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, Lei; Zwirner, S.; 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.; Naumann, M.; Walczak, H.; Green, D.R.; Lopes, M.; Lavrik, I.; Luedde, T.; Heikenwalder, M.; Weber, A.

A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development

Tools

Preview

PDF (Original article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
13MB

Item Type:	Article
Title:	A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development
Creators:	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. ORCID: https://orcid.org/0000-0003-0717-7530, Wolf, M.J., Rehrauer, H., Koppe, C., Speicher, T., Padrissa-Altés, S., Maire, R., Schattenberg, J.M., Jeong, J.S., Liu, Lei, Zwirner, S., 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. ORCID: https://orcid.org/0000-0001-5189-0793, Wallach, D., Dejardin, E., Zender, L., Naumann, M., Walczak, H., Green, D.R., Lopes, M., Lavrik, I., Luedde, T., Heikenwalder, M. and Weber, A.
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.
Keywords:	Liver, Hepatocellular Carcinoma, DNA Damage Response, Replication Stress, Apoptosis, Animals, Mice
Source:	Cancer Cell
ISSN:	1535-6108
Publisher:	Cell Press / Elsevier
Volume:	32
Number:	3
Page Range:	342-359
Date:	11 September 2017
Additional Information:	Copyright © 2017 The Authors.
Official Publication:	https://doi.org/10.1016/j.ccell.2017.08.010
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

Repository Staff Only: item control page

Download Statistics

Downloads

Downloads per month over past year