TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer

Bettermann, Kira, Vucur, Mihael, Haybaeck, Johannes, Koppe, Christiane, Janssen, Jörn, Heymann, Felix, Weber, Achim, Weiskirchen, Ralf, Liedtke, Christian, Gassler, Nikolaus, Müller, Michael, de Vos, Rita, Wolf, Monika Julia, Boege, Yannick, Seleznik, Gitta Maria, Zeller, Nicolas, Erny, Daniel, Fuchs, Thomas, Zoller, Stefan, Cairo, Stefano, Buendia, Marie-Annick, Prinz, Marco, Akira, Shizuo, Tacke, Frank, Heikenwalder, Mathias, Trautwein, Christian and Luedde, Tom (2010) TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell, 17 (5). pp. 481-496. ISSN 1878-3686

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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.

Item Type: Article
Additional Information: (c) 2010 Elsevier Inc. All rights reserved.
Uncontrolled Keywords: animals,apoptosis,cell transformation, neoplastic,hyperplasia,intracellular signaling peptides and proteins,liver neoplasms, experimental,map kinase kinase kinases,mice,mice, transgenic,nf-kappa b,necrosis
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 20:50
Last Modified: 21 Apr 2020 22:52
URI: https://ueaeprints.uea.ac.uk/id/eprint/47680
DOI: 10.1016/j.ccr.2010.03.021

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