The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.
Mol Cell
; 43(3): 432-48, 2011 Aug 05.
Article
en En
| MEDLINE
| ID: mdl-21737329
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 â¼2MDa 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Daño del ADN
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Proteínas de Unión al ARN
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Apoptosis
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Proteínas de Complejo Poro Nuclear
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Proteínas Inhibidoras de la Apoptosis
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Caspasa 8
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Proteína de Dominio de Muerte Asociada a Fas
Límite:
Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2011
Tipo del documento:
Article
País de afiliación:
Reino Unido