Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 neuraminidase/trans-sialidase of Trypanosoma cruzi, the agent of Chagas' disease, promotes differentiation and survival of growth factor-deprived neuronal and glial cells. To gain further insights into the possible neuroprotection of this parasite-derived counterpart of neurotrophic factors (PDNF), we sought to determine whether it mimics growth factors in a cellular model of neurodegenerative diseases. Ascertaining cell viability by morphology, vital dye exclusion, mitochondrial reducing function, and absence of DNA fragmentation, we show here that PDNF rescues from death two dopaminergic neuronal cell lines and one differentiated immortalized mesencephalic neurons exposed to the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), both widely used in models of Parkinson's disease. We further show that PDNF promoted survival at concentrations comparable to bona fide growth factors in a MAPK/Erk activation-dependent manner. PDNF also strongly suppresses the overproduction of MPTP-induced reactive oxygen species (ROS), and the activation of both initiator caspase-9 and effector caspase-3. This down-regulation of ROS and caspases explains, at least in part, the PDNF-induced salvaging of the dopaminergic cells from the Parkinsonism-promoting toxin, confirming the novel and striking functional mimicry by the trypanosome neuraminidase of host growth factors in a cellular model of neurodegeneration.
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PMID:PDNF, a human parasite-derived mimic of neurotrophic factors, prevents caspase activation, free radical formation, and death of dopaminergic cells exposed to the Parkinsonism-inducing neurotoxin MPP+. 1459 29

Sialylation is emerging as an important issue in developing thymocytes and is considered among the most significant cell surface modifications, although its physiologic relevance is far from being completely understood. It is regulated by the concerted expression of sialyl transferases along thymocyte development. After in vivo administration of trans-sialidase, a virulence factor from the American trypanosomatid Trypanosoma cruzi that directly transfers the sialyl residue among macromolecules, we found that the alteration of the sialylation pattern induces thymocyte apoptosis inside the "nurse cell complex." This suggests a glycosylation survey in the development of the T cell compartment. In this study, we report that this thymocyte apoptosis mechanism requires the presence of androgens. No increment in apoptosis was recorded after trans-sialidase administration in females or in antiandrogen-treated, gonadectomized, or androgen receptor mutant male mice. The androgen receptor presence was required only in the thymic epithelial cells as determined by bone marrow chimeric mouse approaches. The presence of the CD43 surface mucin, a molecule with a still undefined function in thymocytes, was another absolute requirement. The trans-sialidase-induced apoptosis proceeds through the TNF-alpha receptor 1 deathly signaling leading to the activation of the caspase 3. Accordingly, the production of the cytokine was increased in thymocytes. The ability of males to delete thymocytes altered in their sialylation pattern reveals a sexual dimorphism in the glycosylation survey during the development of the T cell compartment that might be related to the known differences in the immune response among sexes.
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PMID:A sexual dimorphism in intrathymic sialylation survey is revealed by the trans-sialidase from Trypanosoma cruzi. 1581 75

Human plasma membrane-associated sialidase (NEU3), specifically hydrolyzing gangliosides, plays crucial roles in the regulation of cell surface functions. Here we demonstrate that NEU3 mRNA level are increased in renal cell carcinomas (RCCs) compared with adjacent non-tumor tissues, significantly correlating with elevation of interleukin-6 (IL-6), a pleiotropic cytokine that has been implicated in immune responses and pathogenesis of several cancers, including RCCs. In human RCC ACHN cells, IL-6 treatment enhanced NEU3 promoter luciferase activity 2.5-fold and the endogenous sialidase activity significantly. NEU3 transfection or IL-6 treatment resulted in both suppression of apoptosis and promotion of cell motility, and the combination had synergistic effects. NEU3 scarcely affected MAPK- or IL-6-induced STAT3 activation but promoted the phosphatidylinositol 3-kinase (PI3K)/Akt cascade in both IL-6-dependent and -independent ways. Consistent with these data, NEU3 markedly inhibited staurosporine-induced caspase-3 activity and enhanced IL-6-dependent inhibition, which was abolished by LY294002, a PI3K inhibitor. Furthermore, IL-6 promoted Rho activation, and the effect was potentiated by NEU3, leading to increased cell motility that was again affected by LY294002. NEU3 silencing by siRNA resulted in the opposite: decreased Akt phosphorylation and inhibition of Rho activation. Glycolipid analysis showed a decrease in ganglioside GM3 and increase in lactosylceramide after NEU3 transfection, with these lipids apparently affecting cell apoptosis and motility. The results indicate that NEU3 activated by IL-6 exerts IL-6-mediated signaling, largely via the PI3K/Akt cascade, in a positive feedback manner and contributes to expression of a malignant phenotype in RCCs. NEU3 thus may be a useful target for RCC diagnosis and therapy.
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PMID:Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility. 1642 83

In Ramos cells, a human Burkitt's lymphoma cell line, stimulation of the B cell antigen receptor with anti-IgM antibody (Ab) induces apoptosis as indicated by a decrease in cell viability and an increase in DNA fragmentation and cell surface exposure of phosphatidylserine. Furthermore, these changes are suppressed by incubating the cells in alpha(1)-acid glycoprotein (AGP)-coated tissue culture plates. Here, we found that, during Anti-IgM Ab-induced apoptosis in Ramos cells, caspase-3 is activated downstream of caspase-8 and the mitochondrial pathway is activated, as indicated by a loss of mitochondrial membrane potential, an increase in the release of cytochrome c to the cytoplasm, and enhanced Bax expression. Anti-IgM Ab-induced apoptosis of neuraminidase-treated Ramos cells was suppressed by incubating the cells on plates coated with AGP, which contains a high concentration of alpha2,6-linked sialic acid. The incubation on plates coated with AGP also suppressed anti-IgM Ab-stimulated caspase-3 activity and increased the level of X-linked inhibitor of apoptosis protein (XIAP), but it did not affect caspase-8 activity, the mitochondrial membrane potential, cytochrome c release, or Bax expression. The results indicate that the interaction of Ramos cells with immobilized alpha2,6-linked sialic acid enhances XIAP expression, directly or indirectly suppressing caspase-3 activity and inhibiting anti-IgM Ab-induced apoptosis.
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PMID:Immobilized alpha2,6-linked sialic acid suppresses caspase-3 activation during anti-IgM antibody-induced apoptosis in Ramos cells. 1711 59

alpha(1)-Acid glycoprotein (AGP, orosomucoid) is a normal constituent of bovine blood. AGP is an immunocalin, a binding protein that can also exert several immunomodulatory functions. In this paper we investigated the effect of bovine alpha(1)-acid glycoprotein (boAGP) on spontaneous and staurosporine-induced apoptosis of blood derived monocytes purified using magnetic cell sorting techniques. Bovine AGP was purified from blood following a chromatographic protocol. The homogeneous protein was used to stimulate the cells as well to raise a polyclonal antibody, that was used throughout all the experiments. When monocytes were incubated with high concentrations of boAGP (0.9 mg/ml), similar to those found in bovine plasma during systemic reaction to inflammation, their spontaneous apoptosis rate was suppressed, as determined by caspase-3/7 enzymatic activity assay. Similar results were obtained when apoptosis was induced by adding staurosporine, a potent protein kinase inhibitor. The apoptosis-modulating activity of boAGP was dependent on its concentration, since physiological concentrations of boAGP (0.3 mg/ml) did not exhibit a statistically significative anti-apoptotic activity. We also investigated whether this apoptosis-modulating activity was dependent on the terminal sialic acid residues exposed on the surface of the protein. Enzymatic treatment with neuraminidase, that cleaves terminal sialic acid residues, completely abolished boAGP's anti-apoptotic activity. These results suggest that the protective effect of AGP is likely mediated by its sialic acid terminal groups.
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PMID:alpha(1)-Acid glycoprotein modulates apoptosis in bovine monocytes. 1732 1

We previously reported that, in Jurkat human T cells, the topoisomerase II inhibitor etoposide enhances sialidase activity and reduces cell surface sialic acid levels at an early stage of apoptosis and that the decreases in sialic acid are suppressed by the sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid [Azuma Y., et al., Glycoconj. J., 17, 301-306 (2000)]. In the current studies, we treated Jurkat cells with etoposide and examined the changes in the cell surface levels of gangliosides GM1, GM2, GM3, GD1a, and GD3 at physiological pH using anti-ganglioside antibodies. We also examined the sialidase activity on the cell surface using 4-methylumbelliferyl N-acetylneuraminic acid and measured the mRNA expression of the plasma membrane-associated sialidase Neu3 and the lysozomal Neu1 using real-time PCR. We found an increase in GM3 and a decrease in GD3 during the early stage (4 h) of etoposide-induced apoptosis that preceded the increase in cell surface exposure of phosphatidylserine (4 to 6 h). The caspase 3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde significantly suppressed changes in GM3 and GD3 and blocked the enhanced cell surface sialidase activity. Furthermore, etoposide caused a gradual up-regulation of Neu3 mRNA expression but not Neu1 mRNA expression. Enhanced Neu3 mRNA expression was suppressed in the presence of caspase 3 inhibitor. These results indicate that Neu3 is up-regulated in Jurkat cells undergoing etoposide-induced apoptosis through intracellular signaling events downstream of caspase 3 activation and that enhanced Neu3 activity is closely related to the changes of cell surface ganglioside composition.
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PMID:Enhanced expression of membrane-associated sialidase Neu3 decreases GD3 and increases GM3 on the surface of Jurkat cells during etoposide-induced apoptosis. 1782 20

In this study we examined the influence of neuraminidase on apoptosis of peripheral blood lymphocytes in rats with an implanted Morris tumor. The main objectives of the study were to determine whether the percentage of apoptotic blood lymphocytes would depend on the dosing regimen of neuraminidase and whether neuraminidase would affect caspase-3 activity, a marker of the apoptosis, in blood lymphocytes. A total of 51 rats were used for the study. In three groups, totalling 39 animals, Morris tumor was implanted and neuraminidase was injected intravenously using two dosing regimens: 10 units three times on Day 4, Day 7, and Day 14 and 5 units as a single dose on Day 4 of the experiment or was skipped (control). The remaining 12 rats constituted a reference group of healthy animals. At the end of the experimental period on Day 21, blood was drawn from the heart, and mononuclear cells were separated and cultured. Apoptosis of blood lymphocytes was assessed in cell cultures from fluorescence spectra generated by a Sybr Green I dye forming bonds with nuclear DNA. Caspase-3 activity was measured colorimetrically in homogenates of lymphocyte cultures using a CASP-3-C kit (Sigma, St. Louis, MO). On the whole, the results demonstrate that the bigger, but not the smaller, dose of neuraminidase was markedly effective in preserving the vitality of blood lymphocytes and in decreasing both the number of apoptotic lymphocytes and capsase-3 activity in the rats with Morris tumor. Neuraminidase treatment failed, however, to lessen the tumor size. In conclusion, the study demonstrates that neuraminidase caused an appreciable decline in apoptosis of blood lymphocytes in rats with the Morris tumor; the effect was dose-dependent. Although neuraminidase failed to influence the local cancer development in terms of tumor size, its anti-apoptotic effect toward the cells of the immune system of a cancer host is of research interest as it may potentially offer a way to strengthen the host's immune response.
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PMID:Effects of neuraminidase on apoptosis of blood lymphocytes in rats with implanted Morris tumor. 1820 35

Human plasma membrane-associated sialidase (NEU3) specifically hydrolyzes gangliosides, and it is up-regulated in colon cancer and plays an essential role in the expression of malignant phenotypes. To clarify the role of NEU3 in tumorigenesis in vivo, we examined the susceptibility of NEU3 transgenic mice to induction of colonic aberrant crypt foci (ACF) by azoxymethane. Mice were injected with azoxymethane (i.p., 15 mg/kg/week) for 6 weeks, and 4 weeks later ACF had formed in the NEU3 transgenic mice significantly more than in the control wild-type mice. Enhanced phosphorylation of epidermal growth factor (EGF) receptor, Akt and ERK and up-regulation of Bcl-xL protein were observed in the transgenic colon mucosa, but no changes were found in cell proliferation, suggesting that the increased ACF formation is due to suppression of apoptosis. Immunohistological analysis with anti-cleaved caspase 3 antibody showed an actual reduction in apoptotic cells in the transgenic mucosa at 6 h after the first azoxymethane injection, when apoptosis in the colonic crypt occurs. Consistent with our previous observations of human colon cancer, thin-layer chromatography of the gangliosides from the transgenic colon mucosa revealed decreased GM3 and increased lactosylceramide as compared to those from the control mucosa, probably because of catalysis of gangliosides by NEU3. The results of this study provide the first evidence that NEU3 essentially increases azoxymethane-induced ACF formation in colon mucosa by suppression of apoptosis, possibly via activation of the EGF signaling pathway, and thus indicate that up-regulation of NEU3 is important to the promotion stage of colorectal carcinogenesis in vivo.
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PMID:Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice. 1921 28

The mechanism of macrophage recognition of oxidatively damaged cells was investigated. Jurkat T cells exposed to various concentrations of H(2)O(2) were bound and phagocytosed by macrophages. The cells exposed to 0.1 mM H(2)O(2) were best bound. The cell-surface ligands recognized by macrophages were suggested to be sialylpolylactosaminyl sugar chains of a major sialoglycoprotein CD43 because 1) the cell binding was inhibited by oligosaccharides containing sialylpolylactosaminyl chains, and their inhibitory activity was destroyed by a polylactosamine-cleaving enzyme endo-beta-galactosidase, and by neuraminidase; 2) the oxidized Jurkat cells pretreated with either glycosidase or with anti-CD43 antibody were not bound. The macrophage receptor involved in the binding was suggested to be cell-surface nucleolin because 1) anti-nucleolin antibody inhibited the binding; 2) nucleolin-transfected HEK293 cells bound the oxidized cells; and 3) this binding was inhibited by anti-nucleolin antibody and by anti-CD43 antibody. CD43 on oxidized Jurkat cells tended to form clusters in good accordance with their susceptibility to the macrophage binding. CD43 clustering and the oxidized-cell binding to macrophages were prevented by a caspase inhibitor Z-VAD-fmk, suggesting that the oxidized and bound cells were undergoing apoptosis. Indeed, caspase-3 activity of Jurkat cells increased by the oxidation. These results suggest that moderately oxidized cells undergo apoptosis and are recognized by macrophages as early apoptotic cells.
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PMID:Clearance of oxidatively damaged cells by macrophages: recognition of glycoprotein clusters by macrophage-surface nucleolin as early apoptotic cells. 1933 85

An escape mutant of human parainfluenza virus type 1 (hPIV1), which was selected by serial passage in the presence of a sialidase inhibitor, 4-O-thiocarbamoylmethyl-2-deoxy-2,3-didehydro-N-acetylneur-aminic acid (TCM-Neu5Ac2en), exhibited remarkable syncytium formation and virus-induced cell death in LLC-MK2 cells but no difference in susceptibility for the sialidase inhibitor TCM-Neu5Ac2en from that of wild-type hPIV1 strain C35 (WT). The mutant virus also had higher replication and plaque formation abilities. The mutant virus acquired two amino acid mutations, Glu to Gly at position 170 and Ala to Glu 442 in fusion (F) glycoprotein, but no mutations in haemaggulutinin-neuraminidase (HN) glycoprotein. Using cells co-expressing F and HN genes with site-specific mutagenesis, we demonstrated that a point mutation of Glu to Gly at position 170, which was estimated to be located in hPIV1 F glycoprotein heptad repeat 1, was required for obvious syncytium formation and caspase-3-dependent cell death. In contrast, wild-type F glycoprotein induced no synctium formation or cell death. The findings suggest that a single amino acid mutation of hPIV1 F glycoprotein promotes syncytium formation that is followed by caspase-3-dependent cell death.
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PMID:A single amino acid mutation at position 170 of human parainfluenza virus type 1 fusion glycoprotein induces obvious syncytium formation and caspase-3-dependent cell death. 2118 50


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