Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types. An antagonist decoy receptor (designated as TRID for TRAIL receptor without an intracellular domain) that may explain the resistant phenotype of normal tissues was identified. TRID is a distinct gene product with an extracellular TRAIL-binding domain and a transmembrane domain but no intracellular signaling domain. TRID transcripts were detected in many normal human tissues but not in most cancer cell lines examined. Ectopic expression of TRID protected mammalian cells from TRAIL-induced apoptosis, which is consistent with a protective role. Another death domain-containing receptor for TRAIL (designated as death receptor-5), which preferentially engaged a FLICE (caspase-8)-related death protease, was also identified.
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PMID:An antagonist decoy receptor and a death domain-containing receptor for TRAIL. 927 98

Fas/Apo1 and other cytotoxic receptors of the tumor necrosis factor receptor (TNFR) family contain a cytoplasmic death domain (DD) [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] that activates the apoptotic process by interacting with the DD-containing adaptor proteins TNFR-associated DD protein (TRADD) [12] [13] and Fas-associated DD protein (FADD/MORT1) [14] [15], leading to the activation of cysteine proteases of the caspase family [16]. Stimulation of Fas/Apo1 leads to the formation of a receptor-bound death-inducing signaling complex (DISC), consisting of FADD and two different forms of caspase-8 [17] [18] [19]. Transient expression of a dominant-negative mutant of FADD impairs TNFR60-mediated and Fas/Apo1-mediated apoptosis [13] [20], but has no effect on TNF-related apoptosis-inducing ligand (TRAIL/Apo2L)-induced cell death [7] [8] [9] [10] [21]. To study the function of FADD in DD-receptor signaling in more detail, we established HeLa cells that stably expressed a green fluorescent protein (GFP)-tagged dominant-negative mutant of FADD, GFP-DeltaFADD. Interestingly, expression of this mutant inhibited cell death induced by TNFR60, Fas/Apo1 and TRAIL-R/Apo2. In addition, GFP-DeltaFADD did not interfere with TNF-mediated gene induction or with activation of NF-kappaB or Jun N-terminal kinase (JNK), demonstrating that FADD is part of the TNFR60-initiated apoptotic pathway but does not play a role in TNFR60-mediated gene induction. Fas/Apo1-mediated activation of JNK was unaffected by the expression of GFP-DeltaFADD, suggesting that in Fas/Apo1 signaling the apoptotic pathway and the activation of JNK diverge at a level proximal to the receptor, upstream of or parallel to FADD.
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PMID:Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction. 942 46

Nitric oxide (NO), an important effector molecule involved in immune regulation and host defense, was shown to induce apoptosis in lymphoma cells. In the present report the NO donor glycerol trinitrate was found to induce apoptosis in Jurkat cells that are sensitive to CD95-mediated kill. In contrast, a CD95-resistant Jurkat subclone showed substantial protection from apoptosis after exposure to NO. NO induced mRNA expression of CD95 (APO-1/Fas) and TRAIL/APO-2 ligands. Moreover, NO triggered apoptosis in freshly isolated human leukemic lymphocytes which were also sensitive to anti-CD95 treatment. The ability of NO to induce apoptosis was completely blocked by a broad-spectrum ICE (interleukin-1beta converting enzyme)-protease/caspase inhibitor and correlated with FLICE/caspase-8 activation. This activation was abrogated in some neoplastic lymphoid cells but not in others by the inhibitor of protein synthesis cycloheximide. Our results were confirmed using an in vitro experimental model of coculture of human lymphoid target cells with activated bovine endothelial cells generating NO as effectors. Furthermore, the inhibition of endogenous NO production with the inducible NO synthase inhibitor NG-monomethyl-L-arginine caused a complete abrogation of the apoptotic effect. Our data provide evidence that NO-induced apoptosis in human neoplastic lymphoid cells strictly requires activation of caspases, in particular FLICE, the most CD95 receptor-proximal caspase. Depending on the cell line tested this activation required or was independent of the CD95 receptor/ligand system.
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PMID:Caspase activation is required for nitric oxide-mediated, CD95(APO-1/Fas)-dependent and independent apoptosis in human neoplastic lymphoid cells. 959 80

Apoptosis, or programmed cell death, is a genetically regulated mechanism with a central role in both metazoan development and homeostasis. Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptosis upon ligation to cognate ligands or ectopic expression. The assembly of a death-inducing signalling complex occurs in a hierarchical manner upon receptor activation. The death domain of the receptor binds to the corresponding domain of the adapter molecule FADD, which in turn recruits the zymogen form of the death protease FLICE (MACH/caspase-8). Upon approximation, FLICE "zymogens" attain a sufficient concentration to self-activate and to trigger the apoptotic pathway. For the first time, a transmembrane receptor directly engaging a protease at the signalling complex and subsequently triggering a proteolytic signalling cascade is described.
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PMID:Signalling by proteolysis: death receptors induce apoptosis. 980 24

In this study we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also called Apo2L, activates the c-Jun N-terminal kinase (JNK). Interestingly, TRAIL-induced JNK activation occurs in a cell type-specific manner. In HeLa cells, TRAIL-induced JNK activation can be completely blocked with the cysteine protease inhibitor zVAD-fmk, whereas the same inhibitor has no, or even a stimulatory, effect on JNK activation in Kym-1 cells. Hence, TRAIL can engage at least two independent pathways leading to JNK activation, one that is cysteine protease-dependent and one that is cysteine protease-independent. To investigate whether the cysteine protease-dependent signaling of TRAIL leading to JNK activation is related to the apoptotic pathway engaged by this ligand, we investigated HeLa cells stably overexpressing a dominant negative mutant of FADD (Fas-associating protein with death domain) (GFP(green fluorescent protein)DeltaFADD). In these cells, TRAIL-induced cell death and activation of the apoptosis executioner caspase-8 (FLICE/MACH) and caspase-3 (YAMA, CPP-32, Apopain), that belong to caspase subfamily of cysteine proteases, were abrogated, whereas JNK activation remained unaffected and was still sensitive toward z-VAD-fmk. Similar data were found in HeLa cells overexpressing Apo1/Fas and GFPDeltaFADD upon stimulation with agonistic antibodies. These data suggest that cross-linking of the TRAIL receptors and Apo1/Fas, respectively, engages a FADD-dependent pathway leading to the activation of apoptotic caspases and, in parallel, a FADD-independent pathway leading to the stimulation of one or more cysteine proteases capable to activate JNK but not sufficient for the induction of cell death.
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PMID:TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase-dependent and caspase-independent pathways. 983 64

Cross-linking of the B cell antigen receptor (BCR) induces resistance to Fas (APO-1 / CD95)-dependent apoptosis and thereby regulates one mechanism of B cell selection during antigen stimulation. To investigate the molecular mechanism by which BCR signaling regulates the Fas pathway, we examined the expression of constituents of the death-inducing signaling complex (DISC), including Fas, FADD, caspase-8 and cellular FLICE-inhibitory protein (c-FLIP). No significant changes in the cellular levels of Fas, FADD or caspase-8 were observed after BCR cross-linking. By contrast, the long isoform of c-FLIP (c-FLIP(L)) was significantly up-regulated by BCR cross-linking in primary B cells and in two B cell lines, A20 and WEHI-279. Moreover, transfection of c-FLIP(L) into A20 cells inhibited Fas-dependent apoptosis and suppressed recruitment of caspase-8 to the DISC. BCR cross-linking or FLIP overexpression also protects B cells from TRAIL-induced apoptosis. Thus, BCR signaling up-regulates c-FLIP(L) and suppresses the Fas- and TRAIL-receptor apoptosis pathways which could be important for tolerance and selection of antigen-specific B cells.
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PMID:Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP. 1060 37

Mad1 is a member of the Myc/Max/Mad network of transcriptional regulators that play a central role in the control of cellular behavior. Mad proteins are thought to antagonize Myc functions at least in part by repressing gene transcription. To systematically examine the function of Mad1 in growth control and during apoptosis, we have generated U2OS cell clones that express Mad1 under a tetracyline-regulatable promoter (UTA-Mad1). Mad1 was induced rapidly and efficiently, localized to the nucleus, and bound to DNA as a heterodimer with Max. The induction of Mad1 reduced cellular growth and, more profoundly, inhibited colony formation of UTA-Mad1 cells. Conditioned medium neutralized this inhibitory effect implying that Mad1 function is regulated by extracellular signals. In addition Mad1 interfered with Fas-, TRAIL-, and UV-induced apoptosis, which coincided with a reduced activation of caspase-8 during Fas-mediated apoptosis in response to Mad1 expression. Furthermore, microinjection of Mad1-expressing plasmids into fibroblasts inhibited apoptosis induced by the oncoproteins c-Myc and E1A. Thus, Mad1 not only interferes with cellular proliferation but also with apoptosis, which defines a novel aspect of Mad1 function.
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PMID:Inhibition of proliferation and apoptosis by the transcriptional repressor Mad1. Repression of Fas-induced caspase-8 activation. 1074 30

In HeLa cells, induction of apoptosis and nuclear factor kappaB (NF-kappaB) activation initiated by TRAIL/Apo2L or the agonistic Apo1/Fas-specific monoclonal antibody anti-APO-1 require the presence of cycloheximide (CHX). Inhibition of caspases prevented TRAIL/anti-APO-1-induced apoptosis, but not NF-kappaB activation, indicating that both pathways bifurcate upstream of the receptor-proximal caspase-8. Under these conditions, TRAIL and anti-APO-1 up-regulated the expression of the known NF-kappaB targets interleukin-6, cellular inhibitor of apoptosis 2 (cIAP2), and TRAF1 (TRAF, tumor necrosis factor receptor-associate factor). In the presence of CHX, the stable overexpression of a deletion mutant of the Fas-associated death domain molecule FADD comprising solely the death domain of the molecule but lacking its death effector domain (FADD-(80-208)) led to the same response pattern as TRAIL or anti-APO-1 treatment. Moreover, the ability of death receptors to induce NF-kappaB activation was drastically reduced in a FADD-deficient Jurkat cell line. TRAIL-, anti-APO-1-, and FADD-(80-208)-initiated gene induction was blocked by a dominant-negative mutant of TRAF2 or the p38 kinase inhibitor SB203580, similar to tumor necrosis factor receptor-1-induced NF-kappaB activation. CHX treatment rapidly down-regulated endogenous cFLIP protein levels, and overexpression of cellular FLICE inhibitory protein (cFLIP) inhibited death receptor-induced NF-kappaB activation. Thus, a novel functional role of cFLIP as a negative regulator of gene induction by death receptors became apparent.
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PMID:Inhibition of death receptor-mediated gene induction by a cycloheximide-sensitive factor occurs at the level of or upstream of Fas-associated death domain protein (FADD). 1082 21

Apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO-2L) has been shown to exert important functions during various immunological processes. The involvement of the death adaptor proteins FADD/MORT1, TRADD, and RIP and the apoptosis-initiating caspases-8 and -10 in death signaling by the two death-inducing TRAIL receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are controversial. Analysis of the native TRAIL death-inducing signaling complex (DISC) revealed ligand-dependent recruitment of FADD/MORT1 and caspase-8. Differential precipitation of ligand-stimulated TRAIL receptors demonstrated that FADD/MORT1 and caspase-8 were recruited to TRAIL-R1 and TRAIL-R2 independently of each other. FADD/MORT1- and caspase-8-deficient Jurkat cells expressing only TRAIL-R2 were resistant to TRAIL-induced apoptosis. Thus, FADD/MORT1 and caspase-8 are essential for apoptosis induction via TRAIL-R2.
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PMID:FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. 1089 60

Fas (APO-1/CD95) and tumor necrosis factor receptor 1 (TNFR1) trigger apoptosis by recruiting the apoptosis initiator caspase-8 through the adaptor FADD. Fas binds FADD directly, whereas TNFR1 binds FADD indirectly, through TRADD. TRADD alternatively recruits the NF-kappaB-inducing adaptor RIP. The TNF homolog Apo2L/TRAIL triggers apoptosis through two distinct death receptors, DR4 and DR5; however, receptor over-expression studies have yielded conflicting results on the ligand's signaling mechanism. Apo2L/TRAIL induced homomeric and heteromeric complexes of DR4 and DR5 and stimulated recruitment of FADD and caspase-8 and caspase-8 activation in nontransfected cells. TRADD and RIP, which bound TNFR1, did not bind DR4 and DR5. Thus, Apo2L/TRAIL and FasL initiate apoptosis through similar mechanisms, and FADD may be a universal adaptor for death receptors.
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PMID:Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. 1089 61


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