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

The killing of L929 mouse fibroblasts by tumor necrosis factor-alpha (TNF-alpha) in the presence of 0.5 microg/ml actinomycin D (Act D) is prevented by inhibition of the mitochondrial permeability transition (MPT) with cyclosporin A (CyA) in combination with the phospholipase A(2) inhibitor aristolochic acid (ArA). The MPT is accompanied by the release of cytochrome c from the mitochondria, caspase-8 and caspase-3 activation in the cytosol, cleavage of the nuclear enzyme poly(ADP-ribose)polymerase (PARP), and DNA fragmentation, all of which were inhibited by CyA plus ArA. The caspase-3 inhibitor z-Asp-Glu-Val-aspartic acid fluoromethyl-ketone (Z-DEVD-FMK) did not prevent the loss of viability or the redistribution of cytochrome c, but it did prevent caspase-3 activation, PARP cleavage, and DNA fragmentation. Inhibition of the MPT reduced the activation of caspase-8 to the level occurring with TNF-alpha alone (no ActD). The caspase-8 inhibitor z-Ile-Glu(OMe)-Thr-Asp(OMe) fluoromethylketone (Z-IETD-FMK) did not prevent the cell killing and decreased only slightly the translocation of Bid to the mitochondria. These data indicate that induction of the MTP by TNF-alpha causes a release of cytochrome c, caspase-3 activation with PARP cleavage and DNA fragmentation. The loss of viability is dependent on the MPT but independent of the activation of caspase-3. The activation of caspase-8 is not dependent on the MPT. There is no evidence linking this enzyme to the loss of viability. Thus, the killing of L929 fibroblasts by TNF-alpha can occur in the absence of either caspase-3 or caspase-8 activity. Alternatively, cell death can be prevented despite an activation of caspase-8.
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PMID:Cytochrome c-dependent activation of caspase-3 by tumor necrosis factor requires induction of the mitochondrial permeability transition. 1085 32

The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-alpha (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspase-dependent protein kinase Cdelta and poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK activities were insensitive to pharmacological caspase inhibition or CrmA. These findings were supported when measuring TNF-induced cytosolic phospholipase A(2) activation, which is a downstream target for MAPK and p38 MAPK. Profiling caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, -3, -7, -6 and -9 activation, with their inhibition characteristics suggesting a role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together these results show delineated ERK-activation pathways employed by TNFR subtypes.
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PMID:Tumour necrosis factor-induced activation of c-Jun N-terminal kinase is sensitive to caspase-dependent modulation while activation of mitogen-activated protein kinase (MAPK) or p38 MAPK is not. 1199 67

Activation of phospholipase A(2), degradation of membrane phospholipids resulting in tissue accumulation of arachidonic acid, and the activation of cyclooxygenase that leads to the formation of prostaglandin and free radicals may occur after hypoxic-ischemic damage. The aim of this study was to investigate the effects of indomethacin, a nonselective cyclooxygenase inhibitor, on caspase activity, glutathione levels and lipid peroxidation in newborn rats with hypoxic-ischemic encephalopathy. The effects of indomethacin were evaluated by measuring caspase-3 and caspase-8 activities and glutathione levels. Lipid peroxidation was evaluated by measuring concentrations of malondialdehyde in rat brains. Seven-day-old rat pups with the Levine-Rice model of hypoxic-ischemic cerebral injury were randomly divided into three study groups. In the indomethacin-treated group, rats were administered three doses of indomethacin, at a dose of 2 mg/kg every 12 h. Sham and the hypoxic-ischemic group of rats were given physiologic saline. The sham group underwent all surgical procedures except for arterial ligation. After 72 hours, the rats were decapitated and brain tissues were evaluated. Caspase-3 and caspase-8 activities and glutathione and malondialdehyde levels were evaluated in all groups. There was an obvious decrease in caspase-3 and caspase-8 activities and depleted glutathione levels were reversed in the indomethacin-treated group compared to the hypoxic-ischemia group (p<0.001). As indomethacin was unable to prevent lipid peroxidation, malondialdehyde concentrations increased to ischemia-induced levels. In conclusion, indomethacin administration after hypoxic-ischemic encephalopathy injury has a neuroprotective effect since it inhibits caspase activity and reverses the depletion of glutathione. However, it also aggravates lipid peroxidation-induced ischemia.
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PMID:The effects of indomethacin on caspases, glutathione level and lipid peroxidation in the newborn rats with hypoxic-ischemic cerebral injury. 1961 46