Abstract:
:The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Bettermann K,Vucur M,Haybaeck J,Koppe C,Janssen J,Heymann F,Weber A,Weiskirchen R,Liedtke C,Gassler N,Müller M,de Vos R,Wolf MJ,Boege Y,Seleznik GM,Zeller N,Erny D,Fuchs T,Zoller S,Cairo S,Buendia MA,Prinz M,Adoi
10.1016/j.ccr.2010.03.021subject
Has Abstractpub_date
2010-05-18 00:00:00pages
481-96issue
5eissn
1535-6108issn
1878-3686pii
S1535-6108(10)00148-0journal_volume
17pub_type
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