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

K. Bettermann; M. Vucur; J. Haybaeck; C. Koppe; J. Janssen; F. Heymann; A. Weber; R. Weiskirchen; C. Liedtke; N. Gassler; M.R. Müller; R. de Vos; M.J. Wolf; Y. Boege; G.M. Seleznik; N. Zeller; D. Erny; T. Fuchs; S. Zoller; S. Cairo; M.A. Buendia; M. Prinz; S. Akira; F. Tacke; M. Heikenwalder; C. Trautwein; T. Luedde

doi:10.1016/j.ccr.2010.03.021

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

K. Bettermann, M. Vucur, J. Haybaeck, C. Koppe, J. Janssen, F. Heymann, A. Weber, R. Weiskirchen, C. Liedtke, N. Gassler, M.R. Müller, R. de Vos, M.J. Wolf, Y. Boege, G.M. Seleznik, N. Zeller, D. Erny, T. Fuchs, S. Zoller, S. CairoM.A. Buendia, M. Prinz, S. Akira, F. Tacke, M. Heikenwalder, C. Trautwein, T. Luedde

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

192 Citations (Scopus)

Abstract

The MAP3-kinase TGF-ß-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-¿B 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-¿B-independent functions of the I¿B-kinase (IKK)-subunit NF-¿B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-¿B-independent function of NEMO in parenchymal liver cells.

Original language	English
Pages (from-to)	481-496
Journal	Cancer Cell
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.03.021
Publication status	Published - 2010

Keywords

hepatocellular-carcinoma
chemical hepatocarcinogenesis
protein-kinases
activation
mice
inflammation
injury
cell
jnk
hepatocytes

UN SDGs

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

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Bettermann, K., Vucur, M., Haybaeck, J., Koppe, C., Janssen, J., Heymann, F., Weber, A., Weiskirchen, R., Liedtke, C., Gassler, N., Müller, M. R., 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-kB-independent pathway to liver cancer. Cancer Cell, 17(5), 481-496. https://doi.org/10.1016/j.ccr.2010.03.021

@article{09f2d23d95694a2ea9587a5d4a190706,

title = "TAK1 suppresses a NEMO-dependent but NF-kB-independent pathway to liver cancer",

abstract = "The MAP3-kinase TGF-{\ss}-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-¿B 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-¿B-independent functions of the I¿B-kinase (IKK)-subunit NF-¿B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-¿B-independent function of NEMO in parenchymal liver cells.",

keywords = "hepatocellular-carcinoma, chemical hepatocarcinogenesis, protein-kinases, activation, mice, inflammation, injury, cell, jnk, hepatocytes",

author = "K. Bettermann and M. Vucur and J. Haybaeck and C. Koppe and J. Janssen and F. Heymann and A. Weber and R. Weiskirchen and C. Liedtke and N. Gassler and M.R. M{\"u}ller and {de Vos}, R. and M.J. Wolf and Y. Boege and G.M. Seleznik and N. Zeller and D. Erny and T. Fuchs and S. Zoller and S. Cairo and M.A. Buendia and M. Prinz and S. Akira and F. Tacke and M. Heikenwalder and C. Trautwein and T. Luedde",

year = "2010",

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

language = "English",

volume = "17",

pages = "481--496",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Elsevier",

number = "5",

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Bettermann, K, Vucur, M, Haybaeck, J, Koppe, C, Janssen, J, Heymann, F, Weber, A, Weiskirchen, R, Liedtke, C, Gassler, N, Müller, MR, de Vos, R, Wolf, MJ, Boege, Y, Seleznik, GM, Zeller, N, Erny, D, Fuchs, T, Zoller, S, Cairo, S, Buendia, MA, Prinz, M, Akira, S, Tacke, F, Heikenwalder, M, Trautwein, C & Luedde, T 2010, 'TAK1 suppresses a NEMO-dependent but NF-kB-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-kB-independent pathway to liver cancer

AU - Bettermann, K.

AU - Vucur, M.

AU - Haybaeck, J.

AU - Koppe, C.

AU - Janssen, J.

AU - Heymann, F.

AU - Weber, A.

AU - Weiskirchen, R.

AU - Liedtke, C.

AU - Gassler, N.

AU - Müller, M.R.

AU - de Vos, R.

AU - Wolf, M.J.

AU - Boege, Y.

AU - Seleznik, G.M.

AU - Zeller, N.

AU - Erny, D.

AU - Fuchs, T.

AU - Zoller, S.

AU - Cairo, S.

AU - Buendia, M.A.

AU - Prinz, M.

AU - Akira, S.

AU - Tacke, F.

AU - Heikenwalder, M.

AU - Trautwein, C.

AU - Luedde, T.

PY - 2010

Y1 - 2010

N2 - The MAP3-kinase TGF-ß-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-¿B 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-¿B-independent functions of the I¿B-kinase (IKK)-subunit NF-¿B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-¿B-independent function of NEMO in parenchymal liver cells.

AB - The MAP3-kinase TGF-ß-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-¿B 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-¿B-independent functions of the I¿B-kinase (IKK)-subunit NF-¿B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-¿B-independent function of NEMO in parenchymal liver cells.

KW - hepatocellular-carcinoma

KW - chemical hepatocarcinogenesis

KW - protein-kinases

KW - activation

KW - mice

KW - inflammation

KW - injury

KW - cell

KW - jnk

KW - hepatocytes

U2 - 10.1016/j.ccr.2010.03.021

DO - 10.1016/j.ccr.2010.03.021

M3 - Article

SN - 1535-6108

VL - 17

SP - 481

EP - 496

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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