Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes

Ivanisenko, Nikita V.; Buchbinder, Jörn H.; Espe, Johannes; Richter, M.; Bollmann, M.; Hillert, Laura K.; Иванисенко, В. А.; Lavrik, Inna N.

doi:10.1186/s12864-019-5539-y

Cited by 10 publications

(4 citation statements)

References 27 publications

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“…The c-FLIP protein within the DISC complex is also involved in the activation of the anti-apoptotic NF-κB signaling pathway. A special role in this process is played by the protein–protein interaction of c‑FLIP with the NEMO (NF-kB essential modulator, known as IKKγ, IκB kinase γ) protein, a key activator of the NF-κB signaling pathway [ 56 – 58 ]. One of the mechanisms for increased tumor cell proliferation in HCC may be activation of the NF-κB signaling pathway through the interaction of c-FLIP/NEMO proteins.…”

Section: Resultsmentioning

confidence: 99%

Primary and Secondary micro-RNA Modulation the Extrinsic Pathway of Apoptosis in Hepatocellular Carcinoma

et al. 2023

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—One of the most common malignant liver diseases is hepatocellular carcinoma, which has a high recurrence rate and a low five-year survival rate. It is very heterogeneous both in structure and between patients, which complicates the diagnosis, prognosis and response to treatment. In this regard, an individualized, patient-centered approach becomes important, in which the use of mimetics and hsa-miRNA inhibitors involved in the pathogenesis of the disease may be determinative. From this point of view hsa-miRNAs are of interest, their aberrant expression is associated with poor prognosis for patients and is associated with tumor progression due to dysregulation of programmed cell death (apoptosis). However, the effect of hsa-miRNA on tumor development depends not only on its direct effect on expression of genes, the primary targets, but also on secondary targets mediated by regulatory pathways. While the former are actively studied, the role of secondary targets of these hsa-miRNAs in modulating apoptosis is still unclear. The present work summarizes data on hsa-miRNAs whose primary targets are key genes of the extrinsic pathway of apoptosis. Their aberrant expression is associated with early disease relapse and poor patient outcome. For these hsa-miRNAs, using the software package ANDSystem, we reconstructed the regulation of the expression of secondary targets and analyzed their impact on the activity of the extrinsic pathway of apoptosis. The potential effect of hsa-miRNAs mediated by action on secondary targets is shown to negatively correlate with the number of primary targets. It is also shown that hsa-miR-373, hsa-miR-106b and hsa-miR-96 have the highest priority as markers of hepatocellular carcinoma, whose action on secondary targets enhances their anti-apoptotic effect.

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Section: Resultsmentioning

confidence: 99%

Primary and Secondary micro-RNA Modulation the Extrinsic Pathway of Apoptosis in Hepatocellular Carcinoma

et al. 2023

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“…Bidirectional regulation between NF-κB and c-FLIP has been reported ( 39 ). c-FLIP upregulates NF-κB expression ( 54 ) and enhances its nuclear translocation ( 55 ). However, the present EMSA results showed that RT did not change NF-κB/DNA binding activity, even when c-FLIP expression was increased in orthotopic HCC tumors.…”

Section: Discussionmentioning

confidence: 99%

A combination of sorafenib and radiotherapy reduces NF‑κB activity and growth of hepatocellular carcinoma in an orthotopic mouse model

et al. 2021

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Hepatocellular carcinoma (HCC) is difficult to diagnose at an early stage, and its prognosis is generally poor. Sorafenib is the primary treatment for unresectable advanced HCC and targets multiple receptor tyrosine kinases. However, sorafenib only extends the average survival time by 3 months. This observation indicates that sorafenib may need to be combined with other treatments to further improve outcomes. We previously showed that combination of sorafenib with radiotherapy (RT) enhances tumor inhibition in subcutaneous HCC mouse models compared with monotherapy. The present study demonstrated that combining sorafenib and RT could suppress tumor growth in an orthotopic HCC model by regulating apoptosis and N F-κ B-related pathways. Moreover, decreased numbers of visible liver tumors and a smaller percentage of spleen metastases were found in the combination group. A transient drop in body weight was initially observed after RT, but progressive recovery of body weight occurred. The current study showed that the combination of sorafenib and RT could be a safe strategy for HCC treatment.

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“…Hence, to consider the mechanisms of c-FLIP action, a number of the structural models of c-FLIP DEDs were constructed in silico. These models are based on the structure of viral FLIP proteins, such as MC159 or ks-v-FLIP, that are homologous to c-FLIP [12,34,73]. Further insights into the role of c-FLIP in the DISC structure were obtained recently using state-of-the-art quantitative mass spectrometry supported by structural modeling [69].…”

Section: Ptms Of C-flipmentioning

confidence: 99%

Controlling Cell Death through Post-translational Modifications of DED Proteins

Seyrek

Ivanisenko

Richter

et al. 2020

Trends in Cell Biology

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Apoptosis is a form of programmed cell death, deregulation of which occurs in multiple disorders, including neurodegenerative and autoimmune diseases as well as cancer. The formation of a death-inducing signaling complex (DISC) and death effector domain (DED) filaments are critical for initiation of the extrinsic apoptotic pathway. Post-translational modifications (PTMs) of DED-containing DISC components such as FADD, procaspase-8, and c-FLIP comprise an additional level of apoptosis regulation, which is necessary to overcome the threshold for apoptosis induction. In this review we discuss the influence of PTMs of FADD, procaspase-8, and c-FLIP on DED filament assembly and cell death induction, with a focus on the 3D organization of the DED filament. Death Effector Domain (DED) Proteins in Extrinsic Apoptosis Signaling In multicellular organisms, tissue homeostasis is maintained through a fine-tuned balance between cell proliferation and cell death [1-5]. Several physiological and pathological stimuli have been reported to trigger programmed cell death [6]. Apoptosis can be induced via two pathways: the extrinsic and the intrinsic or mitochondrial pathway [2] (Figure 1). The extrinsic pathway is triggered upon binding of death ligands, including CD95 ligand (CD95L) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to death receptors (DRs) such as Fas/CD95 and TRAIL receptor-1/2 (TRAILR1/2), respectively [7]. This association leads to the recruitment of proteins with death domains (DD) such as Fas-associated protein with death domain (FADD) to the DD of CD95 or TRAIL-R1/2, resulting in the formation of the death-inducing signaling complex (DISC) [8,9], which in turn directs cleavage and activation of caspases for inducing apoptosis. DISC is comprised of procaspase-8/10 and cellular FLICE-like inhibitory protein (c-FLIP). Upon induction of apoptosis, the DED of FADD interacts with DEDs of procaspase-8, procaspase-10, and c-FLIP, resulting in the formation of DED-filaments, which serve as a platform for procaspase-8 dimerization and subsequent activation [10-12] (Figure 1). DED belongs to the DD superfamily [3,13]. DED comprises six α-helixes arranged in a Greek key structural motif. FADD contains one DD and one DED, whereas both caspase-8 and c-FLIP contain two DEDs at their N terminus. DED filaments are formed through so-called type I, II, and III interactions between DEDs (Box 1) [12]. Proper architecture of DED filaments at DR complexes provide an extra layer of regulatory control of cell death. Recent findings are revealing a role for post-translational modifications (PTMs) such as phosphorylation, ubiquitylation, SUMOylation, and nitrosylation in regulating these interactions [6,14-17]. These modifications assist in maintaining proper conformations of DEDs in DED filaments, which is required for efficient caspase-8 activation, and in overcoming a threshold for apoptosis induction [18,19]. In this review, we consider the role of PTMs in controlling the mechanisms of DISC and DED filament...

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Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes

Cited by 10 publications

References 27 publications

Primary and Secondary micro-RNA Modulation the Extrinsic Pathway of Apoptosis in Hepatocellular Carcinoma

Primary and Secondary micro-RNA Modulation the Extrinsic Pathway of Apoptosis in Hepatocellular Carcinoma

A combination of sorafenib and radiotherapy reduces NF‑κB activity and growth of hepatocellular carcinoma in an orthotopic mouse model

Controlling Cell Death through Post-translational Modifications of DED Proteins

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