title: TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.
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.
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
authors.forename: Kira
authors.initials: K
authors.lastname: Bettermann
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Christiane
authors.initials: C
authors.lastname: Koppe
authors.forename: Jörn
authors.initials: J
authors.lastname: Janssen
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Rita
authors.initials: R
authors.lastname: de Vos
authors.forename: Monika Julia
authors.initials: MJ
authors.lastname: Wolf
authors.forename: Yannick
authors.initials: Y
authors.lastname: Boege
authors.forename: Gitta Maria
authors.initials: GM
authors.lastname: Seleznik
authors.forename: Nicolas
authors.initials: N
authors.lastname: Zeller
authors.forename: Daniel
authors.initials: D
authors.lastname: Erny
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.forename: Stefan
authors.initials: S
authors.lastname: Zoller
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.forename: Marie-Annick
authors.initials: MA
authors.lastname: Buendia
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
mesh_terms: D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7; C514981:NEMO protein, mouse