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)

A role for caspase-10, previously implicated in the autoimmune lymphoproliferative syndrome, in death receptor signaling has not been directly shown. Here we show that caspase-10 can function independently of caspase-8 in initiating Fas- and tumor necrosis factor-related apoptosis-inducing ligand-receptor-mediated apoptosis. Moreover, Fas crosslinking in primary human T cells leads to the recruitment and activation of caspase-10. Fluorescent resonance energy transfer analysis indicates that the death-effector domains of caspase-8 and -10 both interact with the death-effector domain of FADD. Nonetheless, we find that caspase-8 and -10 may have different apoptosis substrates and therefore potentially distinct roles in death receptor signaling or other cellular processes.
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PMID:Caspase-10 is an initiator caspase in death receptor signaling. 1171 45

We have analysed the genetic alteration of the entire coding region and all splice sites of caspase-8 and -10 genes in 99 gastric cancers by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. We found LOH of the caspase-8 and -10 in nine (28%) of 32 and in four (15%) of 26 informative cases, respectively. Overall, three of 99 gastric cancers (3%) were found to have the caspase-10 mutations, which were identified in the coding regions of the death effector domain (codon 147) and the p17 large protease domain (codons 257 and 410), whereas no mutation was detected in caspase-8. In vitro expression studies, the M147T and Q257stop mutants severely impaired caspase-10-mediated apoptosis, whereas the V410I which was the same mutation detected in ALPS patient had a significant, albeit less severe, effect on apoptosis. The data presented here suggest that somatic alterations of the caspase-10 gene might contribute to the pathogenesis in a subset of gastric cancers through the loss of their apoptotic function.
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PMID:Inactivating mutations of the caspase-10 gene in gastric cancer. 1197 54

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.
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PMID:Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. 1235 64

Human and mouse natural mutants presenting with lymphoproliferative syndrome and autoimmunity (ALPS) have enlightened the role of the Fas and FasL in lymphocyte cell death and peripheral tolerance. Further study of the genetic basis of the human pathology led to the identification of apoptosis signaling defect, and pointed out to the crucial role of caspase-10 in the process of apoptosis induction. In contrast, the absence of lymproliferation in engineered mutants of 'death pathways' suggests that additional events are necessary to recapitulate the overt phenotype of ALPS patients or MRL/lpr mice. Moreover, these models highlight the roles of Fas and associated molecules, such as FADD and caspase-8, in lymphocyte development or activation. This review will discuss the main findings provided by the study of mouse models and human conditions.
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PMID:Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. 1265 1

In the immune system, lymphocyte activation by antigen is followed by cell proliferation and induction of effector functions. Subsequently, physiologic cell-death signals are induced, resulting in removal of expanded effector-cell populations, to maintain homeostasis. Caspases are intracellular participants in both activation responses and cell death by apoptosis. Targets of caspases include inflammatory activators and also other members of the caspase family that mediate apoptosis. Caspase-8 and caspase-10 participate in the protease cascade following cell surface CD95 engagement by its ligand. Humans with defects in these caspases were initially evaluated for the autoimmune lymphoproliferative syndrome because of their spleen and lymph node enlargement. Although both caspase-8- and caspase-10-deficient individuals had impaired apoptosis, those with caspase-8 deficiency, who also had immunodeficiency, had additional defects in activation of lymphocytes and natural killer cells. These disorders help to define the importance and specificity of the caspase proteases in intracellular signaling pathways.
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PMID:Immune disorders caused by defects in the caspase cascade. 1290 72

Triggering of the Fas receptor induces T cell apoptosis and is involved in shutting-off the immune response. Inherited defects impairing Fas function cause the autoimmune lymphoproliferative syndrome, and may play a role in other autoimmune diseases. The aim of this work was to analyse the Fas function in paediatric patients with thyroid autoimmunities. We found that T cells from 24/28 patients with Graves' disease (GD) and 12/35 patients with Hashimoto's thyroiditis (HT) displayed defective Fas function. In HT, the defect was more frequent in patients requiring replacement therapy (11/20) than in those not requiring (1/15); moreover, in untreated HT the highest defect was displayed by patients with the highest levels of autoantibodies. Fas was always expressed at normal levels and no Fas mutations were detected. Analysis of the healthy parents of seven Fas-resistant patients showed that several of them were Fas-resistant, which suggests a genetic component. Fusion of Fas-resistant T cells with the Fas-sensitive HUT78 T cell line generated Fas-resistant hybrid cells, which suggests the presence of molecules exerting a dominant negative effect on Fas function. Analysis of Fas-induced activation of caspase-8 and -9 showed decreased activity of both caspases in HT, whereas activity of caspase-9 was increased and that of caspase-8 was decreased in GD. These data suggest that heterogeneous inherited defects impairing Fas function favour the development of thyroid autoimmunities.
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PMID:Defective function of Fas in T cells from paediatric patients with autoimmune thyroid diseases. 1293 Mar 71

Human autoimmune lymphoproliferative syndrome has been described as a result of various mutations concerning genes encoding receptor CD95 and/or its ligand - CD178. However, recently, several cases with identical clinical manifestation, despite a normal structure of CD95 or CD178 have also been reported. In this study we analyzed PBMC obtained from patient with clinically overt lymphoproliferative disorder. Using in vitro assays as well as molecular methods we tested expression and biological activity of CD95 and CD178 molecules. We found that analyzed patient's lymphocytes displayed normal cytotoxic activity against CD95-bearing targets. However, CD95-dependent induction of apoptosis in analyzed lymphocytes was diminished, as compared to healthy control. Surprisingly, the molecular studies did not reveal any abnormalities in structure of patient-derived CD95 receptor molecule. Therefore, expression of other factors involved in CD95-mediated signaling pathway was estimated using RNase protection assay. The expression of FADD was comparable to that of healthy control. However, it has been found that patient-derived lymphocytes expressed reduced amount of caspase-8 mRNA, as compared to control subject cells. This report confirms previous observations that lymphoproliferative disorder could be associated not only with CD95 and/or CD178 mutations, but also with dysfunction of other components of apoptosis induction pathway. However, the detailed molecular mechanism of observed abnormalities in caspase-8 expression remains to be elucidated.
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PMID:Impaired apoptosis of lymphocytes derived from patient with decreased expression of caspase-8 results in Alps-like phenotype. 1549 69

Fas (CD95, APO-1, TNFRSF6) is a TNF receptor superfamily member that directly triggers apoptosis and contributes to the maintenance of lymphocyte homeostasis and prevention of autoimmunity. Although FADD and caspase-8 have been identified as key intracellular mediators of Fas signaling, it is not clear how recruitment of these proteins to the Fas death domain leads to activation of caspase-8 in the receptor signaling complex. We have used high-resolution confocal microscopy and live cell imaging to study the sequelae of early events in Fas signaling. These studies have revealed a new stage of Fas signaling in which receptor ligation leads to the formation of surface receptor oligomers that we term signaling protein oligomerization transduction structures (SPOTS). Formation of SPOTS depends on the presence of an intact Fas death domain and FADD but is independent of caspase activity. Analysis of cells expressing Fas mutations from patients with the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted by distinct mechanisms in ALPS.
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PMID:SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. 1555 23

Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine), a folic acid antagonist, may exert, in addition to antiprotozoan effects, immunomodulating activities, including induction of peripheral blood lymphocyte apoptosis. However, the molecular mechanisms underlying this proapoptotic activity remain to be elucidated. Here we show that pyrimethamine, used at a pharmacologically relevant concentration, induced per se apoptosis of activated lymphocytes via the activation of the caspase-8- and caspase-10-dependent cascade and subsequent mitochondrial depolarization. Importantly, this seems to occur independently from CD95/Fas engagement. The proapoptotic activity of pyrimethamine was further confirmed in a patient with autoimmune lymphoproliferative syndrome, an immune disorder associated with a defect of Fas-induced apoptosis. In this patient, pyrimethamine treatment resulted in a "normalization" of lymphocyte apoptosis with a significant amelioration of laboratory parameters. Altogether, these results suggest a mechanism for pyrimethamine-mediated apoptosis that seems to bypass CD95/Fas engagement but fully overlaps CD95/Fas-induced subcellular pathway. On these bases, a reappraisal of the use of pyrimethamine in immune lymphoproliferative disorders characterized by defects in CD95/Fas-mediated apoptosis should be taken into account.
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PMID:Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethylpyrimidine) induces apoptosis of freshly isolated human T lymphocytes, bypassing CD95/Fas molecule but involving its intrinsic pathway. 1615 60

Caspase-8 is best known for its cell death function via death receptors. Recent evidence indicates that caspase-8 also has nonapoptotic functions. Caspase-8 deficiency is associated with pathologies that are unexpected for a proapoptotic molecule, such as abrogation of activation-induced lymphocyte proliferation, perturbed immune homeostasis, and immunodeficiency. In this study, we report the long-term physiological consequences of T cell-specific deletion of caspase-8 (tcasp8-/-). We show that tcasp8-/- mice develop an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and accumulation of T cell infiltrates in the lungs, liver, and kidneys. Peripheral casp8-/- T cells manifest activation marker up-regulation and are proliferating in the absence of any infection or stimulation. We also provide evidence suggesting that this immune disorder is different from the autoimmune lymphoproliferative syndrome. Interestingly, the condition described in tcasp8-/- mice manifests features consistent with the disorder described in humans with Caspase-8 deficiency. These findings suggest that tcasp8-/- mice may serve as an animal model to evaluate Caspase-8-deficient patient prognosis and therapy. Overall, our study uncovers novel in vivo functions for caspase-8 in immune regulation.
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PMID:Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. 1615 84


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