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)

In necrotic liver failure like upon acetaminophen overdose, loss of the major intracellular thiol antioxidant glutathione was shown to be causal for hepatic dysfunction. In sharp contrast, fulminant apoptotic liver destruction upon overstimulation of the death receptors TNFR1 and CD95 was not associated with reduced hepatic glutathione levels. In view of the importance of the role of reactive oxygen intermediates versus antioxidants for apoptosis, we investigated the effect of phorone-induced enzymatic GSH depletion on the sensitivity of the liver towards CD95- or TNFR1-mediated hepatotoxicity. Our findings demonstrate in vivo that receptor-mediated hepatic apoptosis is disabled when glutathione is depleted, i.e. that an intact glutathione status is a critical determinant for the execution of apoptosis. In vitro, we did mechanistic studies in lymphoid cell lines and found that pro-caspase-8 at the CD95 death receptor and the mitochondrial activation of pro-caspase-9 are the enzyme targets that require sufficient intracellular reduced glutathione for their activation.
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PMID:Redox control of hepatic cell death. 1262 46

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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PMID:Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. 1288 14

Following Gram-negative bacterial infection there is a reduction in matrix-producing cells. The goal of the present study was to examine the apoptotic effects of lipopolysaccharide (LPS) on fibroblastic cells and to investigate the role that the host response plays in this reaction. This was accomplished in vivo by subcutaneous inoculation of LPS in wild type and TNFR1(-/-)R2(-/-) mice. The direct effects of LPS on fibroblast apoptosis was studied in vitro with normal diploid human fibroblasts. The results indicate that LPS in vivo induces apoptosis of fibroblasts. By RNA profiling we demonstrated that LPS stimulates global expression of apoptotic genes and down-regulates anti-apoptotic genes. Fluorometric studies demonstrated that LPS in vivo significantly increased caspase-8 and caspase-3 activity and by use of specific inhibitors, the activation of caspase-3 was shown to be initiated by caspase-8 with no contribution from caspase-9. In vitro studies demonstrated that LPS did not induce apoptosis of fibroblasts, whereas tumor necrosis factor (TNF) did. In addition, the pattern of apoptotic gene expression induced by TNF in vitro was nearly identical to that induced by LPS in vivo, as measured by RNase protection assay. Moreover, pre-treatment of cells with TNF greatly enhanced apoptosis induced by a second stimulation with TNF 24 h later, suggesting that the global induction of pro-apoptotic genes was functionally significant. Thus, LPS acts to modulate the expression of a large number of genes that favor apoptosis of fibroblastic cells that is dependent upon activation of caspase-8 and is largely mediated by TNF.
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PMID:Lipopolysaccharides indirectly stimulate apoptosis and global induction of apoptotic genes in fibroblasts. 1455 Dec 16

Myriadenolide is a diterpene that we have recently isolated from the extract of Alomia myriadenia (Asteraceae). Here we show for the first time that myriadenolide has caspase-dependent cytotoxic activity against human leukemia cells from both lymphocytic (Jurkat) and monocytic (THP-1) lineages, because preincubation of Jurkat or THP-1 cells with the broad-spectrum caspase inhibitor z-VAD-fmk completely abrogated cell death. Moreover, the mitochondrial pathway is implicated as mitochondrial depolarization and caspase-9 and caspase-3 activation were observed. Interestingly, caspase-8 and cleavage of the proapoptotic member of the Bcl-2 family BID was also observed during apoptosis induced by myriadenolide, suggesting a role for the caspase-8/BID pathway. However, interference with Fas or TNFR1 signaling did not interfere with apoptosis in our experimental system. Furthermore, pretreatment of cells with the caspase-3 inhibitor DEVD-fmk completely blocked the activation of caspase-8, suggesting that the activation of the caspase-8/BID pathway is part of an amplification loop initiated by caspase-3. Taken together, our results indicate myriadenolide as a novel candidate for the treatment of hematological malignancies.
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PMID:Myriadenolide, a labdane diterpene isolated from Alomia myriadenia (asteraceae) induces depolarization of mitochondrial membranes and apoptosis associated with activation of caspases-8, -9, and -3 in Jurkat and THP-1 cells. 1456 99

Apoptosis pathways activated by death receptors of the tumour necrosis factor (TNF) family such as Fas, TNFR1, or the TRAIL receptors DR4 and DR5 are implicated in diverse diseases. These are also the best-understood apoptosis pathways and many of our ideas about apoptosis regulation come from studying these pathways. Cell killing from such receptors occurs because of recruitment to the receptor of the adaptor protein FADD, which in turn recruits the pro form of caspase-8. Aggregation of pro-caspase-8 leads to its auto-activation and subsequent activation of effector caspases such as caspase-3. The apoptotic signal can be amplified through the mitochondria and inhibited through the action of competing molecules such as the inhibitor c-FLIP, which binds to the receptor complex in place of caspase-8. This simple mechanism explains much of the cell death that is induced by death receptors. However, recent studies indicate that we must incorporate new information into this model. Some examples that add new layers of complexity will be discussed in this review.
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PMID:Death receptor-induced cell killing. 1463 84

Signaling through the tumor necrosis factor receptor (TNFR) superfamily can lead to apoptosis or promote cell survival, proliferation, and differentiation. A subset of this family, including TNFR1 and Fas, signals cell death via an intracellular death domain and therefore is termed the death receptor (DR) family. In this study, we identified new members of the DR family, designated xDR-M1 and xDR-M2, in Xenopus laevis. The two proteins, which show high homology (71.7% identity), have characteristics of the DR family, that is, three cysteine-rich domains, a transmembrane domain, and a death domain. To elucidate how members of xDR-M subfamily regulate cell death and survival, we examined the intracellular signaling mediated by these receptors in 293T and A6 cells. Overexpression of xDR-M2 induced apoptosis and activated caspase-8, c-Jun N-terminal kinase, and nuclear factor-kappaB, although its death domain to a greater extent than did that of xDR-M1 in 293T cells. A caspase-8 inhibitor potently blocked this apoptosis induced by xDR-M2. In contrast, xDR-M1 showed a greater ability to induce apoptosis through its death domain than did xDR-M2 in A6 cells. Interestingly, a general serine protease inhibitor, but not the caspase-8 inhibitor, blocked the xDR-M1-induced apoptosis. These results imply that activation of caspase-8 or serine protease(s) may be required for the xDR-M2- or xDR-M1-induced apoptosis, respectively. Although xDR-M1 and xDR-M2 are very similar to each other, the difference in their death domains may result in diverse signaling, suggesting distinct roles of xDR-M1 and xDR-M2 in cell death or survival.
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PMID:Xenopus death receptor-M1 and -M2, new members of the tumor necrosis factor receptor superfamily, trigger apoptotic signaling by differential mechanisms. 1466 40

Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.
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PMID:Switching leukemia cell phenotype between life and death. 1532 18

During periods of periodontal attachment loss, one of the most significant cellular changes is a decrease in the number of fibroblasts. We previously demonstrated that LPS induces apoptosis of fibroblastic cells in vivo, largely through TNF-alpha. We conducted in vivo experiments by subcutaneous inoculation of LPS in wild-type, TNFR1-/-R2-/-, TNFR1-/-, and TNFR2-/- mice to identify which TNF receptors are involved and the specific caspase pathway activated. LPS stimulated apoptosis through TNFR1 but not TNFR2, which was accompanied by the induced expression of 12 apoptotic genes. Fluorometric studies demonstrated that LPS in vivo significantly increased caspase-8 and caspase-3 activity, which was also dependent on TNF receptor signaling. By the use of specific caspase inhibitors, caspases-3 and -8 were shown to play an important role in LPS-induced apoptosis in vivo. Thus, LPS acts through TNFR1 to modulate the expression of apoptotic genes and activate caspases-3 and -8.
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PMID:Apoptotic effects of LPS on fibroblasts are indirectly mediated through TNFR1. 1532 70

Previously we reported that both human TNFR1 and TNFR2 mediate TNF-induced apoptosis in the transfected rat/mouse T cell hybridoma PC60. We show here that TNFR2-mediated apoptosis in PVC60 cells can be blocked by the broad-spectrum caspase inhibitor zVAD-fmk, the caspase-8 inhibitor zIETD-fmk and by CrmA, a viral inhibitor of caspase-1 and caspase-8. This suggests an involvement of caspase-8 in TNFR2-mediated apoptosis. The upstream adaptor of caspase-8, FADD, is also involved in TNFR2-induced cell death, since transient overexpression of a dominant negative deletion mutant of FADD inhibited apoptosis induced by this receptor. TNFR2-induced apoptosis is independent of endogenous TNF or other death-inducing ligand production and subsequent activation of TNFR1 or other death receptors. Furthermore, TNFR2 stimulation does not enhance sensitivity for a subsequent TNFR1-induced apoptotic signal, as has been reported for Jurkat cells. TRAF2 downregulation, which has been proposed as the mechanism by which TNFR2 enhances TNFR1 signaling, was observed in PC60 cells, but the TNRF1 signal was not modulated. These data confirm the capacity of TNFR2 to generate an apoptotic cell death signal independent of TNFR1.
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PMID:Induction of apoptosis by TNF receptor 2 in a T-cell hybridoma is FADD dependent and blocked by caspase-8 inhibitors. 1565 78

TNFR1 associated death domain protein (TRADD) contains an N-terminal TRAF binding domain and a C-terminal death domain along with nuclear import and export sequences that cause shuttling between the cytoplasm and nucleus. The death domain of TRADD contains the nuclear import sequence and expression of the core death domain (nuclear TRADD) results in exclusive nuclear localization and activation of a distinct apoptotic pathway. Cytoplasmic TRADD activates apoptosis through Fas-associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant-negative FADD. These inhibitors did not inhibit death induced by nuclear TRADD, which could only be inhibited by combining caspase inhibitors and a serine protease inhibitor. The pathway activated by nuclear TRADD requires caspase-9 catalytic activity. However, apoptosis activating factor deficiency confers only partial protection from death. This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm.
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PMID:The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. 1576 71


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