Lipid raft connection between extrinsic and intrinsic apoptotic pathways
Lipid raft connection between extrinsic and intrinsic apoptotic pathways
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DOI：
10.1016/j.bbrc.2009.01.147
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发表时间：
2009-03-20
影响因子：
3.1
通讯作者：
Mollinedo, Faustino
中科院分区：
文献类型：
--
作者：
Gajate, Consuelo;Gonzalez-Camacho, Fernando;Mollinedo, Faustino
哺乳动物细胞的凋亡分别通过死亡受体介导的死亡诱导信号复合物（DISC）和细胞源性溶酶体的形成，受到外源性和内源性信号通路的调控。我们发现，通过超微结构的方法，抗肿瘤药物edelfosine诱导白血病细胞中含有Fas/CD 95受体和Fas相关的死亡结构域蛋白的脂筏聚集。在多发性骨髓瘤细胞中，依地福新治疗期间，死亡受体与DISC和溶酶体成分一起被招募到筏中。这种凋亡反应涉及半胱天冬酶-8/-9/-10易位到筏。胆固醇耗尽导致的脂筏破坏抑制了线粒体跨膜电位的丧失、半胱天冬酶的激活和细胞凋亡，而胆固醇补充则恢复了这些反应。我们的数据表明，筏作为外在和内在的凋亡信号通路集中的支架，形成凋亡信号分子富集的筏簇（CASMER），其作为新的超分子实体在触发凋亡中发挥作用，并在依地膦诱导的血癌细胞凋亡中发挥重要作用。(C)2009 Elsevier Inc. All rights reserved.
Apoptosis in mammalian cells is modulated by extrinsic and intrinsic signaling pathways through the formation of death receptor-mediated death-inducing signaling complex (DISC) and mitochondrial-derived apoptosome, respectively. We found by ultrastructural approaches that the antitumor drug edelfosine induced aggregates of lipid rafts containing Fas/CD95 receptor and Fas-associated death domain-containing protein in leukemic cells. Death receptors together with DISC and apoptosome constituents were recruited in rafts during edelfosine treatment in multiple myeloma cells. This apoptotic response involved caspases-8/-9/-10 that were translocated to rafts. Lipid raft disruption by cholesterol depletion inhibited loss of mitochondrial transmembrane potential, caspase activation and apoptosis, whereas cholesterol replenishment restored these responses. Our data indicate that rafts act as scaffolds where extrinsic and intrinsic apoptotic signaling pathways concentrate, forming Clusters of apoptotic signaling molecule-enriched rafts (CASMER), which function as novel supramolecular entities in the triggering of apoptosis, and play an important role in edelfosine-induced apoptosis in blood cancer cells. (C) 2009 Elsevier Inc. All rights reserved.