Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase
Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase
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DOI：
10.1016/s0002-9440(10)65708-2
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发表时间：
1998-12-01
影响因子：
6
通讯作者：
Tsokos, M
中科院分区：
文献类型：
--
作者：
Mitsiades, N;Poulaki, V;Tsokos, M
Fas配体（FasL）以跨膜和可溶性形式存在，与Fas受体交联后可诱导细胞凋亡。我们评估了61例尤文肉瘤家族肿瘤（ESFT）组织和9个细胞系中Fast和Fas的生物学意义。62.5%的原发性ESFT中存在Fast，79.4%的原发性ESFT中存在Fas，转移性肿瘤具有更高的Fast表达（95%），表明与转移表型相关。免疫荧光法检测到Fast蛋白主要分布于ESFT细胞的胞浆和胞膜。蛋白质印迹法显示跨膜和可溶性快速胞质提取物和可溶性快速条件培养基。在与ESFT细胞或其培养基的共培养实验中，跨膜和可溶性Fast均诱导Fas敏感性Jurkat细胞凋亡。用菲咯啉和合成金属蛋白酶抑制剂BB-3103处理降低了培养基中可溶性Fast的水平，表明在ESFT中，Fast被金属蛋白酶加工并在细胞外环境中释放。释放的可溶性Fast可用于攻击免疫系统的细胞和/或干扰跨膜Fast与Fas的结合，并导致跨膜Fast的下调。合成的金属蛋白酶抑制剂可以改变跨膜与可溶性FasL的比例。
Fas ligand (FasL) exists in transmembrane and soluble forms and induces apoptosis on cross-linking with the Fas receptor. We evaluated the biological significance of Fast and Fas in 61 tumor tissues and 9 cell lines of the Ewing's sarcoma family of tumors (ESFT). Fast was present in 62.5% and Fas in 79.4% of primary ESFT, Metastatic tumors had higher expression of Fast (95%), suggesting association with a metastatic phenotype. Fast was detected in the cytoplasm and membrane of ESFT cells by immunofluorescence. Western blotting revealed transmembrane and soluble Fast in cytosolic extracts and soluble Fast in conditioned media. Both transmembrane and soluble Fast induced apoptosis of Fas-sensitive Jurkat cells in co-culture experiments with ESFT cells or their media. Treatment with phenanthroline and the synthetic metalloproteinase inhibitor BB-3103 reduced the levels of soluble Fast in the media, suggesting that in ESFT, Fast is processed by a metalloproteinase and released in the extracellular milieu. The released soluble Fast may serve to attack cells of the immune system and/or interfere with the binding of transmembrane Fast with Fas, and results in down-regulation of transmembrane Fast. Synthetic metalloproteinase inhibitors may modify the ratio of transmembrane to soluble FasL.