UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Individual subunits of protein phosphatase 2A (PP2A), protein phosphatase 4, and protein phosphatase 5 were knocked out in Drosophila Schneider 2 cells by using RNA interference. Ablation of either the scaffold (A) or catalytic (C) subunits of PP2A caused the disappearance of all PP2A subunits. Treating cells with double-stranded RNA targeting all four of the Drosophila PP2A regulatory subunits caused the disappearance of both the A and C subunits. The loss of PP2A subunits was associated with decreased protein stability indicating that only the heterotrimeric forms of PP2A are stable in intact cells. Ablation of total PP2A by using double-stranded RNA against either the A or C subunit, or specific ablation of the R2/B regulatory subunit, enhanced insulin-induced ERK activation. These results indicated that the R2/B subunit targets PP2A to the mitogen-activated protein (MAP) kinase cascade in Schneider 2 cells, where it acts as a negative regulator. A severe loss of viability occurred in cells in which total PP2A or both isoforms of the Drosophila R5/B56 subunit had been ablated. The reduced viability of these cells correlated with the induction of markers of apoptosis including membrane blebbing and stimulation of caspase-3-like activity. These observations indicated that PP2A has a powerful antiapoptotic activity that is specifically mediated by the R5/B56 regulatory subunits. In contrast to PP2A, ablation of protein phosphatase 4 caused only a slight reduction in cell growth but had no effect on MAP kinase signaling or apoptosis. Depletion of protein phosphatase 5 had no effects on MAP kinase, cell growth, or apoptosis.
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PMID:Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. 1190 83

The cellular composition and concentration of fatty acids are crucial for proliferation and survival. We recently showed stimulation of protein phosphatase type-2C (PP2C) by unsaturated fatty acids. Here, we describe that treatment of cultured chick neurons with 100 microM oleic acid for 24h increased the percentage of damaged neurons to 61+/-9% compared with 25+/-4% in controls. Oleic acid-induced cell death showed features of apoptosis such as chromatin condensation, shrinkage of the nucleus, DNA fragmentation and caspase-3 activation. Extensive studies with a variety of fatty acids revealed a striking correlation between activation of PP2C and induction of apoptosis. Lipophilicity, oxidizability, and an acidic group were required for both effects. In addition, activation of PP2C and induction of apoptosis could discriminate between cis- and trans-conformation of the fatty acids. The results are in favor of PP2C playing an important, yet unidentified role in apoptosis.
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PMID:Relationship between protein phosphatase type-2C activity and induction of apoptosis in cultured neuronal cells. 1210 76

Okadaic acid (OA), a protein phosphatase inhibitor, is used as a research model of Alzheimer's disease to induce tau phosphorylation and neuronal death. We reported previously that OA induces neuronal apoptosis of immature neurons (in vitro days (IVD) 3-5), which is inhibited by cycloheximide (CHX). In this study, we demonstrate that CHX fails to prevent OA-induced neuronal death in mature neurons (IVD 14-15). Upon comparison of both types of dying cells, the immature neurons displayed characteristic features of apoptosis, such as nuclear fragmentation, phosphatidylserine externalization and prominent caspase-3 activation, while the mature neurons showed few characteristic features of apoptosis. Lack of the beneficial effects of CHX and the lesser activation of caspase-3 in the mature neurons argue against typical apoptotic neuronal death in the OA-induced neurodegeneration model.
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PMID:Differential activation of caspase-3 at two maturational stages during okadaic acid-induced rat neuronal death. 1243 76

Salvicine is a novel topoisomerase II inhibitor possessing significant antitumor activity, both in vitro and in vivo. The antitumor effect of salvicine is associated with its ability to induce tumor cell apoptosis. Telomerase plays an important role in the apoptotic pathway. However, little is known about the mechanisms of telomerase regulation during apoptosis induced by anticancer drugs. This study investigated the regulation of telomerase activity in salvicine-induced human leukemia HL-60 cell apoptosis. Salvicine treatment resulted in HL-60 cell apoptosis and down-regulation of telomerase activity in a time- and concentration-dependent manner. Repression of telomerase activity preceded a decrease in expression of the telomerase catalytic subunit (hTERT) and telomerase-associated protein (TP1) at the mRNA level, suggesting that the salvicine-induced decrease in telomerase activity may be additionally regulated by mechanisms other than telomerase subunit transcription. We observed that okadaic acid (OA), a protein phosphatase inhibitor, prevented the induction of apoptosis and the down-regulation of telomerase activity by salvicine. The significant increase in protein phosphatase 2A (PP2A) activity induced by salvicine treatment was blocked completely by OA. Moreover, although salvicine induced HL-60 cell apoptosis in a caspase-3-dependent manner, a specific caspase-3 inhibitor, Z-DEVD-FMK, did not prevent a decrease in telomerase activity or an increase in PP2A activity in apoptotic HL-60 cells, ruling out a role for caspase-3 in PP2A activation by salvicine. The results collectively suggest that the salvicine-induced decline in telomerase activity is not a consequence of HL-60 cell apoptosis and that it may be caused principally by the dephosphorylation of telomerase components mediated by PP2A activation.
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PMID:Down-regulation of telomerase activity via protein phosphatase 2A activation in salvicine-induced human leukemia HL-60 cell apoptosis. 1244 57

Docosahexaenoic acid (DHA) is known to have anti-cancer activities by mechanisms that are not well understood. In the present study, we test one possible pathway for DHA action in Jurkat leukaemic cells. Low doses of DHA (10 microM) are shown to induce cell-cycle arrest, whereas higher doses are cytotoxic. However, when cells that were pre-treated with 10 microM DHA are given an additional 10 microM DHA dose, cell viability rapidly decreases. Immunoblotting reveals that repeated low doses of DHA results in activation of caspase 3, implying induction of apoptosis. DHA (10 microM) is shown to increase ceramide levels after 6 h of incubation and, after 24 h, the cells appear to be arrested in S phase. With DHA, the amount of phosphorylated retinoblastoma protein (pRb) decreases significantly. Western blot analysis also shows that DHA greatly reduces the level of cyclin A, while increasing the level of p21 WAF1, a cellular inhibitor of cyclin A/cyclin-dependent kinase 2 (cdk2) activity. Furthermore, the observed DHA-induced doubling of the ratio of hypophosphorylated pRb (hypo-pRb) to total pRb is inhibited by tautomycin and phosphatidic acid (PA), known inhibitors of protein phosphatase 1 (PP1), and by the PP2 inhibitor okadaic acid. The present study demonstrates one possible connected pathway for DHA action. By this pathway, low doses of DHA increase ceramide levels, which leads to inhibition of cdk2 activity and stimulation of PP1 and PP2A. The net effect of cdk2 inhibition and protein phosphatase activation is an inhibition of pRb phosphorylation, consequently arresting Jurkat cell growth.
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PMID:Cell-cycle arrest in Jurkat leukaemic cells: a possible role for docosahexaenoic acid. 1249 1

Mammalian STE20-like kinase 2 (MST2), a member of the STE20-like kinase family, has been shown in previous studies to undergo proteolytic activation by caspase-3 during cell apoptosis. A few studies have also implicated protein phosphorylation reactions in MST2 regulation. In this study, we examined the mechanism of MST2 regulation with an emphasis on the relationship between caspase-3 cleavage and protein phosphorylation. Both the full-length MST2 and the caspase-3-truncated form of MST2 overexpressed in 293T cells exist in a phosphorylated state. On the other hand, the endogenous full-length MST2 from rat thymus or from proliferating cells is mainly unphosphorylated whereas the caspase-3-truncated endogenous MST2 from apoptotic cells is highly phosphorylated. Cell transfection studies using mutant MST2 constructs indicate that MST2 depends on the autophosphorylation of a unique threonine residue, Thr(180), for kinase activity. The autophosphorylation reaction shows strong dependence on MST2 concentration suggesting that it is an intermolecular reaction. While both the full-length MST2 and the caspase-3-truncated form of MST2 undergo autophosphorylation, the two forms of the phosphorylated MST2 display marked difference in susceptibility to protein phosphatases. The full-length phospho-MST2 is rapidly dephosphorylated by protein phosphatase 1 or protein phosphatase 2A whereas the truncated MST2 is remarkably resistant to the dephosphorylation. Based on the present results, a novel molecular mechanism for MST2 regulation in apoptotic cells is postulated. In normal cells, because of the low concentration and the ready reversal of the autophosphorylation by protein phosphatases, MST2 is present mainly in the unphosphorylated and inactive state. During cell apoptosis, MST2 is cleaved by caspase-3 and undergoes irreversible autophosphorylation, thus resulting in the accumulation of active MST2.
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PMID:Regulation of mammalian STE20-like kinase 2 (MST2) by protein phosphorylation/dephosphorylation and proteolysis. 1255 36

We have previously shown that the protein phosphatase inhibitor okadaic acid (OA) induces caspase-3 activation and apoptosis in CHP-100 human neuroepithelioma cells. Herein we provide a more general picture of the effects brought about by OA in this system, also investigating whether caspase activation is necessary for apoptosis induction. We report that incubation for 24 h with 10 nM OA induced a large fraction of the cell population to undergo premature chromosome condensation (PCC) or mitotic arrest, but not apoptosis. The former two effects were also observed after cell treatment with 20 nM OA; however, at this concentration, typical apoptotic cells were also detected, characterized by pycnotic and fragmented nuclei. Occurrence of the above-mentioned apoptotic figures turned extensive at 100 nM OA. The pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.fmk, 100 microM) fully prevented apoptosis induced by 20 nM OA, increasing PCC incidence. Conversely, 100 nM OA induced an apoptotic-like phenotype, even in the presence of Z-VAD.fmk: in this case, however, nuclei, albeit pycnotic, displayed morphological characteristics distinct from those of typical apoptotic cells; moreover, as assessed by flow cytometry, they were largely unfragmented. The reported OA effects occurred in a setting in which neither p53 nor p21(Cip1/Waf1) was upregulated, thus ruling out a role for these proteins in apoptosis induction. On the other hand, apoptotic doses of OA induced a shift of the retinoblastoma gene product to the hypophosphorylated state and its downregulation by a caspase-dependent mechanism.
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PMID:Caspase inhibition shifts neuroepithelioma cell response to okadaic acid from apoptosis to an apoptotic-like form of death. 1265 41

Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.
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PMID:[Neuroprotective actions of lithium]. 1270 Dec 14

1. Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis. 2. Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time- and concentration-dependent manner. FTY720 also induced Bad (Ser(136)) and ribosomal p70S6 kinase (p70(S6k)) (Thr(389)) dephosphorylation. 3. FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3'-kinase (PI 3-kinase) pathway inhibition. 4. FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis. 5. Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70(S6k), suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. 6. OA partially inhibited FTY720-induced caspase-3 activation. 7. PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 8. Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria.
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PMID:A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. 1271 31

Many pro-apoptotic signals activate caspase-9, an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction. However, survival signals can impinge on this pathway and suppress apoptosis. Activation of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway is associated with protection of cells from apoptosis and inhibition of caspase-3 activation, although the targets are unknown. Here, we show that the ERK MAPK pathway inhibits caspase-9 activity by direct phosphorylation. In mammalian cell extracts, cytochrome c-induced activation of caspases-9 and -3 requires okadaic-acid-sensitive protein phosphatase activity. The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2. Caspase-9 is phosphorylated at Thr 125, a conserved MAPK consensus site targeted by ERK2 in vitro, in a MEK-dependent manner in cells stimulated with epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Phosphorylation at Thr 125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. We suggest that phosphorylation and inhibition of caspase-9 by ERK promotes cell survival during development and tissue homeostasis. This mechanism may also contribute to tumorigenesis when the ERK MAPK pathway is constitutively activated.
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PMID:Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. 1279 50

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