UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
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The effects of HIV-1 Tat protein on mitochondria membrane permeability and apoptosis were analysed in lymphoid cells. In this report we show that stable-transfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal. This effect was observed in both the Jhan T cell line and the K562 cells, the latter expressing the bcr-abl chimeric gene, which confers resistance to apoptosis induced by different stimuli. Using a cytofluorimetric approach we have determined that serum withdrawal induces a disruption of the transmembrane mitochondrial potential (Deltapsim) followed by an increase of reactive oxygen species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in the K562-pcDNA cell line. These pre-apoptotic events were associated with the cleavage of the caspase-3, while the expression of Bcl-2, Bcl-XL and Bax proteins was not affected by the presence of Tat. Regardless of the steady state of the Bax protein, we found that in both K562 and K562-Tat cells, this protein is located in the nucleus, but after serum withdrawal its localization was mainly in the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum withdrawal paralleled with the mitochondria permeability transition. Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the specific inhibitor, z-DEVD-cmk, did not affect the disruption of the mitochondria potential induced by serum withdrawal. Interestingly, we found that HIV-Tat protein accumulates at the mitochondria in the K562-Tat cells cultured under low serum conditions, and this mitochondrial localization correlated with the Deltapsim disruption detected in these cells. In addition, HIV-1 Tat protein synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562 cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS patients.
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PMID:Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms. 1060 13

Homocysteine, an excitatory amino acid and a homolog of cysteine, induces neuronal cell death in brain via stimulation of N-methyl-D-aspartate (NMDA) receptors. It also selectively activates NMDA receptors of retinal ganglion cells, but it is not known if high levels of homocysteine are toxic to these cells. The purpose of this study was to determine whether increased levels of homocysteine caused death of neurons in the ganglion cell layer; if so whether this death occurred via an apoptotic mechanism and to determine the consequences of simultaneous elevation of homocysteine and glutamate, a known retinal excitotoxin, on the viability of neurons of the ganglion cell layer. C57BL/6 mice were injected intravitreally with either homocysteine or glutamate/homocysteine combined (final concentrations: 25, 75, and 200 microM); injection of glutamate (25 and 200 microM) served as a positive control. Eyes were harvested and cryosections prepared 5-6 days post-injection. Systematic morphometric analysis of retinas of mice injected with homocysteine indicated that the total number of cells in the ganglion cell layer decreased by about 23% following exposure to 200 microM homocysteine. To determine whether the neurons of the ganglion cell layer were dying by apoptosis, the TUNEL method was used and was confirmed by immunohistochemical studies of caspase-3, known to be expressed at high levels during retinal ganglion cell apoptosis. Microscopic analysis revealed significantly more TUNEL-positive cells in the ganglion cell layer in homocysteine-injected eyes than in contralateral PBS-injected eyes. Retinas injected with 75 and 200 microM homocysteine displayed significantly more TUNEL-positive neurons in the ganglion cell layer (2 and 2.9, respectively) than PBS-injected retinas (0.25). In eyes injected simultaneously with homocysteine/glutamate, the number of apoptotic cells in the ganglion cell layer almost doubled that for homocysteine or glutamate injections alone. Immunohistochemical analysis of activated caspase-3 revealed numerous positively labelled neurons in the ganglion cell layer in homocysteine and homocysteine/glutamate-injected eyes, but not in PBS-injected eyes. Quantification of this data revealed a significantly greater number of caspase-3-positive neurons in the ganglion cell layer of retinas injected with 75 and 200 microM homocysteine (2.9 and 4.4, respectively) than for PBS-injected retinas (0.5). This confirms that death of neurons in the ganglion cell layer is occurring by apoptosis. The present study provides the first evidence that homocysteine is toxic to neurons of the ganglion cell layer. In addition, it provides evidence that these retinal neurons are dying by apoptosis and it demonstrates for the first time that excitotoxic damage to neurons of the ganglion cell layer is potentiated by simultaneous elevation of homocysteine and glutamate. These findings are relevant to retinal ganglion cell death characteristic of diabetic retinopathy, which is thought to be mediated by overstimulation of the NMDA receptor.
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PMID:Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. 1142 62

Earlier work in this laboratory showed that noradrenaline (NA) induces apoptosis in primary cultures of alveolar epithelial cells (AECs). Apoptosis of alveolar epithelial cells may promote the collapse of lung barrier function. On this basis we hypothesized that exogenous NA, administered by intratracheal (I.T.) instillation, might induce AEC apoptosis in vivo followed by acute lung injury. Delivery of NA (10 microM) I.T. into male Wistar rats increased labelling of both fragmented DNA, measured by in situ end labelling (ISEL), and the active form of caspase 3 (anti-Casp3) 6 and 20 h after administration (P < 0.05), but instillation of the vehicle alone (PBS) had no effect. Both ISEL and anti-Casp3 labelling were attenuated by concurrent I.T. delivery of the broad-spectrum caspase inhibitor ZVADfmk. After 6 h, most ISEL- and Casp3-positive cells were located in the surfaces of alveolar walls, but after 20 h more were found in alveolar spaces (P < 0.05). Instillation of NA also increased the bronchoalveolar lavage (BAL) content of fluorescent albumin (BODIPY-alb), which had previously been injected intravenously; the increase was reversed by concurrent ZVADfmk administration. These data suggest that NA-induced apoptosis of AECs in vivo is sufficient to invoke transient collapse of AEC barrier function that is rapidly repaired.
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PMID:Apoptosis-dependent acute lung injury and repair after intratracheal instillation of noradrenaline in rats. 1262 32

The hypothesis that prolactin (PRL) functions as an immunomodulator was based on studies showing lymphocyte PRL receptors, and its effects on growth, differentiation, and apoptosis in lymphoid cells. However, studies of PRL (PRL-/-) and PRL receptor knockout mice indicated that PRL was not required for immune system development or function under basal conditions. Because PRL maintains survival in glucocorticoid (GC)-treated Nb2-T lymphocytes in vitro, and PRL and GCs are elevated during stress, we investigated whether PRL protected T cells in vivo from GC-induced apoptosis. Adrenalectomized mice [PRL -/-, undetectable PRL; pituitary grafted PRL-/- (PRL-/-Graft), elevated PRL; and PRL+/-, normal PRL] were treated with dexamethasone (DEX) or PBS. Thymocytes and splenocytes were isolated and annexin V labeling of phosphatidylserine, DNA fragmentation, and caspase-3 activation were assessed as indices of apoptosis. Total thymocytes and CD4+ and CD8+ T cells obtained from DEX-treated PRL-/- mice exhibited significantly increased annexin V binding. In contrast, binding was not altered by DEX in PRL-/-Graft thymocytes. In addition, DEX induced classic DNA fragmentation in PRL-/- thymocytes. Elevated serum PRL reduced this effect. Thymocytes from DEX-treated PRL-/- mice exhibited increased caspase-3 activation, which was inhibited in cells from PRL-/-Graft mice. Finally, elevated expression of X-linked inhibitor of apoptosis, XIAP, was observed in thymi from DEX-treated PRL -/-Graft mice. This is the first demonstration that elevated PRL antagonizes apoptosis in thymocytes exposed to GCs in vivo. These observations suggest that, under conditions of increased GCs, such as during stress, elevated PRL functions physiologically to maintain survival and function of T-lymphocytes.
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PMID:Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. 1269 19

Transthyretin Leu55Pro is one of the most aggressive mutations in familial amyloidotic polyneuropathy, an autosomal dominant disorder characterized by extracellular deposition of fibrillar amyloid protein. This variant has the ability to form fibrils in vitro under physiological conditions (PBS, pH 7.4). We studied by transmission electron microscopy the effect of the drug 4'-iodo-4'-deoxydoxorubicin (I-DOX) on the in vitro assembly of TTR Leu55Pro fibrils by following fibril growth over a 15 day period. Our results showed that I-DOX at a concentration of 10-5 M/100 microg fibrils does not inhibit fibril formation in up to 10 days since fibrils identical to the ones present in the untreated sample were observed. However, after 15 days of treatment, only round particles, resembling soluble native TTR, were observed. We also tested the ability of tetracyclines and nitrophenols to interfere with amyloid fibril formation for 17 days; the group of compounds tested showed fibril disruption activity to different extents: doxycycline and 2,4-dinitrophenol resulted in complete disaggregation of fibrils. The species generated upon I-DOX and tetracyclines treatments were nontoxic, as revealed by the lack of significant caspase-3 activation on a Schwannoma cell line, making them potential therapeutic drugs in TTR-related and other amyloidosis.
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PMID:4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. 1272 38

Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.
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PMID:Prostaglandin E2 promotes the survival of bone marrow-derived dendritic cells. 1555 92

To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOIkappaB expressing both HSV-TK and a mutant form of the NF-kappaB inhibitor IkappaBalpha (IkappaBalphaM) was developed. TOIkappaB was constructed by recombining the IkappaBalphaM gene into the U(L)41 locus of a replication-defective lacZ expression vector, TOZ.1. Expression of IkappaBalphaM was confirmed by Western blotting, and the ability of the mutant protein to inhibit NF-kappaB nuclear translocation was examined by electrophoretic mobility shift assay. In human glioblastoma U-87MG cells, the p50/p50 dimer of NF-kappaB was already translocated to the nucleus without receptor-dependent signaling by TNF-alpha. Following infection with TOIkappaB, nuclear translocation of NF-kappaB in U-87MG cells was significantly inhibited and caspase-3 activity increased compared with TOZ.1-infected cells. The cytotoxicity of TOIkappaB for U-87MG cells was investigated by colorimetric MTT assay. At an MOI of 3, TOIkappaB infection killed 85% of the cells compared to 20% killed by TOZ.1 infection. In the presence of GCV, these numbers increased to 95-100% for TOIkappaB and 80-85% for TOZ.1. TOIkappaB neurotoxicity measured on cultured murine neurons was relatively low and similar to that of TOZ.1. The survival of nude mice implanted into the brain with U-87MG tumor cells was markedly prolonged by intratumoral TOIkappaB injection and GCV administration. Survival of TOIkappaB+GCV group was significantly longer (P<.02, Wilcoxon test) than for the control groups (TOZ.1 or TOIkappaB only, PBS or PBS+GCV). These results suggest that IkappaBalphaM expression may be a safe enhancement of replication-defective HSV-based suicide gene therapy in vitro and in vivo.
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PMID:Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase. 1569 8

Although ischemia has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia-reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of PBS solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited extracellular 80-kDa and intracellular 40-kDa E-cadherin fragments after 4 h of ischemia, and at 6 h the expression of full-length E-cadherin decreased. While no fragments of N-cadherin, alpha-catenin, and gamma-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 h of ischemia. The MMP inhibitors GM-6001 and TAPI-O inhibited cleavage and/or loss of E- and N-cadherin protein expression. Tissue inhibitors of metalloproteinases (TIMP)-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibit ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that are associated with a disruption of junctional contacts.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases. 1576 36

Flavonoids, which are main constituents of herbal medicines, have been reported to inhibit the growth of Helicobacter pylori (HP). Therefore, to evaluate the anti-HP activity of some flavonoids (flavanols, flavones, flavonols and isoflavonoids), their effects on the growth and vacuolation of HP as well as the infective properties of HP against HeLa cells were investigated. Catechins, quercetin and naringenin weakly inhibited the growth of HP, but all tested compounds did not inhibit HP infection into KATO III cells and HP urease activity. Quercetin and naringenin inhibited HP VacA vacuolation in HeLa cells with IC (50) values of 0.046 and 0.36 mM, respectively. Quercetin also inhibited procaspase-3 activation to caspase-3 in HeLa cells induced by HP VacA toxin, which may induce cell death via the proteolytic activation of a cascade of caspases. However, quercetin did not affect Bax and Bcl-2 protein levels. Based on these findings, quercetin may improve gastric cell death by inhibiting apoptotic signaling by HP VacA toxin. Abbreviations. HP: Helicobacter pyloriBSA:bovine serum albumin ESL:enhanced chemiluminescence MIC:minimum inhibitory concentration MTT:methylthiazolyldiphenyl-tetrazolium bromide PBS:phosphate-buffered saline VacA:Vacuolating cytotoxin.
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PMID:In vitro inhibitory effect of flavonoids on growth, infection and vacuolation of Helicobacter pylori. 1577 May 37

Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.
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PMID:Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. 1610 86

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