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Göteborgs universitets publikationer

The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIP L turnover

Författare och institution:
Lufen Chang (-); Hideaki Kamata (-); Giovanni Solinas (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Jun-Li Luo (-); Shin Maeda (-); K Venuprasad (-); Yun-Cai Liu (-); Michael Karin (-)
Publicerad i:
Cell, 124 ( 3 ) s. 601-613
ISSN:
0092-8674
E-ISSN:
1097-4172
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2006
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
The proinflammatory cytokine tumor necrosis factor (TNF) α signals both cell survival and death. The biological outcome of TNFα treatment is determined by the balance between NF-κB and Jun kinase (JNK) signaling; NF-κB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFα-induced apoptosis has been outstanding. Here we show that TNFα-mediated JNK activation accelerates turnover of the NF-κB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFα-induced acute liver failure, and cells from these mice do not display inducible c-FLIPL ubiquitination and degradation. Thus, JNK antagonizes NF-κB during TNFα signaling by promoting the proteasomal elimination of c-FLIPL.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper
Postens nummer:
241732
Posten skapad:
2016-09-13 16:49

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