Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased expression of Fas receptor by haemopoietic progenitors in aplastic anaemia (AA) suggests that excessive apoptosis contributes to multilineage bone marrow (BM) failure. To investigate the role of Fas ligand (FasL) in triggering progenitor cell death, we examined FasL levels in T lymphocytes of patients with severe untreated AA (n = 8). Expression of FasL on the surface of CD3+ cells was not detectable. However, flow cytometric analysis of saponin-permeabilized cells demonstrated higher levels of intracellular FasL in AA than in normal T cells (P < 0.005), both prior to and following activation with phytohaemagglutinin. Confocal microscopy revealed that FasL-specific signals overlapped with cathepsin D staining, indicating that intracellular FasL is stored in lysosomal granules. Levels of intracellular FasL in patients examined 1 month after immunosuppression with antilymphocyte globulin and cyclosporin A were lower than prior to treatment. The caspase inhibitors, DEVD and zVAD, enhanced colony formation and prolonged survival of AA BM cells in liquid cultures by about 10-fold (P < 0.05). Taken together, these data provide further evidence that apoptosis by the Fas/FasL system plays a role in the depletion of stem cells in AA.
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PMID:Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia. 1156 81

Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J(2)-series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). The observation that the level of 15d-PGJ(2) increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ(2) may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ(2) induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45, cyclin G1, and cathepsin D, were significantly up-regulated in the cells treated with 15d-PGJ(2). Indeed, the 15d-PGJ(2) induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ(2) was functional. The 15d-PGJ(2)-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.
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PMID:15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis. 1203 89

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell-cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase- and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.
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PMID:The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse. 1659 35

Activated T cells secrete Fas ligand (FasL)-containing vesicles (secreted vesicles) that induce death of target cells. We provide evidence that secreted vesicles from culture supernatants (Csup) of various origins are able to generate both Fas-dependent apoptotic and Fas-independent, nonapoptotic cell death. In the absence of Fas, the nonapoptotic, Fas-independent pathway could still induce cell death. In contrast to RIP-independent classical Fas-induced cell death triggered by cross-linked or membrane-bound FasL, CSup-derived stimuli-induced apoptosis exhibited unique molecular and enzymatic characteristics. It could be partially inhibited by blocking cathepsin D enzyme activity and required the presence of RIP. Whereas stimulation with CSup, derived from both FasL-overexpressing Jurkat cells and PBMC, could induce cell death, the requirements for Fas-associated death domain protein and caspase-9 were different between the two systems. Our study highlights an important distinction between cell contact-mediated and secreted vesicle-generated activation-induced cell death and also demonstrates that the type of the secreted vesicles can also modify the cell death route. We propose that besides cell-to-cell interaction-mediated Fas triggering, stimuli induced by secreted vesicles can mediate important additional cell death signals regulating activation-induced cell death under physiological conditions.
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PMID:Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths. 2289 Dec 83