Universität zu Köln

Van, Trieu-My, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Straub, Beate Katharina, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Papadopoulou, Nikoletta and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2017). Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis. J. Clin. Invest., 127 (7). S. 2662 - 2678. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF receptor 1 (TNFR1) signaling. In contrast, mice with LPC-specific knockout of Ripk1 showed reduced diethylnitrosamine-induced (DEN-induced) liver tumorigenesis that correlated with increased DEN-induced hepatocyte apoptosis. Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, showing that kinase-independent functions of RIPK1 promote DEN-induced hepatocarcinogenesis. Moreover, mice lacking both RIPK1 and TNFR1 in LPCs displayed normal tumor formation in response to DEN, demonstrating that RIPK1 deficiency decreases DEN-induced liver tumor formation in a TNFR1-dependent manner. Therefore, these findings indicate that RIPK1 cooperates with NF-kappa B signaling to prevent TNFR1-independent hepatocyte apoptosis and the development of chronic liver disease and cancer, but acts downstream of TNFR1 signaling to promote DEN-induced liver tumorigenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Van, Trieu-My UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Straub, Beate Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Papadopoulou, Nikoletta UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-227158
DOI:	10.1172/JCI92508
Journal or Publication Title:	J. Clin. Invest.
Volume:	127
Number:	7
Page Range:	S. 2662 - 2678
Date:	2017
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; CELL-DEATH; HEPATOCELLULAR-CARCINOMA; PROTECTS MICE; DNA-DAMAGE; APOPTOSIS; NECROPTOSIS; HEPATOCARCINOGENESIS; INFLAMMATION; HOMEOSTASIS Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22715