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dc.contributor.authorKondylis, Vangelis
dc.contributor.authorPolykratis, Apostolos
dc.contributor.authorEhlken, Hanno
dc.contributor.authorOchoa-Callejero, Laura
dc.contributor.authorStraub, Beate Katharina
dc.contributor.authorKrishna-Subramanian, Santosh
dc.contributor.authorVan, Trieu-My
dc.contributor.authorCurth, Harald-Morten
dc.contributor.authorHeise, Nicole
dc.contributor.authorWeih, Falk
dc.contributor.authorKlein, Ulf
dc.contributor.authorSchirmacher, Peter
dc.contributor.authorKelliher, Michelle A.
dc.contributor.authorPasparakis, Manolis
dc.date2022-08-11T08:09:19.000
dc.date.accessioned2022-08-23T16:26:24Z
dc.date.available2022-08-23T16:26:24Z
dc.date.issued2015-11-09
dc.date.submitted2015-12-03
dc.identifier.citationCancer Cell. 2015 Nov 9;28(5):582-98. doi: 10.1016/j.ccell.2015.10.001. <a href="http://dx.doi.org/10.1016/j.ccell.2015.10.001">Link to article on publisher's site</a>
dc.identifier.issn1535-6108 (Linking)
dc.identifier.doi10.1016/j.ccell.2015.10.001
dc.identifier.pmid26555174
dc.identifier.urihttp://hdl.handle.net/20.500.14038/36558
dc.description.abstractIkappaB 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26555174&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.ccell.2015.10.001
dc.rights<p>Copyright 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (<a href="http://creativecommons.org/licenses/by-nc-nd/4.0/" target="_blank">http://creativecommons.org/licenses/by-nc-nd/4.0/</a>).</p>
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCancer Biology
dc.subjectCell Biology
dc.titleNEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis
dc.typeJournal Article
dc.source.journaltitleCancer cell
dc.source.volume28
dc.source.issue5
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1056&amp;context=mccb_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/mccb_pubs/56
dc.identifier.contextkey7900004
refterms.dateFOA2022-08-23T16:26:25Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathmccb_pubs/56
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.source.pages582-98


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<p>Copyright 2015 The Authors.  Published by Elsevier Inc.  This is an open access article under the CC BY-NC-ND license (<a href="http://creativecommons.org/licenses/by-nc-nd/4.0/" target="_blank">http://creativecommons.org/licenses/by-nc-nd/4.0/</a>).</p>
Except where otherwise noted, this item's license is described as <p>Copyright 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (<a href="http://creativecommons.org/licenses/by-nc-nd/4.0/" target="_blank">http://creativecommons.org/licenses/by-nc-nd/4.0/</a>).</p>