caspase-8; Acetoxycycloheximide; Apoptosis; NF-κB; TNF receptor 1; シクロヘキシミド; Fasリガンド; TNF-α; TACE; シェディング; エンドサイトーシス; パーフォリン; 細胞傷害顆粒; エポシシシクロヘキセノン; コンカナマイシンA; バイオプローブ

Cytotoxic T lymphocytes (CTLs) kill virus-infected cells and transformed cells via the perforin-dependent and Fas ligand-dependent pathways. Epoxycyclohexenone derivatives, ECH and RKTS-33, inhibit activation of caspase-8 and specifically block Fas-dependent apoptosis. ECH and RKTS-33 had only weak inhibitory effects on inducible expression of cell-surface Fas ligand, but strongly inhibited the Fas ligand-dependent killing pathway mediated by perforin-defective CD4^+ CTLs and concanamycin A-treated CD8^+ CTLs. However, ECH and RKTS-33 failed to prevent the perforin-dependent killing pathway mediated by CD8^+ CTLs. These results indicate that ECH and RKTS-33 are specific inhibitors for the Fas ligand-dependent killing pathway in CTL-mediated cytotoxicity.The protein synthesis inhibitor acetoxycycloheximide (E-73) inhibits activation of the transcription factor NF-κB induced by TNF-α, but not IL-1. When human lung carcinoma A549 cells were treated with E-73, the cellular level of TNF receptor 1 decreased accompanied by the increase of cleaved TNF receptor 1 in the medium. The metalloproteinase inhibitor GM6001 and the TACE (TNF-α converting enzyme) inhibitor TAPI-2 blocked the extracellular accumulation of TNF receptor 1 induced by E-73. These results indicate that E-73 decreases cell surface TNF receptor 1 by inducing TACE-dependent shedding and thereby reduces the responsiveness of A549 cells to TNF-α.

细胞毒性 T 淋巴细胞 (CTL) 通过穿孔素依赖性和 Fas 配体依赖性途径杀死病毒感染的细胞和转化细胞，环氧环己烯酮衍生物 ECH 和 RKTS-33，抑制 caspase-8 的激活并特异性阻断 Fas 依赖性细胞凋亡。 RKTS-33对细胞表面Fas配体的诱导表达仅有微弱的抑制作用，但强烈抑制Fas配体依赖性杀伤途径介导然而，ECH 和 RKTS-33 未能阻止 CD8^+ CTL 介导的穿孔素依赖性杀伤途径。这些表明 ECH 和 RKTS-33 的结果。是 CTL 介导的细胞毒性中 Fas 配体依赖性杀伤途径的特异性抑制剂。蛋白质合成抑制剂乙酰氧基放线菌酮 (E-73)抑制 TNF-α 诱导的转录因子 NF-κB 的激活，但不抑制 IL-1 当用 E-73 处理人肺癌 A549 细胞时，细胞内 TNF 受体 1 的水平下降，同时裂解的 TNF 受体增加。 1. 金属蛋白酶抑制剂 GM6001 和 TACE（TNF-α 转换酶）抑制剂 TAPI-2 阻断了 E-73 诱导的 TNF 受体 1 的细胞外积累。表明E-73通过诱导TACE依赖性脱落来减少细胞表面TNF受体1，从而降低A549细胞对TNF-α的反应性。

项目成果

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

• DOI: 10.1038/sj.cdd.4401408
• 发表时间: 2004-07-01
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: O'Reilly, LA;Divisekera, U;Strasser, A
• 通讯作者: Strasser, A

Yohsuke Higuchi: "Synthetic approach to exo-endo cross-conjugated cyclohexadienones and its application to the syntheses of dehydrobrachylaenolide, isodehydrochamaecynone, and trans-isodehydrochamaecynone"Journal of Natural Products. 66. 588-594 (2003)

Yohsuke Higuchi：“外-内交叉共轭环己二烯酮的合成方法及其在脱氢短苯内酯、异去氢苯丙酮和反式异脱氢苯丙酮合成中的应用”天然产物杂志。

Cellular FLIP (long form) regulates CD8^+ T cell activation through caspase-8-dependent NF-_kB activation

细胞 FLIP（长形式）通过 caspase-8 依赖性 NF-_kB 激活调节 CD8^ T 细胞激活

• 发表时间: 2005
• 期刊: Journal of Immunology 174(9)
• 作者: Jian-lin Wu;Tomokazu Mitsui;Takao Kataoka;Austin Dohrman
• 通讯作者: Austin Dohrman

Synthetic approach to exo-endo cross-conjugated cyclohexadienones and its application to the syntheses of dehydrobrachylaenolide, isodehydrochmaecynone, and trans-isodehydrochamaecynone

外型-内型交叉共轭环己二烯酮的合成方法及其在脱氢短苯内酯、异去氢苯丙酮和反式异脱氢苯丙酮合成中的应用

• 发表时间: 2003
• 期刊: J.Nat.Prod. 66(5)
• 作者: Yohsuke Higuchi;Fumio Shimoma;Rei Koyanagi;Kouji Suda;Tomokazu Mitsui;Takao Kataoka;Kazuo Nagai;Masayoshi Ando
• 通讯作者: Masayoshi Ando

Synthetic approach to exo^endo cross-conjugated cyclohexadienones and its application to the synthesesof dehydrobrachylaenolide, isodehydrochamaecy none, and trans-isodehydrochamaecynone

外切内交叉共轭环己二烯酮的合成方法及其在脱氢短苯内酯、异去氢蓼酮、反式异脱氢蓼酮合成中的应用

• 发表时间: 2003
• 期刊: Journal of Natural Products 66(5)
• 作者: Tomokazu Mitsui;Takao Kataoka;Takao Kataoka;Tanapat Palaga;Shin-ichiro Takayanagi;Lorraine O'Reilly;満井 智和;Yohsuke Higuchi
• 通讯作者: Yohsuke Higuchi