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的细胞。环氧环己烯酮衍生物，ECH和RKTS-33，抑制半胱天冬酶-8的活化，并特异性阻断Fas依赖性细胞凋亡。ECH和RKTS-33对细胞表面Fas配体的诱导表达仅有微弱的抑制作用，但对穿孔素缺陷型CD 4 ^+ CTL和Concanamycin A处理的CD 8 ^+ CTL介导的Fas配体依赖性杀伤途径有强烈的抑制作用。然而，ECH和RKTS-33未能阻止由CD 8 ^+ CTL介导的穿孔素依赖性杀伤途径。上述结果表明，ECH和RKTS-33是CTL介导的细胞毒作用中Fas配体依赖性杀伤通路的特异性抑制剂，而蛋白质合成抑制剂乙酰氧基环己酰亚胺（E-73）可抑制TNF-α诱导的转录因子NF-κB的活化，但对IL-1无影响。当用E-73处理人肺癌A549细胞时，TNF受体1的细胞水平下降，同时培养基中切割的TNF受体1增加。金属蛋白酶抑制剂GM 6001和TACE（TNF-α转化酶）抑制剂TAPI-2可阻断E-73诱导的TNF受体1的细胞外蓄积。这些结果表明，E-73通过诱导TACE依赖性脱落减少细胞表面TNF受体1，从而降低A549细胞对TNF-α的反应性。

项目成果

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。

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

Three new Triterpenes from Nerium oleander and biological activity of the isolated compounds

• DOI: 10.1021/np040072u
• 发表时间: 2005-02-01
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Fu, LW;Zhang, SJ;Ando, M
• 通讯作者: Ando, M

N-terminal fragment of c-FLIP(L) processed by caspase-8 specifically interacts with TRAF2 and induces activation of the NF-_kB signaling pathway

由 caspase-8 处理的 c-FLIP(L) N 端片段与 TRAF2 特异性相互作用并诱导 NF-_kB 信号通路激活

• 发表时间: 2004
• 期刊: Molecular and Cellular Biology 24(7)
• 作者: Liwei Fu;Shujun Zhang;Na Li;Jinlan Wang;Ming Zhao;Junichi Sakai;Toshiaki Hasegawa;Tomokazu Mitsui;Takao Kataoka;Seiko Oka;Miwa Kiuchi;Katutoshi Hirose;Masayoshi Ando;Takao Kataoka;Kimiko Kadohara;Austin Dohrman;Tomokazu Mitsui;Tomokazu Mitsui;満井 智和;Lorraine O'Reilly;Shin-ichiro Takayanagi;Tanapat Palaga;Takao Kataoksa
• 通讯作者: Takao Kataoksa

Tomokazu Mitsui: "ECH, an epoxycyclohexenone derivative that specifically inhibits Fas ligand-dependent apoptosis in CTL-mediated cytotoxicity"The Journal of Immunology. 172. 3428-3436 (2004)

Tomokazu Mitsui：“ECH，一种环氧环己烯酮衍生物，在 CTL 介导的细胞毒性中特异性抑制 Fas 配体依赖性细胞凋亡”《免疫学杂志》。