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)

Endostatin (ES) was reported to stimulate apoptosis in endothelial cells, but the exact mechanism remains controversial. In the present study, we elucidate the mechanism of ES-induced endothelial cell apoptosis. Our results indicate that ES induces cytochrome c release and caspase-9 activation in human microvascular endothelial cells (HMECs) at the concentration of 1 microM for 24 h, which initiates the apoptosis process. Further, ATP production, mitochondrial membrane potential, and tubule formation assays showed that ES promotes the mitochondrial permeability transition pore (mPTP) opening via voltage-dependent anion channel 1 (VDAC1), a major component of mitochondrial outer membrane. Knocking down VDAC1 by small interfering RNA attenuates ES-induced apoptosis, while overexpression of VDAC1 enhances the sensitivity of endothelial cells to ES. Moreover, we reveal that ES induces the reduction of hexokinase 2 (HK2), which, in turn, promotes VDAC1 phosphorylation and accumulation. Data from two-dimensional electrophoresis, immunoprecipitation, mPTP opening, and caspase-3 activation assays indicate that two serine residues of VDAC1, Ser-12 and Ser-103, can modulate VDAC1 protein level and thus the sensitivity to apoptosis stimuli. On the basis of these findings, we conclude that VDAC1 plays a vital role in modulating ES-induced endothelial cell apoptosis.
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PMID:Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis. 1838 14

Apoptosis is a major cause of cell death in the nervous system. It plays a role in embryonic and early postnatal brain development and contributes to the pathology of neurodegenerative diseases. Here, we report that activation of the P2X(7) nucleotide receptor (P2X(7)R) in rat primary cortical neurons (rPCNs) causes biochemical (i.e., caspase activation) and morphological (i.e., nuclear condensation and DNA fragmentation) changes characteristic of apoptotic cell death. Caspase-3 activation and DNA fragmentation in rPCNs induced by the P2X(7)R agonist BzATP were inhibited by the P2X(7)R antagonist oxidized ATP (oATP) or by pre-treatment of cells with P2X(7)R antisense oligonucleotide indicating a direct involvement of the P2X(7)R in nucleotide-induced neuronal cell death. Moreover, Z-DEVD-FMK, a specific and irreversible cell permeable inhibitor of caspase-3, prevented BzATP-induced apoptosis in rPCNs. In addition, a specific caspase-8 inhibitor, Ac-IETD-CHO, significantly attenuated BzATP-induced caspase-9 and caspase-3 activation, suggesting that P2X(7)R-mediated apoptosis in rPCNs occurs primarily through an intrinsic caspase-8/9/3 activation pathway. BzATP also induced the activation of C-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated kinases (ERK1/2) in rPCNs, and pharmacological inhibition of either JNK1 or ERK1/2 significantly reduced caspase activation by BzATP. Taken together, these data indicate that extracellular nucleotides mediate neuronal apoptosis through activation of P2X(7)Rs and their downstream signaling pathways involving JNK1, ERK and caspases 8/9/3.
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PMID:P2X(7) nucleotide receptors mediate caspase-8/9/3-dependent apoptosis in rat primary cortical neurons. 1840 18

During apoptosis, cytochrome c is released from mitochondria to the cytosol, where it binds Apaf-1. The Apaf-1/cytochrome c complex then oligomerizes either into heptameric caspase-9-activating apoptosome, which subsequently activates caspase-3 and caspase-7, or bigger inactive aggregates, depending on the availability of nucleotide dATP/ATP. A tumor suppressor protein, PHAPI, enhances caspase-9 activation by promoting apoptosome formation through an unknown mechanism. We report here the identification of cellular apoptosis susceptibility protein (CAS) and heat shock protein 70 (Hsp70) as mediators of PHAPI activity. PHAPI, CAS, and Hsp70 function together to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1/cytochrome c aggregation. CAS expression is induced by multiple apoptotic stimuli including UV irradiation. Knockdown of CAS by RNA interference (RNAi) in cells attenuates apoptosis induced by UV light and causes endogenous Apaf-1 to form aggregates. These studies indicated that PHAPI, CAS, and Hsp70 play an important regulatory role during apoptosis.
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PMID:PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1. 1843 2

Anthrax is an infectious disease caused by toxigenic strains of the Gram-positive bacterium Bacillus anthracis. To identify the mitochondrial proteins that are expressed differently in murine macrophages infected with spores of B. anthracis Sterne, proteomic and MALDI-TOF/MS analyses of uninfected and infected macrophages were conducted. As a result, 13 mitochondrial proteins with different expression patterns were discovered in the infected murine macrophages, and some were identified as ATP5b, NIAP-5, ras-related GTP binding protein B isoform CRAa, along with several unnamed proteins. Among these proteins, ATP5b is related to energy production and cytoskeletal rearrangement, whereas NIAP-5 causes apoptosis of host cells due to binding with caspase-9. Therefore, this paper focused on ATP5b, which was found to be downregulated following infection. The downregulated ATP5b also reduced ATP production in the murine macrophages infected with B. anthracis spores. Consequently, this study represents the first mitochondrial proteome analysis of infected macrophages.
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PMID:Bacillus anthracis spores influence ATP synthase activity in murine macrophages. 1846 76

Previous studies have shown that cerebral hypoxia results in increased activity of caspase-9, a key initiator of programmed cell death, in the cytosolic fractions of the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypoxia results in increased expression of procaspase-9 and procaspase-3 in neuronal nuclear, mitochondrial and cytosolic fractions of the cerebral cortex of newborn piglets. To test this hypothesis, expression of procaspase-9 and procaspase-3 was determined in 10 newborn piglets divided into two groups: normoxic (Nx, n=5) and hypoxic (Hx, n=5). The hypoxic piglets were exposed to an FiO(2) of 0.06 for 1h. Tissue hypoxia was documented by ATP and phosphocreatinine (PCr) levels. Neuronal nuclear, mitochondrial and cytosolic fractions were isolated and the expression of procaspase-9 and procaspase-3 was determined by immunoblotting using specific anti-procaspase-9 and anti-procaspase-3 antibodies. ATP levels (micromol/g brain) were 4.34+/-0.36 in the Nx and 1.43+/-0.28 in the Hx (p<0.001 vs. Nx) groups. PCr levels (micromol/g brain) were 3.75+/-0.27 in the Nx and 0.69+/-0.26 in the Hx (p<0.001 vs. Nx) group. Cytosolic procaspase-9 density (ODxmm(2)) was 88.82+/-17.55 in the Nx and 215.54+/-22.77 in the Hx (p<0.001 vs. Nx). Mitochondrial procaspase-9 density (ODxmm(2)) was 104.67+/-12.75 in the Nx and 183.44+/-16.69 in the Hx (p<0.001 vs. Nx). Nuclear procaspase-9 density (ODxmm(2)) was 135.56+/-15.36 in the Nx and 190.66+/-29.35 in the Hx (p<0.001 vs. Nx). Cytosolic procaspase-3 density (ODxmm(2)) was 23.72+/-3.71 in the Nx and 92.44+/-8.46 in the Hx (p<0.001 vs. Nx). Mitochondrial procaspase-3 density (ODxmm(2)) was 22.12+/-2.97 in the Nx and 51.22+/-10.67 in the Hx (p<0.001 vs. Nx). Nuclear procaspase-3 density (ODxmm(2)) was 53.80+/-7.18 in the Nx and 84.67+/-5.63 in the Hx (p<0.001 vs. Nx). We conclude that procaspase-9 and procaspase-3 proteins increased in all cell compartments including cytosolic, mitochondrial and nuclear during hypoxia, indicating increased expression of procaspase-9 during hypoxia. We propose that following increased expression of procaspase-9 and procaspase-3, these molecules traffic among the various cell compartments and become available for their activation resulting in increased caspase-9 and caspase-3 activity.
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PMID:Effect of hypoxia on the expression of procaspase-9 and procaspase-3 in neuronal nuclear, mitochondrial and cytosolic fractions of the cerebral cortex of newborn piglets. 1846 94

Toosendanin (Tsn), a triterpenoid extracted from Melia toosendan Sieb et Zucc, possesses different pharmacological effects in human and important values in agriculture. However, liver injury has been reported when toosendanin or Melia-family plants, which contain toosendanin are applied. The mechanism by which toosendanin induces liver injury remains largely unknown. Here we reported that toosendanin induced primary rat hepatocytes death by mitochondrial dysfunction and caspase activation. Toosendanin led to decrease of mitochondrial membrane potential, fall in intracellular ATP level, release of cytochrome c to cytoplasm, activation of caspase-8, 9, and 3 and ultimately cell death. Level of reactive oxygen species (ROS) was also increased in hepatocytes after incubation with toosendanin. Catalase, the H2O2-decomposing enzyme, can prevent the reduction in ATP level and protect hepatocytes from toosendanin-induced death. The ERK1/2 (p44/42 MAP kinases) and JNK (c-Jun N-terminal kinase) were activated, but p38 MAPK was not activated by toosendanin. Inhibition of ERK1/2 activation sensitized hepatocytes to death and increased activity of caspase-9 and 3 in response to toosendanin. Inhibition of JNK attenuated toosendanin-induced cell death. These results suggested that toosendanin causes death of primary rat hepatocytes by mitochondrial dysfunction and caspase activation. Generation of ROS and MAP kinases activation might be involved in this process.
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PMID:Roles of reactive oxygen species and MAP kinases in the primary rat hepatocytes death induced by toosendanin. 1849 25

Apoptosome refers to the multimeric protein complex that mediates activation of an initiator caspase at the onset of apoptosis. This chapter describes the assembly of three related apoptosomes from mammals, fruit flies, and worms. The assembly of the mammalian apoptosome, which is responsible for the activation of caspase-9, involves Apaf-1 and requires cytochrome c and ATP/dATP binding. Assembly of the apoptosome in Drosophila melanogaster, which activates caspase-9 homologue Dronc, involves the Apaf-1 homologue known as Dark/Hac-1/Dapaf-1. In Caenorhabditis elegans, assembly of the CED-4 apoptosome requires EGL-1-mediated dissociation of CED-9 (a Bcl-2 homologue) from the CED-4-CED-9 complex and subsequent oligomerization of CED-4. Recent biochemical and structural investigation revealed insights into the assembly and function of the various apoptosomes.
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PMID:Apoptosome assembly. 1866 68

To explore how the intrinsic apoptosis pathway is controlled in the spontaneous fog (forebrain overgrowth) mutant mice with an Apaf1 splicing deficiency, we examined spleen and bone marrow cells from Apaf1(+/+) (+/+) and Apaf1(fog/fog) (fog/fog) mice for initiator caspase-9 activation by cellular stresses. When the mitochondrial inner membrane potential (Deltapsim) was disrupted by staurosporine, +/+ cells but not fog/fog cells activated caspase-9 to cause apoptosis, indicating the lack of apoptosome (apoptosis protease activating factor 1 (Apaf-1)/cytochrome c/(d)ATP/procaspase-9) function in fog/fog cells. However, when a marginal ( approximately 20%) decrease in Deltapsim was caused by hydrogen peroxide (0.1 mM), peroxynitritedonor 3-morpholinosydnonimine (0.1 mM) and UV-C irradiation (20 J/m(2)), both +/+ and fog/fog cells triggered procaspase-9 auto-processing and its downstream cascade activation. Supporting our previous results, procaspase-9 pre-existing in the mitochondria induced its auto-processing before the cytosolic caspase activation regardless of the genotypes. Cellular ATP concentration significantly decreased under the hypoactive Deltapsim condition. Furthermore, we detected accumulation of citrate, a kosmotrope known to facilitate procaspase-9 dimerization, probably due to a feedback control of the Krebs cycle by the electron transfer system. Thus, mitochondrial in situ caspase-9 activation may be caused by the major metabolic reactions in response to physiological stresses, which may represent a mode of Apaf-1-independent apoptosis hypothesized from recent genetic studies.
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PMID:Apaf-1-deficient fog mouse cell apoptosis involves hypo-polarization of the mitochondrial inner membrane, ATP depletion and citrate accumulation. 1866 78

It has been postulated that dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, and nitric oxide (NO) induce mitochondrial dysfunction in a synergistic manner. We examined the combined effects of NO and DOPAC on PC-12 cells in terms of cell viability, nuclear morphology, mitochondrial parameters and cell death mechanisms. The apoptotic cell death induced by the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), was differently modulated by DOPAC as a function of DOPAC/cell ratios. Whereas below 200nmol/10(6) cells, DOPAC inhibited a typical apoptotic pathway induced by exposure the cells to the NO donor, above 200nmol DOPAC/10(6) cells, the cell death was not only enhanced but encompassed a distinct mechanism. Loading the cells with dopamine mimicked the effects of DOPAC. Specifically, the combination of DOPAC and NO induced an early mitochondrial membrane potential dissipation and ATP depletion followed by loss of cellular membrane integrity. Mitochondrial dysfunction was accompanied by the release of cytochrome c in both cases, NO individually and in combination with DOPAC, but caspase-3 and caspase-9 activation were only observed in the absence of DOPAC. DOPAC alone was ineffective. Thus, our results suggest a role for DOPAC as a modulator of cell fate and point to a pathway of cell death involving DOPAC and NO, via mechanisms that include mitochondrial dysfunction but do not involve the activation of the typical apoptotic caspase cascade. The significance of these results is discussed in connection with the mechanisms of cell death underlying Parkinson's disease.
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PMID:3,4-Dihydroxyphenylacetic acid (DOPAC) modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dysfunctioning. 1870 27

Hydrogen sulfide (H(2)S) has been proposed as a novel neuromodulator, which plays critical roles in the central nervous system affecting both neurons and glial cells. However, its relationship with neurodegenerative diseases is unexplored. The present study was undertaken to investigate the effects of H(2)S on cell injury induced by rotenone, a commonly used toxin in establishing in vivo and in vitro Parkinson's disease (PD) models, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report here that sodium hydrosulfide (NaHS), an H(2)S donor, concentration-dependently suppressed rotenone-induced cellular injury and apoptotic cell death. NaHS also prevented rotenone-induced p38- and c-Jun NH(2)-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (DeltaPsi(m)) dissipation, cytochrome c release, caspase-9/3 activation and poly(ADP-ribose) polymerase cleavage. Furthermore, 5-hydroxydecanoate, a selective blocker of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, attenuated the protective effects of NaHS against rotenone-induced cell apoptosis. Thus, we demonstrated for the first time that H(2)S inhibited rotenone-induced cell apoptosis via regulation of mitoK(ATP) channel/p38- and JNK-MAPK pathway. Our data suggest that H(2)S may have potential therapeutic value for neurodegenerative diseases, such as PD.
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PMID:Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. 1883 35


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