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Mol Cell. 2011 Aug 5;43(3):432-48. doi: 10.1016/j.molcel.2011.06.006. Epub 2011 Jul 7.

The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.

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  • 1The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK. tencho.tenev@icr.ac.uk

Erratum in

  • Mol Cell. 2011 Aug 19;43(4):689.

Abstract

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

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PMID:
21737329
[PubMed - indexed for MEDLINE]
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