scholarly journals Cellular FLICE-inhibitory Protein (cFLIP) Isoforms Block CD95- and TRAIL Death Receptor-induced Gene Induction Irrespective of Processing of Caspase-8 or cFLIP in the Death-inducing Signaling Complex

2011 ◽  
Vol 286 (19) ◽  
pp. 16631-16646 ◽  
Author(s):  
Shyam M. Kavuri ◽  
Peter Geserick ◽  
Daniela Berg ◽  
Diana Panayotova Dimitrova ◽  
Maria Feoktistova ◽  
...  
Keyword(s):  
Death Receptor ◽  
Gene Induction ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Trail Death Receptor

scholarly journals Hypo-Expression of Flice-Inhibitory Protein and Activation of the Caspase-8 Apoptotic Pathways in the Death-Inducing Signaling Complex Due to Ischemia Induced by the Compression of the Asphyxiogenic Tool on the Skin in Hanging Cases

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 938
Author(s):  
Aniello Maiese ◽  
Alessandra De Matteis ◽  
Giorgio Bolino ◽  
Emanuela Turillazzi ◽  
Paola Frati ◽  
...  
Keyword(s):  
Tertiary Structure ◽  
Active Form ◽  
Three Dimensional ◽  
Death Receptor ◽  
Cell Receptor ◽  
Control Group ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Induced Apoptosis

The FLICE-inhibitory protein (c-FLIPL) (55 kDa) is expressed in numerous tissues and most abundantly in the kidney, skeletal muscles and heart. The c-FLIPL has a region of homology with caspase-8 at the carboxy-terminal end which allows the molecule to assume a tertiary structure similar to that of caspases-8 and -10. Consequently, c-FLIPL acts as a negative inhibitor of caspase-8, preventing the processing and subsequent release of the pro-apoptotic molecule active form. The c-FLIP plays as an inhibitor of apoptosis induced by a variety of agents, such as tumor necrosis factor (TNF), T cell receptor (TCR), TNF-related apoptosis inducing ligand (TRAIL), Fas and death receptor (DR). Increased expression of c-FLIP has been found in many human malignancies and shown to be involved in resistance to CD95/Fas and TRAIL receptor-induced apoptosis. We wanted to verify an investigative protocol using FLIP to make a differential diagnosis between skin sulcus with vitality or non-vital skin sulcus in hanged subjects and those undergoing simulated hanging (suspension of the victim after murder). The study group consisted of 21 cases who died from suicidal hanging. The control group consisted of traumatic or natural deaths, while a third group consisted of simulated hanging cases. The reactions to the Anti-FLIP Antibody (Abcam clone-8421) was scored for each section with a semi-quantitative method by means of microscopic observation carried out with confocal microscopy and three-dimensional reconstruction. The results obtained allow us to state that the skin reaction to the FLIP is extremely clear and precise, allowing a diagnosis of unequivocal vitality and a very objective differentiation with the post-mortal skin sulcus.

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

scholarly journals Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL

2010 ◽  
Vol 190 (3) ◽  
pp. 377-389 ◽  
Author(s):  
Nicolai Fricker ◽  
Joel Beaudouin ◽  
Petra Richter ◽  
Roland Eils ◽  
Peter H. Krammer ◽  
...  
Keyword(s):  
Death Receptor ◽  
Caspase 8 ◽  
Converting Enzyme ◽  
Receptor Stimulation ◽  
Western Blots ◽  
Antiapoptotic Protein ◽  
Signaling Complex ◽  
Signaling Dynamics ◽  
Induced Apoptosis

Cellular FADD-like interleukin-1β–converting enzyme inhibitory proteins (c-FLIPs; isoforms c-FLIP long [c-FLIPL], c-FLIP short [c-FLIPS], and c-FLIP Raji [c-FLIPR]) regulate caspase-8 activation and death receptor (DR)–induced apoptosis. In this study, using a combination of mathematical modeling, imaging, and quantitative Western blots, we present a new mathematical model describing caspase-8 activation in quantitative terms, which highlights the influence of c-FLIP proteins on this process directly at the CD95 death-inducing signaling complex. We quantitatively define how the stoichiometry of c-FLIP proteins determines sensitivity toward CD95-induced apoptosis. We show that c-FLIPL has a proapoptotic role only upon moderate expression in combination with strong receptor stimulation or in the presence of high amounts of one of the short c-FLIP isoforms, c-FLIPS or c-FLIPR. Our findings resolve the present controversial discussion on the function of c-FLIPL as a pro- or antiapoptotic protein in DR-mediated apoptosis and are important for understanding the regulation of CD95-induced apoptosis, where subtle differences in c-FLIP concentrations determine life or death of the cells.

scholarly journals Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex

2001 ◽  
Vol 276 (23) ◽  
pp. 20633-20640 ◽  
Author(s):  
Andreas Krueger ◽  
Ingo Schmitz ◽  
Sven Baumann ◽  
Peter H. Krammer ◽  
Sabine Kirchhoff
Keyword(s):  
Splice Variants ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Protein Splice

scholarly journals Erythroid Differentiation Sensitizes K562 Leukemia Cells to TRAIL-Induced Apoptosis by Downregulation of c-FLIP

2003 ◽  
Vol 23 (4) ◽  
pp. 1278-1291 ◽  
Author(s):  
Ville Hietakangas ◽  
Minna Poukkula ◽  
Kaisa M. Heiskanen ◽  
Jarkko T. Karvinen ◽  
Lea Sistonen ◽  
...  
Keyword(s):  
Death Receptor ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Caspase 8 ◽  
Malignant Cells ◽  
Signaling Complex ◽  
Specific Effects ◽  
Organ Systems ◽  
Increased Sensitivity ◽  
Induced Apoptosis

ABSTRACT Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIPL and c-FLIPS, was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIPL and c-FLIPS rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIPL and c-FLIPS potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals.

scholarly journals Death Receptor-Induced Signaling Pathways Are Differentially Regulated by Gamma Interferon Upstream of Caspase 8 Processing

2005 ◽  
Vol 25 (15) ◽  
pp. 6363-6379 ◽  
Author(s):  
Daniela Siegmund ◽  
Andreas Wicovsky ◽  
Ingo Schmitz ◽  
Klaus Schulze-Osthoff ◽  
Sebastian Kreuz ◽  
...  
Keyword(s):  
Cross Talk ◽  
Death Receptor ◽  
Gamma Interferon ◽  
Caspase 8 ◽  
Apoptosis Induction ◽  
Activated T Cells ◽  
Signaling Complex ◽  
Proinflammatory Responses ◽  
Ifn Γ ◽  
Induced Apoptosis

ABSTRACT FasL and gamma interferon (IFN-γ) are produced by activated T cells and NK cells and synergistically induce apoptosis. Although both cytokines can also elicit proinflammatory responses, a possible cross talk of these ligands with respect to nonapoptotic signaling has been poorly addressed. Here, we show that IFN-γ sensitizes KB cells for apoptosis induction by facilitating death-inducing signaling complex (DISC)-mediated caspase 8 processing. Moreover, after protection against death receptor-induced apoptosis by caspase inhibition or Bcl2 overexpression, IFN-γ also sensitized for Fas- and TRAIL death receptor-mediated NF-κB activation leading to synergistic upregulation of a variety of proinflammatory genes. In contrast, Fas-mediated activation of JNK, p38, and p42/44 occurred essentially independent from IFN-γ sensitization, indicating that the apoptosis- and NF-κB-related FasL-IFN-γ cross talk was not due to a simple global enhancement of Fas signaling. Overexpression of FLIPL and FLIPS inhibited Fas- as well as TRAIL-mediated NF-κB activation and apoptosis induction in IFN-γ-primed cells suggesting that both responses are coregulated at the level of the DISC.

scholarly journals c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis

2004 ◽  
Vol 199 (8) ◽  
pp. 1041-1052 ◽  
Author(s):  
Stephan Mathas ◽  
Andreas Lietz ◽  
Ioannis Anagnostopoulos ◽  
Franziska Hummel ◽  
Burkhard Wiesner ◽  
...  
Keyword(s):  
Death Receptor ◽  
B Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Death Domain ◽  
Inhibitory Protein ◽  
Antiapoptotic Proteins ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
High Level ◽  
Interfering Rna

Resistance to death receptor–mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain–containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1β–converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-κB. Despite expression of other NF-κB–dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.

scholarly journals Caspase-8 prevents sustained activation of NF-κB in monocytes undergoing macrophagic differentiation

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1442-1450 ◽  
Author(s):  
Cédric Rébé ◽  
Séverine Cathelin ◽  
Sophie Launay ◽  
Rodolphe Filomenko ◽  
Laurent Prévotat ◽  
...  
Keyword(s):  
Death Receptor ◽  
Adaptor Protein ◽  
Cell Types ◽  
Caspase 8 ◽  
Specific Cell ◽  
Death Domain ◽  
Blood Monocytes ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Macrophage Colony

Abstract Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-κB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-κB activity through RIP1 cleavage.

scholarly journals C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells

2020 ◽  
Vol 21 (4) ◽  
pp. 1298 ◽  
Author(s):  
Hyo-Jin Kim ◽  
Bo-Gyeong Seo ◽  
Kwang Dong Kim ◽  
Jiyun Yoo ◽  
Joon-Hee Lee ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
B Cell Lymphoma ◽  
Human Lung Cancer ◽  
Caspase 8 ◽  
Death Domain ◽  
Extrinsic Pathway ◽  
Inhibitory Protein ◽  
Apoptosis Pathways ◽  
Induced Apoptosis

Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.

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