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World J Gastroenterol. Dec 7, 2014; 20(45): 17049-17064
Published online Dec 7, 2014. doi: 10.3748/wjg.v20.i45.17049
Published online Dec 7, 2014. doi: 10.3748/wjg.v20.i45.17049
CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes
Toni Urbanik, Bruno Christian Koehler, Laura Wolpert, Christin Elßner, Anna-Lena Scherr, Nicole Kautz, Stefan Welte, Dirk Jäger, Henning Schulze-Bergkamen, National Center for Tumor Diseases, Department of Medical Oncology, University Clinic of Heidelberg, 69120 Heidelberg, Baden-Wuerrtemberg, Germany
Thomas Longerich, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Baden-Wuerrtemberg, Germany
Nadine Hövelmeyer, Institute for Molecular Medicine, Johannes Gutenberg-University Mainz, 55131 Mainz, Rheinland-Palatinate, Germany
Author contributions: Urbanik T, Wolpert L and Kautz N performed the experiments; Urbanik T designed the study, performed interpretation of the data and statistical analysis; Urbanik T, Koehler BC and Schulze-Bergkamen H wrote the manuscript; Elßner C, Scherr AL, Longerich T, Welte S, Hövelmeyer N, Jäger D and Waisman A made substantial contribution to the discussion of the results; all authors read and approved the final manuscript.
Supported by Research grants from the Dietmar Hopp Stiftung, http://www.dietmar-hopp-stiftung.de and from German Research Foundation (Deutsche Forschungsgemeinschaft, http://www.dfg.de/, DFG SCHU 1443/3-2) to HSB (SFB/TRR 77, associated project)
Correspondence to: Henning Schulze-Bergkamen, MD, National Center for Tumor Diseases, Department of Medical Oncology, University Clinic of Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Baden-Wuerrtemberg, Germany. henning.schulze@med.uni-heidelberg.de
Telephone: +49-6221560 Fax: +49-6221-5633966
Received: May 29, 2014
Revised: June 30, 2014
Accepted: August 13, 2014
Published online: December 7, 2014
Revised: June 30, 2014
Accepted: August 13, 2014
Published online: December 7, 2014
Core Tip
Core tip: Activation of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor (TNF)-R1, is involved in the pathophysiology of acute and chronic liver diseases. Inactivation of the deubiquitinase CYLD is accompanied by increased survival of different cell types. However, the role of CYLD in death receptor-mediated apoptosis of hepatocytes has not been addressed so far. The study showed for the first time that CYLD negative hepatocytes are less sensitive to CD95 and TNF-R-mediated apoptosis, at least in part via triggering nuclear factor-κB signaling leading to induction of anti-apoptotic proteins. Inhibition of CYLD might represent a therapeutic approach to protect hepatocytes from death receptor-mediated apoptosis.