| The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. | |
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MedLine Citation:
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PMID: 21737329 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ∼2MDa cell death-inducing platform, referred to as "Ripoptosome." It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells. |
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Authors:
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Tencho Tenev; Katiuscia Bianchi; Maurice Darding; Meike Broemer; Claudia Langlais; Fredrik Wallberg; Anna Zachariou; Juanita Lopez; Marion MacFarlane; Kelvin Cain; Pascal Meier |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-07-07 |
Journal Detail:
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Title: Molecular cell Volume: 43 ISSN: 1097-4164 ISO Abbreviation: Mol. Cell Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-05 Completed Date: 2011-10-10 Revised Date: 2011-10-25 |
Medline Journal Info:
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Nlm Unique ID: 9802571 Medline TA: Mol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 432-48 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK. tencho.tenev@icr.ac.uk |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Apoptosis / drug effects, physiology* CASP8 and FADD-Like Apoptosis Regulating Protein / genetics, metabolism, physiology Caspase 8 / chemistry, metabolism, physiology* Cell Line, Tumor DNA Damage* Enzyme Activation Etoposide / pharmacology Fas-Associated Death Domain Protein / chemistry, metabolism, physiology* Humans Inhibitor of Apoptosis Proteins / genetics*, physiology Ligands Mitochondria / metabolism Nuclear Pore Complex Proteins / chemistry, metabolism, physiology* RNA-Binding Proteins / chemistry, metabolism, physiology* Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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0/AGFG1 protein, human; 0/Antineoplastic Agents; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/FADD protein, human; 0/Fas-Associated Death Domain Protein; 0/Inhibitor of Apoptosis Proteins; 0/Ligands; 0/Nuclear Pore Complex Proteins; 0/RNA-Binding Proteins; 33419-42-0/Etoposide; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8 |
| Comments/Corrections | |
Comment In:
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Nat Rev Mol Cell Biol. 2011 Sep;12(9):547
[PMID:
21850033
]
Mol Cell. 2011 Aug 5;43(3):323-5 [PMID: 21816342 ] |
Erratum In:
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Mol Cell. 2011 Aug 19;43(4):689 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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