Identification of a protein (s) that interacts with Fas igand.

鉴定与 Fas 配体相互作用的蛋白质。

• 批准号: 10670140
• 负责人: NAGATA Shigekazu
• 金额: $ 2.05万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670140/
• 关键词: apoptosis; Fas ligand; metalloproteinase; inflammation; IL-1β; カスペース; メタロプロテーゼ; IL-1; カスパーゼ; 炎症反応

Fas ligand (FasL) is a type II membrane protein belonging to the tumor necrosis factor (TNF) family, and induces apoptosis by binding its receptor Fas. A metalloproteinase cleaves the membrane-bound FasL, to produce its soluble form. To determine which forms of FasL, the membrane-bound or soluble form induces apoptosis, we prepared the soluble recombinant FasL and also established transformant cell lines that express non-cleavable membrane-bound FasL. Mouse hepatocytes and human Jurkat cells were killed by the membrane-bound FasL, butnot by soluble FasL, indicating that the membrane-bound form of FasL is the effector molecule, and its cleavage by shedding is to down-regulate the function. TNF is known to be cleaved by TACE (TNF alpha converting enzyme). Biochemical analysis of TACE indicated that TACE should be expressed in the same cells as TNF, and it does not cleave FasL. When the tumor cells expressing FasL are transplanted to peritoneal cavity of mice, it caused inflammation by recruiting neutrophils. Accordingly, when cells from the peritoneal cavity are incubated with FasL, they produced IL-1β while undergoing apoptosis. These results suggested that the apoptotic cells recruit inflammatory cells to clean up the corps.

Fas配体（FasL）是肿瘤坏死因子（TNF）家族的II型膜蛋白，通过与其受体Fas结合诱导细胞凋亡。一种金属蛋白酶裂解膜结合的FasL，以产生其可溶形式。为了确定哪种形式的FasL，膜结合形式还是可溶性形式诱导细胞凋亡，我们制备了可溶性重组FasL，并建立了表达不可切割膜结合FasL的转化细胞系。小鼠肝细胞和人Jurkat细胞均被膜结合的FasL杀死，而可溶性FasL不被杀死，说明FasL的膜结合形式是效应分子，其脱落裂解是下调功能。已知TNF可被TACE （TNF α转换酶）切割。TACE的生化分析表明，TACE应该与TNF在相同的细胞中表达，并且不切割FasL。将表达FasL的肿瘤细胞移植到小鼠腹腔后，通过募集中性粒细胞引起炎症反应。因此，当来自腹腔的细胞与FasL孵育时，它们在发生凋亡的同时产生IL-1β。这些结果表明，凋亡细胞招募炎症细胞来清理军团。

项目成果

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Miwa, K. et al.: "Caspase 1-independent IL-1 release and inflammation"Nature Med.. 4. 1287-1291 (1998)

Miwa，K.等人：“Caspase 1独立的IL-1释放和炎症”Nature Med.4.1287-1291(1998)

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Sakahira, H. et al.: "Cleavage of CAD inhibitor in CAD activation and DNA…"Nature. 391. 96-99 (1998)

Sakahira, H. 等人：“CAD 激活和 DNA 中 CAD 抑制剂的裂解……”《自然》，391. 96-99 (1998)。

Sakahira H.et al.: "Cleavage of CAD inhibitor in CAD activation and DNA・・・"Nature. 391. 96-99 (1998)

Sakahira H.等人：“CAD 激活和 DNA 中 CAD 抑制剂的裂解……”《自然》，391. 96-99 (1998)。