TY - JOUR
T1 - TAK1 Suppresses a NEMO-Dependent but NF-κB-Independent Pathway to Liver Cancer
AU - Bettermann, Kira
AU - Vucur, Mihael
AU - Haybaeck, Johannes
AU - Koppe, Christiane
AU - Janssen, Jörn
AU - Heymann, Felix
AU - Weber, Achim
AU - Weiskirchen, Ralf
AU - Liedtke, Christian
AU - Gassler, Nikolaus
AU - Müller, Michael
AU - de Vos, Rita
AU - Wolf, Monika Julia
AU - Boege, Yannick
AU - Seleznik, Gitta Maria
AU - Zeller, Nicolas
AU - Erny, Daniel
AU - Fuchs, Thomas
AU - Zoller, Stefan
AU - Cairo, Stefano
AU - Buendia, Marie Annick
AU - Prinz, Marco
AU - Akira, Shizuo
AU - Tacke, Frank
AU - Heikenwalder, Mathias
AU - Trautwein, Christian
AU - Luedde, Tom
N1 - Funding Information:
We thank K. Kreggenwinkel, S. Behnke, B. Riepl, and Prof. Seifert for excellent technical assistance. This work was supported by grants from the European Research Council within the FP-7 (ERC-2007-Stg/208237-Luedde-Med3-Aachen, to T.L.), the German-Research-Foundation (SFB/TRR57, Project P06; P09; Ta434/2-1, to T.L. and F.T.), the Ernst-Jung-Foundation/Hamburg (to T.L.), the Interdisciplinary-Centre-for-Clinical-Research “BIOMAT” at the RWTH/Aachen (to T.L.), the Oncosuisse Foundation (OCS 02113-08-2007 to M.H.), the Julius-Müller Foundation (to M.H.), the Novartis Foundation for Biomedical Research (EMDO to M.H. and Y.B.), and the Prof. Dr. Max Cloëtta Foundation (to M.H.).
PY - 2010/5/18
Y1 - 2010/5/18
N2 - The MAP3-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.
AB - The MAP3-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.
KW - CELLCYCLE
UR - https://www.scopus.com/pages/publications/77952107213
U2 - 10.1016/j.ccr.2010.03.021
DO - 10.1016/j.ccr.2010.03.021
M3 - Article
C2 - 20478530
AN - SCOPUS:77952107213
SN - 1535-6108
VL - 17
SP - 481
EP - 496
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -