Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/13471
Title: Regulation of CD95-induced NF-[Kappa]B activation
Author(s): Buchbinder, Jörn Holger
Referee(s): Lavrik, Inna
Granting Institution: Otto-von-Guericke-Universität Magdeburg, Fakultät für Naturwissenschaften
Issue Date: 2019
Type: Doctoral thesis
Exam Date: 2018
Language: English
Publisher: Otto von Guericke University Library, Magdeburg, Germany
URN: urn:nbn:de:gbv:ma9:1-1981185920-135583
Subjects: Zellbiologie
Abstract: It is well understood that the death receptor CD95 induces apoptotic cell death but also pro-survival signaling. Defective regulation of CD95 signaling is connected to a number of diseases. While the induction of CD95-induced apoptosis is dependent on caspases, the molecular mechanisms leading to activation of the CD95-mediated pro-survival NF-κB pathway are not yet fully understood. The protein c-FLIP is known to block activation of caspases at the CD95 death inducing signaling complex (DISC) and plays an important role in driving CD95-induced NF-κB activation. The present study was designed to get new insights into the mechanism of CD95-mediated NF-κB activation. In the course of this study, a new imaging flow cytometry-based method to analyze apoptosis and the NF-κB pathway on single cell level was established. This new method uncovered that both pathways are activated in parallel, which provided further insights into the mechanism of NF-κB activation. It was shown that the DISC protein c-FLIP interacts with a central regulator of the NF-κB pathway, NEMO. Peptides derived from an in silico model of the c-FLIP-NEMO interaction were able to reduce CD95-induced NF-κB activation in cells expressing high levels of c-FLIPL. In addition, the effect of the CBM complex on CD95-induced NF-κB activation was analyzed. The core components of CBM complex were found to be associated to c-FLIP and NEMO in a mass spectrometry screen. Finally, the autophagy receptor NDP52 was described as a negative regulator of CD95- and TNF-R-induced NF-κB activation. Furthermore, this study showed that NDP52 interacts with NEMO and the DUB A20 and thereby limits NF-κB activation by reducing NEMO ubiquitination. Taken together, this study uncovered new regulatory mechanisms of CD95-induced NF-κB activity. The identification and further improvement of NEMO-derived peptides that block tumor-promoting CD95-induced NF-κB activation without blocking of CD95-mediated apoptosis has potential for new anti-cancer treatment.
URI: https://opendata.uni-halle.de//handle/1981185920/13558
http://dx.doi.org/10.25673/13471
Open Access: Open access publication
License: (CC BY-NC 4.0) Creative Commons Attribution NonCommercial 4.0
Appears in Collections:Fakultät für Naturwissenschaften

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