TAK1: Another mesh in the NF-κB - JNK controlled network causing hepatocellular carcinoma

Florian R Greten

doi:10.1016/j.jhep.2011.02.037

TAK1: Another mesh in the NF-κB - JNK controlled network causing hepatocellular carcinoma

J Hepatol. 2011 Sep;55(3):721-723. doi: 10.1016/j.jhep.2011.02.037. Epub 2011 May 10.

Author

Florian R Greten¹

Affiliation

¹ Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675 Munich, Germany. Electronic address: florian.greten@lrz.tum.de.

PMID: 21601601
DOI: 10.1016/j.jhep.2011.02.037

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 of 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.

MeSH terms

Animals
Carcinoma, Hepatocellular / etiology*
Cell Transformation, Neoplastic / metabolism*
I-kappa B Kinase / physiology*
JNK Mitogen-Activated Protein Kinases / metabolism
Liver Neoplasms, Experimental / etiology*
MAP Kinase Kinase Kinases / physiology*
MAP Kinase Signaling System
Mice
NF-kappa B / metabolism

Substances

NF-kappa B
I-kappa B Kinase
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7