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 Cairo; Marie-Annick Buendia; Marco Prinz; Shizuo Akira; Frank Tacke; Mathias Heikenwalder; Christian Trautwein; Tom Luedde

doi:10.1016/j.ccr.2010.03.021

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

Research output: Contribution to journal › Article › peer-review

191 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 language	English
Pages (from-to)	481-496
Number of pages	16
Journal	Cancer Cell
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.03.021
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccr.2010.03.021

Cite this

Bettermann, K., Vucur, M., Haybaeck, J., Koppe, C., Janssen, J., Heymann, F., Weber, A., Weiskirchen, R., Liedtke, C., Gassler, N., Müller, M., de Vos, R., Wolf, M. J., Boege, Y., Seleznik, G. M., Zeller, N., Erny, D., Fuchs, T., Zoller, S., ... Luedde, T. (2010). TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell, 17(5), 481-496. https://doi.org/10.1016/j.ccr.2010.03.021

@article{61aa4ff68e3b498a960acb3531ef3234,

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.",

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",

author = "Kira Bettermann and Mihael Vucur and Johannes Haybaeck and Christiane Koppe and J{\"o}rn Janssen and Felix Heymann and Achim Weber and Ralf Weiskirchen and Christian Liedtke and Nikolaus Gassler and Michael M{\"u}ller and {de Vos}, Rita and Wolf, {Monika Julia} and Yannick Boege and Seleznik, {Gitta Maria} and Nicolas Zeller and Daniel Erny and Thomas Fuchs and Stefan Zoller and Stefano Cairo and Marie-Annick Buendia and Marco Prinz and Shizuo Akira and Frank Tacke and Mathias Heikenwalder and Christian Trautwein and Tom Luedde",

year = "2010",

month = may,

day = "18",

doi = "10.1016/j.ccr.2010.03.021",

language = "English",

volume = "17",

pages = "481--496",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Bettermann, K, Vucur, M, Haybaeck, J, Koppe, C, Janssen, J, Heymann, F, Weber, A, Weiskirchen, R, Liedtke, C, Gassler, N, Müller, M, de Vos, R, Wolf, MJ, Boege, Y, Seleznik, GM, Zeller, N, Erny, D, Fuchs, T, Zoller, S, Cairo, S, Buendia, M-A, Prinz, M, Akira, S, Tacke, F, Heikenwalder, M, Trautwein, C & Luedde, T 2010, 'TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer', Cancer Cell, vol. 17, no. 5, pp. 481-496. https://doi.org/10.1016/j.ccr.2010.03.021

TY - JOUR

T1 - TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer

AU - Bettermann, Kira

AU - Vucur, Mihael

AU - Haybaeck, Johannes

AU - Koppe, Christiane

AU - Janssen, Jörn

AU - Heymann, Felix

AU - Weber, Achim

AU - Weiskirchen, Ralf

AU - Liedtke, Christian

AU - Gassler, Nikolaus

AU - Müller, Michael

AU - de Vos, Rita

AU - Wolf, Monika Julia

AU - Boege, Yannick

AU - Seleznik, Gitta Maria

AU - Zeller, Nicolas

AU - Erny, Daniel

AU - Fuchs, Thomas

AU - Zoller, Stefan

AU - Cairo, Stefano

AU - Buendia, Marie-Annick

AU - Prinz, Marco

AU - Akira, Shizuo

AU - Tacke, Frank

AU - Heikenwalder, Mathias

AU - Trautwein, Christian

AU - Luedde, Tom

PY - 2010/5/18

Y1 - 2010/5/18

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Cell Transformation, Neoplastic

KW - Hyperplasia

KW - Intracellular Signaling Peptides and Proteins

KW - Liver Neoplasms, Experimental

KW - MAP Kinase Kinase Kinases

KW - Mice

KW - Mice, Transgenic

KW - NF-kappa B

KW - Necrosis

U2 - 10.1016/j.ccr.2010.03.021

DO - 10.1016/j.ccr.2010.03.021

M3 - Article

C2 - 20478530

VL - 17

SP - 481

EP - 496

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -