Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif
Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif
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DOI：
10.1016/j.bbrc.2004.07.098
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发表时间：
2004-09-10
影响因子：
3.1
通讯作者：
Nagata, S
中科院分区：
文献类型：
--
作者：
Shiraishi, T;Suzuyama, K;Nagata, S
Fas（CD 95）配体（FasL）通过与Fas结合诱导表达Fas的胶质瘤细胞凋亡。几种分子种类已被设计为用于治疗目的的可溶性Fas配体。我们成功地构建了一个嵌合的可溶性FasL融合异亮氨酸拉链基序的自我寡聚化和FLAG序列的细胞外结构域的人Fas配体（FIZ-shFasL）。FIZ-shFasL对Jurkat细胞的细胞毒作用与膜结合的FasL相当，并且比激动性抗Fas抗体（CH-11）强约10倍。流式细胞术分析表明，Fas的差异表达与FIZ-shFasL诱导的人脑肿瘤细胞凋亡水平部分相关。对大鼠安全全身给药的FIZ-shFasL的上限估计为血浆浓度低于2 μ g/ml。FIZ-shFasL可用作癌症的治疗剂。(C)2004年爱思唯尔公司All rights reserved.
Fas (CD95) ligand (FasL) has the ability to induce apoptosis in Fas-expressing glioma cells by binding to Fas. Several molecular species have been designed to be soluble Fas ligands for therapeutic purposes. We successfully constructed a chimeric soluble FasL by fusing an isoleucine zipper motif for self-oligomerization and a FLAG sequence to the extracellular domain of the human Fas ligand (FIZ-shFasL). The cytotoxic effect of FIZ-shFasL on Jurkat cells was equivalent to that of membrane-bound FasL and approximately 10-fold stronger than that of agonistic anti-Fas antibody (CH-11). Flow cytometric analysis demonstrated that the differential Fas expression of human brain tumor cell lines partially correlated with levels of apoptosis through FIZ-shFasL. The upper limit of FIZ-shFasL for safe systemic administration to rat is estimated as below 2 mug/ml in plasma concentration. FIZ-shFasL could be applicable as a therapeutic agent for cancer. (C) 2004 Elsevier Inc. All rights reserved.