Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The significance of CD95/Fas ligand expression by melanoma cells has remained a controversial matter in recent years. On the other hand, CD95 activation may represent a powerful tool for eliminating tumor cells. Here, we demonstrate expression of CD95 in 15/17 human melanoma cell lines analysed, but complete lack of CD95 ligand (CD95L). Overexpression of CD95 in a tetracycline-inducible expression system enhanced melanoma cell sensitivity to CD95 ligation but was unable to trigger apoptosis by itself. In clear contrast, all melanoma cells tested responded with increased apoptosis to conditional expression of CD95L (2-10-fold), both after transient and after stable transfection. Activation of caspase-8, Bid cleavage, cytochrome c release and caspase-3 activation followed after CD95L induction indicating a functional CD95-signaling cascade. CD95L was also able to enhance the proapoptotic effect of chemotherapeutics applied in parallel. Nude mouse experiments revealed that tumorigenicity was lost when melanoma xenografts were triggered to express CD95L. In addition, further progression of pre-existing melanomas was inhibited and even regression was seen after induction of CD95L expression. Due to these data, transfection of CD95L proofs as a highly efficient tool against melanoma cells in vitro and in vivo, and targeted expression of CD95L may thus represent a suitable strategy for melanoma therapy.
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PMID:CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants. 1466 94

CD56 is an important marker for prospecting clinicopathologic features of cytotoxic T-cell and natural killer (NK)/T-cell lymphomas. We examined 22 cases of subcutaneous panniculitis-like lymphoma and classified these into CD56-positive and CD56-negative groups. The 11 CD56-negative cases were mainly in the younger age group and had systemic subcutaneous nodules without ulceration. They exhibited subcutaneous invasion by medium-sized lymphoma cells, scattered erythrophagocytosis, patchy necrosis, and little tumor invasion in the superficial dermis. Their lymphoma cells had characteristics of CD3 epsilon-, CD8-, TcR beta F1-, T-cell intracellular antigen (TIA)1-, and granenzyme B-positive cytotoxic T cells and were negative for apoptosis-promoting proteins CD95 (Fas), Bax, CPP32 (caspase 3), and p53 (DO7). Ten patients were alive despite clinical signs of hemophagocytic syndrome and relapses in 7 cases. The 11 CD56-positive cases had systemic ulcerative skin tumors composed of pleomorphic lymphoma cells with massive necrosis and little erythrophagocytosis involving the subcutis and also often the whole dermis. Their tumor cells were positive for CD3 epsilon, TIA1, granenzyme B, CD95, CD95L (Fas ligand), Bax, and CPP32. Three cases were of the TcR beta F1-positive phenotype, 1 was of the TcR gamma/delta-positive T-cell phenotype, and 6 were of the TcR beta F1- and TcR gamma/delta-negative NK/T-cell phenotype. Six cases were p53 (DO7) positive. Seven cases had complications of liver dysfunction and cytopenia, and 8 died of disease. One CD56-negative case and 3 CD56-positive cases had nuclear signals of Epstein-Barr virus-encoded RNA in their lymphoma cells. The 2 groups had significantly (P <0.01) different prognoses by Kaplan-Meier and log-rank methods. Patients with CD56-negative and CD56-positive groups had statistically different clinicopathologic, immunohistologic, and functional findings and prognoses.
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PMID:Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitis-like lymphoma in Japan. 1499 42

Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
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PMID:Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway. 1506 94

High doses of Ag can paradoxically suppress immune responses in vivo. This Ag-specific unresponsiveness (termed high dose tolerance) involves extrathymic mechanisms in mature T lymphocytes. To investigate these mechanisms, we used the in vitro model of PBL activated with anti-CD3 or PHA. In these conditions, increasing mitogen concentrations resulted in a reduction of the proliferative response, associated with an increased percentage of apoptotic cells. Apoptosis did not require prior exposure to IL-2, it was not the consequence of CD178/CD95 or TNF/TNFR interactions, and was therefore clearly distinct from activation-induced cell death. Although the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) decreased DNA fragmentation, cytochrome c release and caspase-9 and caspase-3 activation were not implicated, suggesting that this apoptosis did not primarily involve the intrinsic mitochondrial pathway. E64d, a cysteine protease inhibitor, as well as specific inhibitors of cathepsin B and cathepsin L conferred protection. We further demonstrated that cathepsin B and cathepsin L were released from the lysosomes and catalytically active in the cytosol. Release of cathepsin B and cathepsin L was the consequence of lysosomal membrane permeabilization without complete disruption of the cytosol-lysosome pH gradient. These results demonstrate a role for cathepsins in supraoptimal activation-induced apoptosis in vitro and suggest their possible participation in high dose tolerance in vivo.
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PMID:Cathepsin-dependent apoptosis triggered by supraoptimal activation of T lymphocytes: a possible mechanism of high dose tolerance. 1510 Feb 81

Lyssaviruses, which are members of the Rhabdoviridae family, induce apoptosis, which plays an important role in the neuropathogenesis of rabies. However, the mechanisms by which these viruses mediate neuronal apoptosis have not been elucidated. Here we demonstrate that the early induction of apoptosis in a model of lyssavirus-infected neuroblastoma cells involves a TRAIL-dependent pathway requiring the activation of caspase-8 but not of caspase-9 or caspase-10. The activation of caspase-8 results in the activation of caspase-3 and caspase-6, as shown by an increase in the cleavage of the specific caspase substrate in lyssavirus-infected cells. However, neither caspase-1 nor caspase-2 activity was detected during the early phase of infection. Lyssavirus-mediated cell death involves an interaction between TRAIL receptors and TRAIL, as demonstrated by experiments using neutralizing antibodies and soluble decoy TRAIL-R1/R2 receptors. We also demonstrated that the decapsidation and replication of lyssavirus are essential for inducing apoptosis, as supported by UV inactivation, cycloheximide treatment, and the use of bafilomycin A1 to inhibit endosomal acidification. Transfection of cells with the matrix protein induced apoptosis using pathways similar to those described in the context of viral infection. Furthermore, our data suggest that the matrix protein of lyssaviruses plays a major role in the early induction of TRAIL-mediated apoptosis by the release of a soluble, active form of TRAIL. In our model, Fas ligand (CD95L) appears to play a limited role in lyssavirus-mediated neuroblastoma cell death. Similarly, tumor necrosis factor alpha does not appear to play an important role.
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PMID:Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. 1516 47

Entorhinal cortex lesion (ECL) is a well described model of anterograde axonal degeneration, subsequent sprouting and reactive synaptogenesis in the hippocampus. Here, we show that such lesions induce transsynaptic degeneration of the target cells of the lesions pathway in the dentate gyrus. Peaking between 24 and 36 hours post-lesion, dying neurons were labeled with DeOlmos silver-staining and antisera against activated caspase 3 (CCP32), a downstream inductor of programmed cell death. Within caspase 3-positive neurons, fragmented nuclei were co-localized using Hoechst 33342 staining. Chromatin condensation and nuclear fragmentation were also evident in semithin sections and at the ultrastructural level, where virtually all caspase 3-positive neurons showed these hallmarks of apoptosis. There is a well-described upregulation of the apoptosis-inducing CD95/L system within the CNS after trauma, yet a comparison of caspase 3-staining patterns between CD95 (Ipr)- and CD95L (gld)-deficient with non-deficient mice (C57/bl6) provided no evidence for CD95L-mediated neuronal cell death in this setting. However, inhibition of NMDA receptors with MK-801 completely suppressed caspase 3 activation, pointing to glutamate neurotoxicity as the upstream inducer of the observed cell death. Thus, these data show that axonal injury in the CNS does not only damage the axotomized neurons themselves, but can also lethally affect their target cells, apparently by activating glutamate-mediated intracellular pathways of programmed cell death.
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PMID:Entorhinal cortex lesion in the mouse induces transsynaptic death of perforant path target neurons. 1544 79

Physalis species is a popular folk medicine used for treating cancer, leukemia, hepatitis and other diseases. Studies have shown that the ethanol extract of Physalis peruviana (EEPP) inhibits growth and induces apoptotic death of human Hep G2 cells in culture, whereas proliferation of the mouse BALB/C normal liver cells was not affected. In this study, we performed detailed studies to define the molecular mechanism of EEPP-induced apoptosis in Hep G2 cells. The results further confirmed that EEPP inhibited cell proliferation in a dose- and time-dependent manner. At 50 microg/ml, EEPP significantly increased the accumulation of the sub-G1 peak (hypoploid) and the portion of apoptotic annexin V positive cells. EEPP was found to trigger apoptosis through the release of cytochrome c, Smac/DIABLO and Omi/HtrA2 from mitochondria to cytosol and consequently resulted in caspase-3 activation. Pre-treatment with a general caspase inhibitor (z-VAD-fmk) prevented cytochrome c release. After 48 h of EEPP treatment, the apoptosis of Hep G2 cells was found to associate with an elevated p53, and CD95 and CD95L proteins expression. Furthermore, a marked down-regulation of the expression of the Bcl-2, Bcl-XL and XIAP, and up-regulation of the Bax and Bad proteins were noted. Taken together, the present results suggest that EEPP-induced Hep G2 cell apoptosis was possibly mediated through the CD95/CD95L system and the mitochondrial signaling transduction pathway.
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PMID:Physalis peruviana extract induces apoptosis in human Hep G2 cells through CD95/CD95L system and the mitochondrial signaling transduction pathway. 1548 39

To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy. However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli. Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation. These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing. CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri. Unexpectedly, the BH3-only protein Bid was strongly induced. Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation. Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation. Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells. These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induced.
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PMID:CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack. 1552 17

The aromatase knockout (ArKO) mouse is unable to synthesize estrogens. Immunohistochemical studies on active caspase-3 and tyrosine hydroxylase (TH) revealed apoptosis of dopaminergic neurons in the medial preoptic area (MPO) and arcuate nucleus (Arc) of the hypothalamus of 1-year-old (1yo) male ArKO mice while no active caspase-3 was detected in wild type (WT). Furthermore, the number of TH-positive cells in the MPO and caudal Arc was significantly decreased in 1yo ArKO compared to WT. RNase protection assays support the presence of apoptosis in 1yo ArKO hypothalamus, revealing an up-regulation of pro-apoptotic genes: FASL, FADD, and caspase-8. Concomitantly, the ratio of bcl-2-related anti-apoptotic genes to pro-apoptotic genes in the hypothalamus of 1yo ArKO mice was significantly down-regulated. Previously, we have reported that no such changes were observed in the hypothalamus of female ArKO mice. Thus, we have provided direct evidence that estrogen is required to maintain the survival and functional integrity of dopaminergic neurons in the MPO and Arc of male, but not female mice.
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PMID:Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice. 1555 24

Apoptosis, or programmed cell death, can occur via death receptor or mitochondrial pathways. Normal spermatogenesis in mammals involves apoptosis mediated, in part, by the death receptor fas and its ligand. The regulation of programmed cell death in the gonads has been shown to be dependent on a number of locally produced factors, including GnRH. Whereas the role of GnRH in the control of apoptosis and follicular atresia has been documented in the mammalian ovary, GnRH regulation of testicular apoptosis remains obscure. A previous study in our laboratory demonstrated the involvement of GnRH on the induction of DNA fragmentation in mature, perispawning testis. In this study, we tested the hypothesis that GnRH plays a differential regulatory role during male gamete maturation by studying the effect of GnRH on the induction of apoptosis during goldfish spermatogenesis. Treatment with GnRH resulted in DNA fragmentation only during late stages of spermatogenesis as assessed by oligonucleotide detection and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays. The GnRH-induced apoptosis in the goldfish testis was found to be mediated by increased levels of fas and fas ligand-like proteins as well as elevated activity of caspase-3 (an executioner caspase) and -8 (a death receptor-activated caspase). The results suggest the involvement of the death receptor pathway in GnRH-induced apoptosis, providing support for the hypothesis that GnRH plays an important role in the control of spermatogenesis in the goldfish testis.
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PMID:Gonadotropin-releasing hormone induction of apoptosis in the testes of goldfish (Carassius auratus). 1556 32


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