TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.
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.
Bettermann
Kira
K
Department of Internal Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
Vucur
Mihael
M
Haybaeck
Johannes
J
Koppe
Christiane
C
Janssen
Jörn
J
Heymann
Felix
F
Weber
Achim
A
Weiskirchen
Ralf
R
Liedtke
Christian
C
Gassler
Nikolaus
N
Müller
Michael
M
de Vos
Rita
R
Wolf
Monika Julia
MJ
Boege
Yannick
Y
Seleznik
Gitta Maria
GM
Zeller
Nicolas
N
Erny
Daniel
D
Fuchs
Thomas
T
Zoller
Stefan
S
Cairo
Stefano
S
Buendia
Marie-Annick
MA
Prinz
Marco
M
Akira
Shizuo
S
Tacke
Frank
F
Heikenwalder
Mathias
M
Trautwein
Christian
C
Luedde
Tom
T
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
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