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

Kira Bettermann, Mihael Vucur, Johannes Haybaeck, Christiane Koppe, Jörn Janssen, Felix Heymann, Achim Weber, Ralf Weiskirchen, Christian Liedtke, Nikolaus Gassler, Michael Müller, Rita de Vos, Monika Julia Wolf, Yannick Boege, Gitta Maria Seleznik, Nicolas Zeller, Daniel Erny, Thomas Fuchs, Stefan Zoller, Stefano CairoMarie-Annick Buendia, Marco Prinz, Shizuo Akira, Frank Tacke, Mathias Heikenwalder, Christian Trautwein, Tom Luedde

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171 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)481-496
Number of pages16
JournalCancer Cell
Volume17
Issue number5
DOIs
Publication statusPublished - 18 May 2010

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

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