| Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. | |
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MedLine Citation:
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PMID: 15659383 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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While investigating the mechanism of action of the novel antitumor drug Aplidin, we have discovered a potent and novel cell-killing mechanism that involves the formation of Fas/CD95-driven scaffolds in membrane raft clusters housing death receptors and apoptosis-related molecules. Fas, tumor necrosis factor-receptor 1, and tumor necrosis factor-related apoptosis-inducing ligand receptor 2/death receptor 5 were clustered into lipid rafts in leukemic Jurkat cells following Aplidin treatment, the presence of Fas being essential for apoptosis. Preformed membrane-bound Fas ligand (FasL) as well as downstream signaling molecules, including Fas-associated death domain-containing protein, procaspase-8, procaspase-10, c-Jun amino-terminal kinase, and Bid, were also translocated into lipid rafts, connecting death receptor extrinsic and mitochondrial intrinsic apoptotic pathways. Blocking Fas/FasL interaction partially inhibited Aplidin-induced apoptosis. Aplidin was rapidly incorporated into membrane rafts, and drug uptake was inhibited by lipid raft disruption. Actin-linking proteins ezrin, moesin, RhoA, and RhoGDI were conveyed into Fas-enriched rafts in drug-treated leukemic cells. Disruption of lipid rafts and interference with actin cytoskeleton prevented Fas clustering and apoptosis. Thus, Aplidin-induced apoptosis involves Fas activation in both a FasL-independent way and, following Fas/FasL interaction, an autocrine way through the concentration of Fas, membrane-bound FasL, and signaling molecules in membrane rafts. These data indicate a major role of actin cytoskeleton in the formation of Fas caps and highlight the crucial role of the clusters of apoptotic signaling molecule-enriched rafts in apoptosis, acting as concentrators of death receptors and downstream signaling molecules and as the linchpin from which a potent death signal is launched. |
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Authors:
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Consuelo Gajate; Faustino Mollinedo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2005-01-19 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 280 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2005 Mar |
Date Detail:
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Created Date: 2005-03-21 Completed Date: 2005-04-21 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 11641-7 Citation Subset: IM |
Affiliation:
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Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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physiology Antigens, CD95 / physiology Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Cytoskeleton / physiology* Depsipeptides / pharmacology Fas Ligand Protein Humans Jurkat Cells Membrane Glycoproteins / metabolism* Membrane Microdomains / metabolism* Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor / metabolism* Receptors, Tumor Necrosis Factor, Type I / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/Antigens, CD95; 0/Antineoplastic Agents; 0/Depsipeptides; 0/FASLG protein, human; 0/Fas Ligand Protein; 0/Membrane Glycoproteins; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Receptors, Tumor Necrosis Factor; 0/Receptors, Tumor Necrosis Factor, Type I; 0/TNFRSF10B protein, human; 0/aplidine |
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