RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer
Open accessAbstract
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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Proteasomal degradation of TRAF2 appears to be prevented (at least in hepatocytes) by RIPK1, independently of its kinase activity.
“To add a further layer of complexity, the proteasomal degradation of TRAF2 appears to be prevented (at least in hepatocytes) by RIPK1, independently of its kinase activity [340, 341].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [340]
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- Authors
- Schneider, A. T., Gautheron, J., Feoktistova, M., Roderburg, C., Loosen, S. H., Roy, S., Benz, F., Schemmer, P., Büchler, M. W., Nachbur, U., Neumann, U. P., Tolba, R., Luedde, M., Zucman-Rossi, J., Panayotova-Dimitrova, D., Leverkus, M., Preisinger, C., Tacke, F., Trautwein, C., Longerich, T., Vucur, M., & Luedde, T.
- Affiliations
- RWTH Aachen University (DE)
- Heidelberg University (DE)
- The University of Melbourne (AU)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Vucur, Mihael
- Luedde, Tom
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 31
- Issue
- 1
- Pages
- 94-109
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2564880418
- Cited by
- 155
- References
- 50
- Citations by year
- 2025: 12 · 2024: 20 · 2023: 33 · 2022: 11 · 2021: 16 · 2020: 16 · 2019: 18 · 2018: 16 · 2017: 13
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Krebshilfe (110885)
- DFG (LU 1360/3-1, SFB-TRR57/P06, LO-1676-2/1)
- IZKF
- Ernst-Jung-Foundation Hamburg
- RWTH Aachen university
- National Center for Tumor Diseases Heidelberg
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- RIPK1, TRAF2, hepatocellular carcinoma, hepatocarcinogenesis, caspase-8 activation, NF-κB activation, proteasomal degradation, E3 ubiquitin ligase, liver parenchymal cells, cancer prognosis, kinase-independent signaling
- MeSH terms
- Animals, Humans, Liver Neoplasms, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, NF-kappa B, Hepatocytes, Proteasome Endopeptidase Complex, TNF Receptor-Associated Factor 2, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases
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