Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.
Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.
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DOI：
10.1371/journal.pone.0054000
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Taupin JL
中科院分区：
文献类型：
--
作者：
Daburon S;Devaud C;Costet P;Morello A;Garrigue-Antar L;Maillasson M;Hargous N;Lapaillerie D;Bonneu M;Dechanet-Merville J;Legembre P;Capone M;Moreau JF;Taupin JL
配体FasL与其受体Fas的结合通过半胱天冬酶级联触发细胞凋亡。FasL本身是同源三聚体，并且产生性凋亡信号需要FasL寡聚化超过同源三聚体状态。我们通过将FasL融合到白血病抑制因子受体gp 190的赋予同型寡聚化的结构域来产生一系列FasL嵌合体，并分析了这些可溶性嵌合体触发细胞死亡的能力。我们观察到，最有效的FasL嵌合体，称为pFasL，也是最聚合的，因为它达到了十二聚体的大小。使用细胞模型，我们研究了我们的嵌合体的FasL/Fas相互作用的结构-功能关系，我们证明了Fas介导的凋亡信号并不完全依赖于配体介导的受体聚集，但也需要Fas受体的构象适应。当注射到小鼠中时，pFasL在移植到免疫缺陷动物的人肿瘤模型中显示出抗肿瘤活性的剂量下不会引发肝损伤，这表明了潜在的治疗用途。因此，FasL构象的优化是开发高效的FasL衍生的靶向Fas的抗癌药物所必须考虑的。
Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.
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影响因子：
13.5
作者：
Descamps, Delphyne;Vigant, Frederic;Benihoud, Karim
通讯作者：
Benihoud, Karim
影响因子：
24.5
作者：
Chida, Y;Sudo, N;Kubo, C
通讯作者：
Kubo, C
影响因子：
4.3
作者：
Schägger, H
通讯作者：
Schägger, H
影响因子：
3.7
作者：
CHEN, TR
通讯作者：
CHEN, TR
影响因子：
64.8
作者：
OGASAWARA, J;WATANABEFUKUNAGA, R;NAGATA, S
通讯作者：
NAGATA, S