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NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis

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NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. / Kondylis, Vangelis; Polykratis, Apostolos; Ehlken, Hanno; Ochoa-Callejero, Laura; Straub, Beate Katharina; Krishna-Subramanian, Santosh; Van, Trieu-My; Curth, Harald-Morten; Heise, Nicole; Weih, Falk; Klein, Ulf; Schirmacher, Peter; Kelliher, Michelle; Pasparakis, Manolis.

In: CANCER CELL, Vol. 28, No. 5, 09.11.2015, p. 582-98.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kondylis, V, Polykratis, A, Ehlken, H, Ochoa-Callejero, L, Straub, BK, Krishna-Subramanian, S, Van, T-M, Curth, H-M, Heise, N, Weih, F, Klein, U, Schirmacher, P, Kelliher, M & Pasparakis, M 2015, 'NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis', CANCER CELL, vol. 28, no. 5, pp. 582-98. https://doi.org/10.1016/j.ccell.2015.10.001

APA

Kondylis, V., Polykratis, A., Ehlken, H., Ochoa-Callejero, L., Straub, B. K., Krishna-Subramanian, S., Van, T-M., Curth, H-M., Heise, N., Weih, F., Klein, U., Schirmacher, P., Kelliher, M., & Pasparakis, M. (2015). NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. CANCER CELL, 28(5), 582-98. https://doi.org/10.1016/j.ccell.2015.10.001

Vancouver

Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S et al. NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. CANCER CELL. 2015 Nov 9;28(5):582-98. https://doi.org/10.1016/j.ccell.2015.10.001

Bibtex

@article{85da785132824ba38a734f5525ac3494,
title = "NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis",
abstract = "IκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.",
author = "Vangelis Kondylis and Apostolos Polykratis and Hanno Ehlken and Laura Ochoa-Callejero and Straub, {Beate Katharina} and Santosh Krishna-Subramanian and Trieu-My Van and Harald-Morten Curth and Nicole Heise and Falk Weih and Ulf Klein and Peter Schirmacher and Michelle Kelliher and Manolis Pasparakis",
note = "Copyright {\textcopyright} 2015 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2015",
month = nov,
day = "9",
doi = "10.1016/j.ccell.2015.10.001",
language = "English",
volume = "28",
pages = "582--98",
journal = "CANCER CELL",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis

AU - Kondylis, Vangelis

AU - Polykratis, Apostolos

AU - Ehlken, Hanno

AU - Ochoa-Callejero, Laura

AU - Straub, Beate Katharina

AU - Krishna-Subramanian, Santosh

AU - Van, Trieu-My

AU - Curth, Harald-Morten

AU - Heise, Nicole

AU - Weih, Falk

AU - Klein, Ulf

AU - Schirmacher, Peter

AU - Kelliher, Michelle

AU - Pasparakis, Manolis

N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2015/11/9

Y1 - 2015/11/9

N2 - IκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.

AB - IκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.

U2 - 10.1016/j.ccell.2015.10.001

DO - 10.1016/j.ccell.2015.10.001

M3 - SCORING: Journal article

C2 - 26555174

VL - 28

SP - 582

EP - 598

JO - CANCER CELL

JF - CANCER CELL

SN - 1535-6108

IS - 5

ER -