RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Anne T. Schneider; Jérémie Gautheron; Maria Feoktistova; Christoph Roderburg; Sven H. Loosen; Sanchari Roy; Fabian Benz; Peter Schemmer; Markus W. Büchler; Ueli Nachbur; Ulf P. Neumann; Rene Tolba; Mark Luedde; Jessica Zucman-Rossi; Diana Panayotova-Dimitrova; Martin Leverkus; Christian Preisinger; Frank Tacke; Christian Trautwein; Thomas Longerich; Mihael Vucur; Tom Luedde

doi:10.1016/j.ccell.2016.11.009

RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Anne T. Schneider, Jérémie Gautheron, Maria Feoktistova, Christoph Roderburg, Sven H. Loosen, Sanchari Roy, Fabian Benz, Peter Schemmer, Markus W. Büchler, Ueli Nachbur, Ulf P. Neumann, Rene Tolba, Mark Luedde, Jessica Zucman-Rossi, Diana Panayotova-Dimitrova, Martin Leverkus, Christian Preisinger, Frank Tacke, Christian Trautwein, Thomas LongerichMihael Vucur, Tom Luedde

Research output: Contribution to journal › Article › peer-review

119 Scopus citations

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.

Original language	English
Pages (from-to)	94-109
Number of pages	16
Journal	Cancer Cell
Volume	31
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.11.009
State	Published - 9 Jan 2017
Externally published	Yes

Keywords

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

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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., ... Luedde, T. (2017). RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. Cancer Cell, 31(1), 94-109. https://doi.org/10.1016/j.ccell.2016.11.009

@article{d170b762afb94526b43d08a34ee3fb34,

title = "RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer",

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.",

keywords = "HCC, NF-κB, RIP1, RIP3, RIPK3, apoptosis, cIAP-1, caspase-8, hepatocarcinogenesis, necroptosis",

author = "Schneider, {Anne T.} and J{\'e}r{\'e}mie Gautheron and Maria Feoktistova and Christoph Roderburg and Loosen, {Sven H.} and Sanchari Roy and Fabian Benz and Peter Schemmer and B{\"u}chler, {Markus W.} and Ueli Nachbur and Neumann, {Ulf P.} and Rene Tolba and Mark Luedde and Jessica Zucman-Rossi and Diana Panayotova-Dimitrova and Martin Leverkus and Christian Preisinger and Frank Tacke and Christian Trautwein and Thomas Longerich and Mihael Vucur and Tom Luedde",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jan,

day = "9",

doi = "10.1016/j.ccell.2016.11.009",

language = "English",

volume = "31",

pages = "94--109",

journal = "Cancer Cell",

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Schneider, AT, Gautheron, J, Feoktistova, M, Roderburg, C, Loosen, SH, Roy, S, Benz, F, Schemmer, P, Büchler, MW, Nachbur, U, Neumann, UP, Tolba, R, Luedde, M, Zucman-Rossi, J, Panayotova-Dimitrova, D, Leverkus, M, Preisinger, C, Tacke, F, Trautwein, C, Longerich, T, Vucur, M & Luedde, T 2017, 'RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer', Cancer Cell, vol. 31, no. 1, pp. 94-109. https://doi.org/10.1016/j.ccell.2016.11.009

TY - JOUR

T1 - RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

AU - Schneider, Anne T.

AU - Gautheron, Jérémie

AU - Feoktistova, Maria

AU - Roderburg, Christoph

AU - Loosen, Sven H.

AU - Roy, Sanchari

AU - Benz, Fabian

AU - Schemmer, Peter

AU - Büchler, Markus W.

AU - Nachbur, Ueli

AU - Neumann, Ulf P.

AU - Tolba, Rene

AU - Luedde, Mark

AU - Zucman-Rossi, Jessica

AU - Panayotova-Dimitrova, Diana

AU - Leverkus, Martin

AU - Preisinger, Christian

AU - Tacke, Frank

AU - Trautwein, Christian

AU - Longerich, Thomas

AU - Vucur, Mihael

AU - Luedde, Tom

PY - 2017/1/9

Y1 - 2017/1/9

N2 - 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.

AB - 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.

KW - HCC

KW - NF-κB

KW - RIP1

KW - RIP3

KW - RIPK3

KW - apoptosis

KW - cIAP-1

KW - caspase-8

KW - hepatocarcinogenesis

KW - necroptosis

UR - http://www.scopus.com/inward/record.url?scp=85009126405&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.11.009

DO - 10.1016/j.ccell.2016.11.009

M3 - Article

C2 - 28017612

AN - SCOPUS:85009126405

SN - 1535-6108

VL - 31

SP - 94

EP - 109

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Abstract

Keywords

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