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)

When cultured cerebellar granule neurones are transferred from a medium containing high extracellular potassium concentration ([K+]e) (25 mm) to one with lower [K+]e (5 mm), caspase-3 activity is induced and cells die apoptotically. In contrast, if cells in non-depolarizing conditions are treated with brain-derived neurotrophic factor (BDNF), caspase-3 activity, chromatin condensation and cell death are markedly diminished. In this study, we show that the C-terminal domain of the tetanus toxin heavy-chain (Hc-TeTx) is able to produce the same neuroprotective effect, as assessed by reduction of tetrazolium salts and by chromatin condensation. Hc-TeTx-conferred neuroprotection appears to depend on phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase, as is demonstrated by the selective inhibitors Wortmannin and PD98059, respectively. Hc-TeTx also induces phosphorylation of the tyrosine kinase BDNF receptor, activation of p21Ras in its GTP-bound form, and phosphorylation of the cascade including extracellular-signal-regulated kinases-1/2 (ERK-1/2), p90 ribosomal S6 kinase (p90rsk) and CREB (cAMP-response-element-binding protein). On the other hand, activation of the Akt pathway is also detected, as well as inhibition of the active form of caspase-3. These results point to an implication of both PI3K- and ERK-dependent pathways in the promotion of cerebellar granule cell survival by Hc-TeTx.
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PMID:The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. 1531 77

Procaspase-3 protein content is highly elevated in fully Ras-transformed mouse embryo fibroblast 10T1/2 cells in which ectopic expression of oncogenic H-Ras is induced by a tetracycline-regulated expression system. Blockage of the ERK pathway results in profound reduction of transcript and protein content of procaspase-3 in both Ras-transformed and non-transformed counterpart 10T1/2 cells, indicating that the ERK pathway is involved in procaspase-3 gene expression. The elevated procaspase-3 protein content appears to facilitate the proteolytic production of active caspase-3 during selective induction of apoptosis of Ras-transformed cells by a discriminating anticancer agent, FR901228, whereas it induces growth arrest of non-transformed counterpart cells. The evidence indicates a potential role of the elevated procaspase-3 protein content and an essential role of the ERK pathway for procaspase-3 expression in the increased susceptibility of Ras-transformed 10T1/2 cells to anticancer agent FR901228.
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PMID:Potentiated caspase-3 in Ras-transformed 10T1/2 cells. 1532 66

The present study investigates the effect of ouabain on caspase-3 activation in human umbilical vein endothelial cells (HUVEC). Ouabain (EC(50) 20 nM) reduced caspase-3 activity in HUVEC treated for 24h in a medium deprived of fibroblast growth factor (FGF). Incubation for 5h in the absence of both FGF and serum produced an increase in caspase-3 activity that was completely abolished by 100 nM ouabain. Pretreatment with the phosphatidylinositol 3 kinase (PI-3K) inhibitor, wortmannin, prevented the protective effect of ouabain against serum deprivation. Furthermore, Western blotting analysis revealed an increase in phosphorylation of extracellular signal-regulated kinases (ERK-1 and ERK-2) induced by 100nM ouabain in serum-deprived cells. In accord, pretreatment of HUVEC with PD98059, inhibitor of the ERK pathway, abrogated the effect of ouabain. Our results show that ouabain has an antiapoptotic effect on HUVEC through the activation of PI-3K and ERK dependent pathways.
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PMID:Antiapoptotic effect of ouabain on human umbilical vein endothelial cells. 1535 65

We previously blocked the heat shock transcription factor 1 function with a dominant-negative mutant (mHSF1) in breast cancer cell line Bcap37, and found that mHSF1 sensitizes Bcap37 cells to hyperthermia by promoting the apoptotic process. Here we studied the mechanism of this abolishing process and how thermotolerance develops in Bcap37 cells. The results indicated that mHSF1 abolished acquired or intrinsic thermotolerance in Bcap37 cells by enhancing JNK and caspase-3 pathways, two stress-induced apoptotic pathways, after hyperthermia, and interference with either one of them attenuated hyperthermia-induced apoptosis. Furthermore, epistasis assay of these two pathways suggested that JNK was upstream of the caspase-3 pathway. Conversely, other hyperthermia-induced kinases implicated in cell survival and death, Akt, ERK or p38, did not influence the effect of mHSF1, indicating that these kinases were not implicated in this abolishing process. In addition, we found that the development of acquired thermotolerance of Bcap37 cells was associated with the suppression of JNK activation after mild preheat treatment and was not reduced by Akt, ERK or p38 inhibition. In contrast, the intrinsic thermotolerance of Bcap37 cells was due to the intrinsic high levels of Akt and ERK activities since Akt or ERK inhibition resulted in increased thermosensitivity of Bcap37 cells. Our results suggest that mHSF1 plays a valuable role in the thermotolerance abolishment of Bcap37 cells, which likely contributes to tumor therapy in combination with hyperthermia.
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PMID:HSF1 blockade-induced tumor thermotolerance abolishment is mediated by JNK-dependent caspase-3 activation. 1535 68

We examined heart tissues of AIDS patients with or without HIV cardiomyopathy (HIVCM) by immunohistochemistry, in situ polymerase chain reaction, in situ riboprobe hybridization, and the TUNEL technique for apoptosis. In HIVCM tissues, only inflammatory cells, but not endothelial cells or cardiomyocytes, displayed HIV-1 DNA and RNA. However, macrophages, lymphocytes, and--in a patchy fashion--cardiomyocytes and endothelial cells exhibited virus envelope protein gp120. Macrophages infiltrated the myocardium in a perivascular fashion and expressed tumor necrosis factor family ligands; adjacent cardiomyocytes suffered apoptosis. In vitro HIV-1 strongly invaded neonatal rat ventricular myocytes (NRVMs) and coronary artery endothelial cells (CAECs) and induced microvilli but did not replicate. HIV-1, gp120, or Tat induced Erk 1/2 phosphorylation, activation of caspase-3, and apoptosis of NRVMs and CAECs; all of these were inhibited by a MAPK/ERK-kinase (MEK) inhibitor U0126. The pathogenesis of HIVCM involves HIV-1 replication in inflammatory cells and induction of cardiomyocyte apoptosis by (1) the extrinsic pathway through apoptotic ligands and (2) the intrinsic pathway through direct virus entry and gp120- and Tat-proapoptotic signaling.
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PMID:HIV-1 induces cardiomyopathyby cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling. 1537 27

During bone resorption, osteoclasts are exposed to high Ca2+ concentrations (up to 40 mM). The role of high extracellular Ca2+ in receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast survival and their functional interrelationship is unclear. In this study, we show that RANKL enhances osteoclast tolerance to high extracellular Ca2+ by protecting the cell from cell death in a dose dependent manner. We have provided evidence that RANKL does this by attenuating high extracellular Ca2+-induced Ca2+ elevations. Moreover, we have found that high extracellular Ca2+-induced cell death was partially inhibited by a caspase-3 inhibitor, suggesting caspase-3-mediated apoptosis is involved. Conversely, using reporter gene assays and Western blot analysis, we have demonstrated that high extracellular Ca2+ desensitizes the RANKL-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK), and inhibits constitutive and RANKL-stimulated ERK phosphorylation, indicating a negative feed-back mechanism via specific RANKL signaling pathways. Taken together, this study provides evidence for a reciprocal regulation between high extracellular Ca2+ and RANKL signaling in RAW cell derived osteoclasts. Our data imply a cross talk mechanism of extracellular Ca2+ on osteoclast survival through the regulation of RANKL.
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PMID:Evidence of reciprocal regulation between the high extracellular calcium and RANKL signal transduction pathways in RAW cell derived osteoclasts. 1538 75

The capability of 17beta-estradiol (E2) to induce the non-genomic activities of its receptors (ER alpha and ER beta) and to evoke different signaling pathways committed to the regulation of cell proliferation has been analyzed in different cell cancer lines containing transfected (HeLa) or endogenous (HepG2, DLD1) ER alpha or ER beta. In these cell lines, E2 induced different effects on cell growth/apoptosis in dependence of ER isoforms present. The E2-ER alpha complex rapidly activated multiple signal transduction pathways (i.e., ERK/MAPK, PI3K/AKT) committed to both cell cycle progression and apoptotic cascade prevention. On the other hand, the E2-ER beta complex induced the rapid and persistent phosphorylation of p38/MAPK which, in turn, was involved in caspase-3 activation and cleavage of poly(ADP-ribose)polymerase, driving cells into the apoptotic cycle. In addition, the E2-ER beta complex did not activate any of the E2-ER alpha-activated signal molecules involved in cell growth. Taken together, these results demonstrate the ability of ER beta isoform to activate specific signal transduction pathways starting from plasma membrane that may justify the effect of E2 in inducing cell proliferation or apoptosis in cancer cells. In particular this hormone promotes cell survival through ER alpha non-genomic signaling and cell death through ER beta non-genomic signaling.
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PMID:Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. 1538 27

Mitogen-activated protein kinase (MAPK) cascades are membrane-to-nucleus signaling modules that recently have been implicated as mediators of cellular injury. In this study, we investigated the involvement of the MAP kinase p44/p42 (extracellular signal-regulated kinase [ERK1/2]) in traumatic brain injury (TBI) in rats. There was a strong increase in activated, phosphorylated ERK 1/2 (p-ERK 1/2) protein at 10 min up to 24 h after the injury. Expression of p-ERK occurred in cells identified as neurons, astrocytes, and microglia. Most of the cells expressing p-ERK were TUNEL positive at later time points. Treatment with the MEK inhibitor U0126 or the free radical scavenger S-PBN, both with neuroprotective properties in TBI, attenuated the early activation of ERK and resulted in less activation of caspase-3 and subsequent DNA fragmentation. Post-treatment with U0126 resulted in a significant decrease (-60%) in cortical cavity size and cortical atrophy at 2 weeks after trauma. Overall, the results suggest that ERK activation is initiated by increased oxygen radical activity and that overactivation of ERK sets off secondary cell death mechanisms in TBI. Clinical studies are warranted to evaluate the concept of MEK inhibition in head-injured patients.
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PMID:Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. 1545 87

Oridonin, an active component isolated from Rabdosia rubescences, has been reported to exhibit antitumor effects, but little is known about its molecular mechanisms of action. In this study, the growth-inhibitory activity of oridonin for L929 cells is in time- and dose-dependent manner. After treatment with various concentrations of oridonin for 12 h, the majority of L929 cells underwent apoptosis as measured by an LDH activity-based assay. Although apoptotic bodies were observed in oridonin-treated L929 cells, DNA fragmentation as a hallmark of apoptosis was not found. The pan-caspase inhibitor, z-VAD, and caspase-3 inhibitor, z-DEVD, sensitized L929 cells to oridonin, however, a PARP inhibitor (DPQ) effectively blocked oridonin-induced cell death. After 12 h treatment, PARP proenzyme was significantly cleaved. This result indicated that oridonin-induced L929 cell death required PARP degradation in a caspase-independent manner. In addition, an MEK/ERK inhibitor (PD98059) markedly blocked oridonin-induced cell death, whereas a p38 inhibitor (SB203580) and JNK inhibitor (SP600125) weakly protected the cells against death. Treatment with 41.2 microM oridonin for 12 h induced significant and persistent ERK activation and p38 inactivation in L929 cells without evident changes in the protein levels. The responsiveness of ERK and p38 to oridonin suggests the involvement of these kinases in this apoptotic process. Moreover, oridonin increased the ratio of Bax/Bcl-2 protein expression, whereas it had no effect on the expression of Bcl-xL. These results indicate that regulation of the Bcl-2 and MAPK families maybe the effector mechanisms of oridonin-induced L929 cell death, independent of the caspase pathway.
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PMID:Oridonin induces a caspase-independent but mitochondria- and MAPK-dependent cell death in the murine fibrosarcoma cell line L929. 1546 89

We describe here the construction of a library of small interfering RNA expression vectors targeted to a few hundred apoptosis-related genes and the application of this library to an investigation of thapsigargin (TG)-induced apoptosis. Thapsigargin triggers endoplasmic reticulum stress, with subsequent apoptosis, but the molecular mechanisms underlying this process are incompletely understood. Using our library, we identified three anti-apoptotic genes, namely, NOXA, E2F1, and MAPK1, in addition to already characterized genes in the apoptotic pathway. In contrast to proposals by others, our data revealed (i) that TG-induced apoptosis is associated with Apaf1 in a caspase-3- and caspase-9-independent manner; (ii) that the E2F1-PUMA pathway might be involved; and (iii) that the ERK pathway, via MAP3K8 (mitogen-activated protein kinase kinase 8), is required for the induction by TG of apoptosis. Our study demonstrates clearly that unexpected and novel genes can be identified effectively by our method, and it provides evidence for the efficacy and utility of the comprehensive analysis of signaling networks and pathways using a library of small interfering RNA expression vectors.
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PMID:Identification of a network involved in thapsigargin-induced apoptosis using a library of small interfering RNA expression vectors. 1548 92


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