| First Author | Kondylis V | Year | 2015 |
| Journal | Cancer Cell | Volume | 28 |
| Issue | 5 | Pages | 582-598 |
| PubMed ID | 26555174 | Mgi Jnum | J:226752 |
| Mgi Id | MGI:5698536 | Doi | 10.1016/j.ccell.2015.10.001 |
| Citation | Kondylis V, et al. (2015) NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer Cell 28(5):582-98 |
| abstractText | 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. |
