Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
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.
 ...
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.
 ...
PMID:Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility. 1642 83

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.
 ...
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

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.
 ...
PMID:Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice. 1921 28

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.
 ...
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

Inappropriate clearance of apoptotic remnants is considered to be the primary cause of systemic autoimmune diseases, like systemic lupus erythematosus. Here we demonstrate that apoptotic cells release distinct types of subcellular membranous particles (scMP) derived from the endoplasmic reticulum (ER) or the plasma membrane. Both types of scMP exhibit desialylated glycotopes resulting from surface exposure of immature ER-derived glycoproteins or from surface-borne sialidase activity, respectively. Sialidase activity is activated by caspase-dependent mechanisms during apoptosis. Cleavage of sialidase Neu1 by caspase 3 was shown to be directly involved in apoptosis-related increase of surface sialidase activity. ER-derived blebs possess immature mannosidic glycoepitopes and are prioritized by macrophages during clearance. Plasma membrane-derived blebs contain nuclear chromatin (DNA and histones) but not components of the nuclear envelope. Existence of two immunologically distinct types of apoptotic blebs may provide new insights into clearance-related diseases.
 ...
PMID:Macrophages discriminate glycosylation patterns of apoptotic cell-derived microparticles. 2207 24

Apoptotic cells and subcellular microparticles expose increased sialidase activity on their surfaces, which results from caspase-3 dependent activation of plasma membrane associated Neuraminidase-1 (Neu1). Desialylation of dying cells is also known to promote efferocytosis. The intriguing question remained whether sialidase on the surface of dying cell merely acts on self targets (cis-action), or whether it can also cleave glycoepitopes of neighboring cells (trans-action). Here, we co-incubated human viable and apoptotic Jurkat lymphocytes or neutrophils with human erythrocytes and evaluated their glycoprofile for terminal sialic acids by agglutination assay, flow cytometry, ELISA and dot-blot analyses. Data suggest that erythrocytes were desialylated as soon as 3 hours after co-incubation with apoptotic cells, but not with viable ones. After co-incubation of L929 murine fibroblasts with viable or apoptotic murine L1210 cells the L929 cells gained a desialylated glycoprofile, only after co-incubation with apoptotic cells. Our data suggests that activated sialidase(s) on the surfaces of apoptotic cells are capable to desialylate neighboring cells in trans.
 ...
PMID:Sweet kiss of dying cell: sialidase activity on apoptotic cell is able to act toward its neighbors. 2292 16

Benzene-induced erythropoietic depression has been proposed to be due to the production of toxic metabolites. Presently, the cytotoxicities of benzene metabolites, including phenol, catechol, hydroquinone, and 1,2,4-benzenetriol, to erythroid progenitor-like K562 cells were investigated. After exposure to these metabolites, K562 cells showed significant inhibition of viability and apoptotic characteristics. Each metabolite caused a significant increase in activities of caspase-3, -8, and -9, and pretreatment with caspase-3, -8, and -9 inhibitors significantly inhibited benzene metabolites-induced phosphatidylserine exposure. These metabolites also elevated expression of Fas and FasL on the cell surface. After exposure to benzene metabolites, K562 cells showed an increase in reactive oxygen species level, and pretreatment with N-acetyl-l-cysteine significantly protected against the cytotoxicity of each metabolite. Interestingly, the control K562 cells and the phenol-exposed cells aggregated together, but the cells exposed to other metabolites were scattered. Further analysis showed that hydroquione, catechol, and 1,2,4-benzenetriol induced a decrease in the cell surface sialic acid levels and an increase in the cell surface sialidase activity, but phenol did not cause any changes in sialic acid levels and sialidase activity. Consistently, an increase in expression level of sialidase Neu3 mRNA and a decrease in mRNA level of sialyltransferase ST3GAL3 gene were detected in hydroquione-, catechol-, or 1,2,4-benzenetriol-treated cells, but no change in mRNA levels of two genes were found in phenol-treated cells. In conclusion, these benzene metabolites could induce apoptosis of K562 cells mainly through caspase-8-dependent pathway and ROS production, and sialic acid metabolism might play a role in the apoptotic process.
 ...
PMID:Phenolic metabolites of benzene induced caspase-dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids. 2377 99