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: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
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PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 88

Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.
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PMID:Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia. 1232 85

Imexon is a new antitumor agent with high activity in multiple myeloma. This drug induces apoptosis, oxidative stress and mitochondrial alterations. However, it was unknown whether imexon activates an intrinsic apoptotic pathway that is associated with activation of caspase-9 or an extrinsic pathway that is induced by receptor-mediated signals such as Fas ligand characterized by caspase-8 activation. In addition, we wanted to investigate the effect of imexon on Bcl-2 family proteins. In RPMI8226 myeloma cells, imexon activated caspase-9 and -3 in a time- and concentration-dependent manner. In contrast, cleavage of procaspase-8 was observed late and only after exposure to very high concentrations of imexon. Confocal microscopy confirmed that caspase-3 is also activated after treatment with imexon. High imexon concentrations activated caspase-3 and -9 at 12 h, while caspase-8 activation occurred only at 48 h. Imexon cytotoxicity was unchanged in three RPMI8226 cell lines with different levels (low, medium and high) of FAS expression. Similarly, the levels of Bcl-2, Bax and Bcl-xL were unchanged in imexon-treated cells. However, Bcl-xL was translocated to the mitochondria. These data suggest that imexon-induced oxidation activates the intrinsic or mitochondrial pathway of apoptosis, involving cytochrome release and activation of caspase-9 and -3.
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PMID:Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells. 1243 37

Apoptotic death is a physiological process with regulatory mechanisms that are under the control of different molecules such as caspases. These are classified as initiators, such as caspases-8 and -9, and effectors, such as caspases-3 and -7. The participation of caspase-2 in the effector phase of apoptosis has been commonly observed in many cell types; however, it is able to act as an initiator caspase, depending on the apoptotic stimulus. Cerebellar granule cells (CGCs) undergo apoptosis when they are transferred from high potassium (K25) to low potassium (K5); this process seems to be mediated by caspase-3 activation. Staurosporine (STS), a full strength inhibitor of kinase proteins, also induces apoptosis in these cells. To characterize the caspase cascade induced by two stimuli in the same cell type we studied the activation of different caspases in CGCs treated with STS or K5. We found that both K5 and STS induce the activation of caspase-3. This result was confirmed by the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), an endogenous caspase-3 substrate. Caspase-2 was activated preferentially by STS, which showed a temporal course suggesting that this caspase was induced before caspase-3. The initiator caspase-9 was also activated by both K5 and STS, as well as cytochrome-c release. The results obtained in this study suggest that STS and K5 induced different activation caspase pathways for apoptotic cell death of CGCs.
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PMID:Caspase activation pathways induced by staurosporine and low potassium: role of caspase-2. 1252 27

Clinical reports suggest that acute ethanol intoxication is often associated with lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested from healthy subjects after an alcohol drinking binge showed enhanced T cell apoptosis (before, 0.4 +/- 0.2% versus after, 19.6 +/- 2.5% apoptotic lymphocytes/field; P < 0.001). In in vitro studies, ethanol in a concentration of 50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs. Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies, after binge drinking, T cell expression of Bcl-2 also decreased. In addition, binge drinking induced the cleavage of caspase-3, suggesting activation of caspase-3 in T cells. These results suggest that ethanol promotes T cell apoptosis through the activation of intrinsic or mitochondrial pathway.
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PMID:Ethanol promotes T cell apoptosis through the mitochondrial pathway. 1260 97

Cerebellar granule cells (CGC) cultured under 5mM KCl (K5) undergo apoptosis after 5 days in vitro (DIV). CGC death is reduced by chronic treatment with 25 mM KCl (K25) or NMDA. Also, when CGC cultured for 6-8 DIV in K25 are transferred to a K5 medium, cells die apoptotically. Moreover, Bcl-2 and Bcl-xL protect neurons from apoptosis, while Bax and Bcl-xS may act as proapototic proteins. It is suggested that these members of the Bcl-2 family may be involved in the cytochrome-c (cyt-c) release to the cytosol. Cytochrome-c is able to form a complex with other proteins to activate a cascade of proteases. In this work, we found that Bcl-2 levels in K5 cells did not show any change during 2-7 days in vitro (DIV); but cells grown with NMDA and K25 displayed an increase (55% approximately) of Bcl-2 from 4 DIV, as compared to control. Under these conditions, Bax levels showed a tendency to decrease with age under control cells and NMDA/K25 induced a reduction of approximately 10% in Bax levels from 4 DIV. On the other hand, in cells maintained in K25 during 7 DIV and then switched to a K5 medium, the levels of Bax showed a consistent decrease (30% after 8h). Under these conditions, the Bcl-2 levels did not show any significant change after 24h. Cytochrome-c levels were unaffected under K5, NMDA and K25 and only a marginal increase of cytochrome-c in the cytosol was detected at 6h after switching. We also found that caspase-9 was only activated under K25-deprivation meanwhile caspase-3 was involved in both protocols. These results suggest that the Bcl-2 family members, caspases activation and cytochrome-c release are involved in CGC death induced by K5 and their participation in this process could be different depending on neuronal maturation in culture.
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PMID:Mechanisms of cell death by deprivation of depolarizing conditions during cerebellar granule neurons maturation. 1282 Sep 87

We previously reported that dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block dieldrin-induced DNA fragmentation. Because dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in dieldrin-induced apoptotic cell death in dopaminergic cells.
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PMID:Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cdelta in dopaminergic cells: relevance to oxidative stress and dopaminergic degeneration. 1283 55

In recent years there has been an increasing interest in compounds present in foods that may prevent or slow the progression of chronic illnesses, such as cardiovascular disease, osteoporosis and cancer. Saponins have been reported to have important time-dependent anti-cancer properties. We have used a highly purified and characterized saponin fraction containing the soyasapogenol B glycosides (the 'B group' saponins) from soybeans (Glycine max L.) to demonstrate a reduction in SNB 19 human glioblastoma cell invasion (45% decrease compared to untreated cells) in vitro in a Matrigel invasion assay. We have also demonstrated that triterpenoid saponin induces apopotosis and affects mictochondiral function. Dose-dependent loss of mitochondrial trans-membrane potential in SNB 19 cells occurred with treatment, along with release of cytochrome c, processing of caspase-9, and -3 and specific cleavage of poly ADP-ribose polymerase (PARP), a substrate of caspase-3. The results suggest that the saponin fraction induces apoptosis in SNB19 human glioblastoma cells by stimulating cytochrome-c release and subsequent activation of a caspase cascade. Our observations clearly demonstrate the pro-apoptotic and anti-invasive activities of the soyasapogenol B glycosides from soybeans.
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PMID:Triterpenoids from Glycine max decrease invasiveness and induce caspase-mediated cell death in human SNB19 glioma cells. 1285 25

During development, a subpopulation (approximately 30%) of neurons in the avian cochlear nucleus, nucleus magnocellularis (NM), dies following removal of the cochlea. It is clear that neuronal activity coming from the auditory nerve provides trophic support critical for cell survival in the NM. Several aspects of the intracellular signaling cascades that regulate apoptosis have been defined for naturally occurring, or programmed cell death, in neurons. These intracellular cascades involve the extrusion of cytochrome-c from the mitochondria into the cytosol and the subsequent activation of proteolytic caspase cascades, which ultimately act on substrates that lead to the death of the cell. In contrast, the intracellular signaling cascades responsible for deafferentation-induced cell death are not fully understood. In the present series of experiments, the potential extrusion of cytochrome-c from the mitochondria into the cytosol, and the activation of caspases were examined in the NM following deafferentation. Cytochrome-c immunoreactivity increased within 6 h following deafferentation and persisted for at least 3-5 days following surgery. However, cytochrome-c was not detectable within immunoprecipitates obtained from cytosolic fractions of deafferented NM neurons. This suggests that the increased immunoreactivity of cytochrome-c is related to mitochondrial proliferation. As a positive control, cytochrome-c was detected in cytosolic fractions of deafferented NM neurons treated with kainic acid, a substance known to cause cytochrome-c release into the cytosol. In addition, immunoreactivity for downstream active caspase-9 did increase following cochlea ablation. This increase was observed within 3 h following cochlea removal, but was not observed 4 days following surgery, a time point after the dying population of NM neurons have already degenerated. Together, these findings suggest that deafferentation of NM neurons results in caspase activation, but this activation may be cytochrome-c independent.
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PMID:Afferent regulation of cytochrome-c and active caspase-9 in the avian cochlear nucleus. 1292 12

The aim of the therapy of human malignancies is the inhibition of cell proliferation and/or induction of apoptosis. We studied the kinetics of the morphological and biochemical changes in HeLa cells during chemotherapy by cisplatin (CP). Apoptosis was evaluated by scoring of cells exhibiting changes characteristic for early and late stages of apoptosis as determined by Hoechst 33258 staining and by examination of positive reaction for activated caspase-3. Expression and intracellular localization of distinct proteins was analyzed by immunoblotting of subcellular fractions and segregation of nucleoli by immunocytochemistry. Chromatin fragmentation characteristic for apoptosis was observed in single cells after 3h cisplatin. A strong cytoplasmic accumulation of cytochrome C detected by immunoblotting 6h post-treatment was accompanied by an activation of caspase-9. Neither inhibition of cell division nor blocking of DNA replication preceded the onset of apoptosis. Our results show that after short treatment by CP, cell proliferation and apoptosis concomitantly occurred.
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PMID:Induction of cell cycle arrest and apoptosis in human cervix carcinoma cells during therapy by cisplatin. 1464 57


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