Department of Molecular, Cell and Cancer Biology
Cancer Biology | Cell Biology
IkappaB kinase/necrosis factor kappaB (IKK/NF-kappaB) 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-kappaB prevents liver disease and cancer. Here, we show that complete NF-kappaB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-kappaB 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-kappaB-dependent and -independent functions.
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Copyright 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Cancer Cell. 2015 Nov 9;28(5):582-98. doi: 10.1016/j.ccell.2015.10.001. Link to article on publisher's site
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 A.; and Pasparakis, Manolis, "NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis" (2015). Molecular, Cell and Cancer Biology Publications. 56.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.