RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer.

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Abstract

Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.

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Author and article information

Journal

Journal ID (iso-abbrev): Cancer Cell

Title: Cancer cell

Publisher: Elsevier BV

ISSN (Electronic): 1878-3686

ISSN (Print): 1535-6108

Publication date (Electronic): Jan 09 2017

Volume: 31

Issue: 1

Affiliations

[1 ] Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.

[2 ] Department of Dermatology and Allergology, RWTH Aachen University, 52074 Aachen, Germany.

[3 ] Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.

[4 ] Department of Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.

[5 ] Department of Medical Biology, Walter and Eliza Hall Institute of Medical Research and University of Melbourne, Parkville, VIC 3050/3052, Australia.

[6 ] Department of Visceral and Transplantation Surgery, RWTH Aachen University, 52074 Aachen, Germany.

[7 ] Department of Laboratory Animal Research, RWTH Aachen University, 52074 Aachen, Germany.

[8 ] Department of Cardiology, University Hospital, 24105 Kiel, Germany.

[9 ] INSERM, UMR-1162, Functional Genomic of Solid Tumors, 75010 Paris, France.

[10 ] Proteomics Facility, IZKF, RWTH Aachen University, 52074 Aachen, Germany.

[11 ] Department of Pathology, RWTH Aachen University, 52074 Aachen, Germany.

[12 ] Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: mvucur@ukaachen.de.

[13 ] Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: tluedde@ukaachen.de.

Article

Publisher Item ID: S1535-6108(16)30552-9

DOI: 10.1016/j.ccell.2016.11.009

PubMed ID: 28017612

SO-VID: b01d4e57-4a5b-4a93-b0e1-1df700f4d99f

History

Keywords: HCC,necroptosis,hepatocarcinogenesis,caspase-8,cIAP-1,apoptosis,RIPK3,RIP3,RIP1,NF-κB

Data availability:

Keywords: HCC, necroptosis, hepatocarcinogenesis, caspase-8, cIAP-1, apoptosis, RIPK3, RIP3, RIP1, NF-κB

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