Journal Article

DKFZ-2017-04329

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

Boege, Y. ; Malehmir, M. ; Healy, M. E. ; Bettermann, K. ; Lorentzen, A. ; Vucur, M. ; Ahuja, A. K. ; Böhm, F. ; Mertens, J. C. ; Shimizu, Y. ; Frick, L. ; Remouchamps, C. ; Mutreja, K. ; Kähne, T. ; Sundaravinayagam, D. ; Wolf, M. J. ; Rehrauer, H. ; Koppe, C. ; Speicher, T. ; Padrissa-Altés, S. ; Maire, R. ; Schattenberg, J. M. ; Jeong, J.-S. ; Liu, L. ; Zwirner, S.DKFZ* ; Boger, R. ; Hüser, N. ; Davis, R. J. ; Müllhaupt, B. ; Moch, H. ; Schulze-Bergkamen, H. ; Clavien, P.-A. ; Werner, S. ; Borsig, L. ; Luther, S. A. ; Jost, P. J. ; Weinlich, R. ; Unger, K. ; Behrens, A. ; Hillert, L. ; Dillon, C. ; Di Virgilio, M. ; Wallach, D. ; Dejardin, E. ; Zender, L.DKFZ* ; Naumann, M. ; Walczak, H. ; Green, D. R. ; Lopes, M. ; Lavrik, I. ; Luedde, T. ; Heikenwalder, M.DKFZ* ; Weber, A.

2017
Cell Press Cambridge, Mass.

This record in other databases:  

Please use a persistent id in citations: doi:10.1016/j.ccell.2017.08.010

Abstract: Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

Keyword(s): Fadd protein, mouse ; Fas-Associated Death Domain Protein ; Histones ; Mcl1 protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; Receptors, Tumor Necrosis Factor, Type I ; gamma-H2AX protein, mouse ; Receptor-Interacting Protein Serine-Threonine Kinases ; Ripk1 protein, mouse ; JNK Mitogen-Activated Protein Kinases ; Caspase 8

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Contributing Institute(s):

1. Translationale Gastrointestinale Onkologie (V076)
2. Chronische Entzündung und Krebs (F180)
3. DKTK Tübingen (L801)

Research Program(s):

1. 319H - Addenda (POF3-319H) (POF3-319H)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 20 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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