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)

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.
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PMID:CD 95-independent mechanisms of IL-2 deprivation-induced apoptosis in activated human lymphocytes. 1082 77

Endothelial cells are the primary targets of circulating immune and inflammatory mediators. We hypothesize that interleukin-18, a proinflammatory cytokine, induces endothelial cell apoptosis. Human cardiac microvascular endothelial cells (HCMEC) were treated with interleukin (IL) 18. mRNA expression was analyzed by ribonuclease protection assay, protein levels by immunoblotting, and cell death by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter analysis. We also investigated the signal transduction pathways involved in IL-18-mediated cell death. Treatment of HCMEC with IL-18 increases 1) NF-kappaB DNA binding activity; 2) induces kappaB-driven luciferase activity; 3) induces IL-1beta and TNF-alpha expression via NF-kappaB activation; 4) inhibits antiapoptotic Bcl-2 and Bcl-X(L); 5) up-regulates proapoptotic Fas, Fas-L, and Bcl-X(S) expression; 6) induces fas and Fas-L promoter activities via NF-kappaB activation; 7) activates caspases-8, -3, -9, and BID; 8) induces cytochrome c release into the cytoplasm; 9) inhibits FLIP; and 10) induces HCME cell death by apoptosis as seen by increased annexin V staining and increased levels of mono- and oligonucleosomal fragmented DNA. Whereas overexpression of Bcl-2 significantly attenuated IL-18-induced endothelial cell apoptosis, Bcl-2/Bcl-X(L) chimeric phosphorothioated 2'-MOE-modified antisense oligonucleotides potentiated the proapoptotic effects of IL-18. Furthermore, caspase-8, IKK-alpha, and NF-kappaB p65 knockdown or dominant negative IkappaB-alpha and dominant negative IkappaB-beta or kinase dead IKK-beta significantly attenuated IL-18-induced HCME cell death. Effects of IL-18 on cell death are direct and are not mediated by intermediaries such as IL-1beta, tumor necrosis factor-alpha, or interferon-gamma. Taken together, our results indicate that IL-18 activates both intrinsic and extrinsic proapoptotic signaling pathways, induces endothelial cell death, and thereby may play a role in myocardial inflammation and injury.
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PMID:Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. 1496 May 79

The role of mitochondria and apical caspases in apoptosis induced by the benzene metabolite hydroquinone (HQ) remains to be elucidated. Here, we investigated the involvement of mitochondria and activation of the apical caspases-8 and -9 in HQ induced apoptosis in myeloperoxidase (MPO)-rich HL-60 and MPO-deficient Jurkat T cells. Treatment of HL-60 and Jurkat cells with HQ resulted in apoptosis as assessed by phosphatidyl serine (PS) exposure, loss of mitochondrial transmembrane potential (MTP), release of cytochrome c, and processing of apical caspases-8 and -9 and executioner caspase-3. In HQ-treated HL-60 cells, pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (ZVAD), which did not inhibit PS exposure, also failed to abrogate the loss of MTP and release of cytochrome c. However, complete processing of caspase-9 was inhibited in the presence of ZVAD. In marked contrast, in HQ-treated Jurkat cells, ZVAD significantly abrogated PS exposure, loss of MTP, and caspase-9 processing but not release of cytochrome c. Although ZVAD-sensitive caspase-8 processing occurred in both cell types, pretreatment with either fas-receptor blocking ZB4 or fas-ligand NOK1 neutralizing antibodies did not inhibit HQ-induced apoptosis. In conclusion, our results demonstrate that HQ induced apoptosis in Jurkat cells occurs via a ZVAD-inhibitable, caspase-dependent process, while in HL-60 cells, apoptosis occurs predominantly via caspase-independent mechanisms. Our results emphasize that both caspase-dependent and independent mechanisms should be considered in the intrinsic apoptotic pathway induced by HQ.
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PMID:Intrinsic pathway of hydroquinone induced apoptosis occurs via both caspase-dependent and caspase-independent mechanisms. 1577 82

The detailed mechanisms behind the apoptosis of macrophages induced by testosterone are not clear. In the present study, we tried to delineate the effect of testosterone on the apoptosis of bone marrow-derived macrophages (BMMs) and the function of Fas/FasL (Fas ligand) pathway in this course. BMMs were stimulated with testosterone in the presence of macrophage colony stimulating factor (M-CSF) or without. Flow cytometry was used to quantify the apoptosis of BMMs. Real-time RT-PCR and Western blot were performed to analyze the expression of caspase-8, caspase-3, and poly(ADP-ribose) polymerase (PARP) during the Fas/FasL pathway. Our data showed that testosterone could induce the apoptosis of BMMs, similar to removing growth factor M-CSF from the culture medium. They were both associated with the enhanced expression of caspase-8, caspase-3, and PARP. And the phosphorothioate antisense oligodeoxynucleotides to fas-associated death domain protein (FADD) could block the expression of FADD, which is an upstream factor of caspase-8 in the Fas/FasL pathway. It led to the reduced obvious expression of caspase-8 and decreasing apoptosis of BMMs. These results suggest that the Fas/FasL pathway may play an important role in the testosterone-induced apoptosis of macrophages.
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PMID:Testosterone induces apoptosis via Fas/FasL-dependent pathway in bone marrow-derived macrophages. 1684 45

Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-gamma is mediated by IRF-1 and IFN-gamma, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.
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PMID:Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells. 1745 73

B7-H1 is a newly identified member of the B7 family with important regulatory functions in cell-mediated immune responses, and it is expressed in human immune cells and several tumors. We first observed that expression of surface B7-H1 on B cells was increased during the immortalization process by EBV, which is strongly related to both inflammation and tumorigenesis. Cross-linking of B7-H1 on EBV-transformed B cells using anti-B7-H1 Ab (clone 130002) induced reactive oxygen species (ROS) generation, mitochondrial disruption, release of apoptotic proteins from mitochondria, and subsequent apoptosis. Inhibition of caspases and ROS generation recovered B7-H1-mediated apoptosis and proteolytic activities of caspase-8, -9, and -3. We observed that B7-H1 stimulation induced both transcription and translation of fasL. ZB4, an antagonistic anti-fas Ab, and NOK-1, an antagonistic anti-fasL Ab, effectively blocked apoptosis without exerting any influence on ROS generation. N-acetylcysteine (NAC) completely blocked the induction of fasL mRNA and protein. We found that B7-H1 stimulation activated the phosphorylation of JNK and c-jun and down-regulated ERK1/2 and p-Akt. NAC blocked the activation of JNK and down-regulation of ERK, but both z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone) and ZB4 did not inhibit JNK activation of B7-H1 stimulation. SP600125 blocked fasL induction and apoptosis but did not affect ROS generation after B7-H1 stimulation. Taken together, we concluded that B7-H1-mediated apoptosis on EBV-transformed B cells may be involved in the induction of fasL, which is evoked by ROS generation and JNK activation after cross-linking of B7-H1. These results provide a new concept for understanding reverse signaling through B7-H1 and another mechanism of tumor immunotherapy using anti-B7-H1.
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PMID:Cross-linking of B7-H1 on EBV-transformed B cells induces apoptosis through reactive oxygen species production, JNK signaling activation, and fasL expression. 1894 Dec 6

Fas-apoptosis inhibitory molecule (FAIM) is inducibly expressed in B lymphocytes and had been shown to antagonize Fas-mediated killing of B-cell lines in vitro. However, its mechanism and role in vivo are unknown. We have generated faim(-/-) mice and found these mutants to be viable. In contrast to fas(-/-) mice, faim(-/-) mice have normal B- and T-cell populations. However, faim(-/-) B cells and thymocytes show increased sensitivity to Fas-triggered apoptosis in vitro, and faim(-/-) mice suffer greater mortality and exhibit exacerbated liver damage in response to Fas (CD95) engagement in vivo. The lack of FAIM results in greater activation of caspase-8 and -3 in Fas-stimulated thymocytes. Detailed biochemical analyses further reveal the decreased expression of c-FLIP(L) and c-FLIP(R) in faim(-/-) thymocytes and increased association of caspase-8 with Fas in Fas-activated mutant cells. Decreased levels of c-FLIP(L) and c-FLIP(R) are also evident in faim(-/-) liver. Thus, FAIM plays a novel role in modulating Fas-mediated apoptosis and acts through influencing the expression of c-FLIP and regulating the physical binding of caspase-8 to Fas.
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PMID:Genetic deletion of faim reveals its role in modulating c-FLIP expression during CD95-mediated apoptosis of lymphocytes and hepatocytes. 1930 Apr 54

Selenoprotein W (SelW) is expressed in various tissues of many animals and acts as an oxidoreductase in mammals. However, little is known about the role of the SelW in birds. To investigate the role of the chicken SelW on H(2)O(2)-induced apoptosis in CHO-K1 cells, overexpression of a chicken SelW cell lines (CHO-K1/SelW) were constructed. Using acridine orange/ethidium bromide (AO/EB) double staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays, as well as WST-1 cell viability assay, we monitored the extent of the H(2)O(2)-induced apoptosis and detected the abundance of the caspase-3, caspase-8, and fas mRNA by real-time quantitative reverse transcription PCR (qPCR). We here found that overexpression of SelW cells, compared with the wild-type cells, resulted in a markedly decrease in sensitivity to H(2)O(2)-induced oxidative stress and had a lower apoptotic cell death in AO/EB and TUNEL assays. Cell viability revealed that overexpression of SelW cells had higher cell viability than wild-type cells. qPCR results found that overexpression of SelW cells had a lower levels of caspase-3, caspase-8, and fas mRNA than wild-type cells. Taken together, our findings suggested that SelW could reduce the oxidative damage induced by H(2)O(2) and had an important protective function in against oxidative damage.
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PMID:Effects of chicken selenoprotein W on H2O2-induced apoptosis in CHO-K1 cells. 2220 19

Disruption of tight junctions is often seen during pathogen infection, inflammation, and tumor progression. Mislocalization of the tight junction proteins occludin and claudin in mammary epithelial monolayers leads to apoptosis through the extrinsic pathway. To further investigate the mechanism of this response, a normal mammary epithelial cell line (EpH4) as well as primary mammary epithelial cells were treated with a claudin-disrupting mimic peptide, DFYNP (aspartic acid-phenylalanine-tyrosine-asparagine-proline). Using fluorescent indicators, we found that caspase-3 activation, resulting from treatment with DFYNP, was restricted to EpH4 and primary mammary epithelial cells with mislocalized claudin-4. Mislocalized claudin-4 and occludin were colocalized in non-junctional puncta, and both molecules were found in the death-inducing signaling complex (DISC) where they colocalized with Fas, fas-associated protein with death domain (FADD), active caspase-8 and caspase-3 at distinct apical domains. Importantly, caspase-3 activation was totally repressed in primary mammary epithelial cells from occludin null mice. Thus, the apoptotic response appears to be initiated by the movement of occludin to the DISC suggesting that this molecule has signaling properties that initiate cell death when its tight junction location is disrupted.
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PMID:Occludin is required for apoptosis when claudin-claudin interactions are disrupted. 2236 48

Fas-associated protein with death domain (FADD) is a pivotal component of death receptor-mediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation. MKRN1 knockdown results in FADD protein stabilization and formation of the rapid death-inducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that MKRN1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of MKRN1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using MDA-MB-231 breast cancer cells. Suppression of tumour growth by MKRN1 depletion is relieved by simultaneous FADD knockdown. Our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway.
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PMID:Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. 2286 71


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