Author/Authors :
Bettermann، نويسنده , , Kira and Vucur، نويسنده , , Mihael and Haybaeck، نويسنده , , Johannes and Koppe، نويسنده , , Christiane and Janssen، نويسنده , , Jِrn and Heymann، نويسنده , , Felix and Weber، نويسنده , , Achim and Weiskirchen، نويسنده , , Ralf and Liedtke، نويسنده , , Christian and Gassler، نويسنده , , Nikolaus and Müller، نويسنده , , Michael and de Vos، نويسنده , , Rita and Wolf، نويسنده , , Monika Julia and Boege، نويسنده , , Yannick and Seleznik، نويسنده , , Gitta Maria and Zeller، نويسنده , , Nicolas and Erny، نويسنده , , Daniel and Fuchs، نويسنده , , Thomas and Zoller، نويسنده , , Stefan and Cairo، نويسنده , , Stefano and Buendia، نويسنده , , Marie-Annick and Prinz، نويسنده , , Marco and Akira، نويسنده , , Shizuo and Tacke، نويسنده , , Frank and Heikenwalder، نويسنده , , Mathias and Trautwein، نويسنده , , Christian and Luedde، نويسنده , , Tom، نويسنده ,
Abstract :
Summary
P3-kinase TGF-β-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-κB 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-κB-independent functions of the IκB-kinase (IKK)-subunit NF-κB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-κB-independent function of NEMO in parenchymal liver cells.
