Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here the purification of the third protein factor, Apaf-3, that participates in caspase-3 activation in vitro. Apaf-3 was identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from S-100 extracts diminished caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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PMID:Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. 1505 83

Ced-4 and Apaf-1 belong to a major class of apoptosis regulators that contain caspase-recruitment (CARD) and nucleotide-binding oligomerization domains. Nod1, a protein with an NH2-terminal CARD-linked to a nucleotide-binding domain and a COOH-terminal segment with multiple leucine-rich repeats, was identified. Nod-1 was found to bind to multiple caspases with long prodomains, but specifically activated caspase-9 and promoted caspase-9-induced apoptosis. As reported for Apaf-1, Nod1 required both the CARD and P-loop for function. Unlike Apaf-1, Nod1 induced activation of nuclear factor-kappa-B (NF-kappaB) and bound RICK, a CARD-containing kinase that also induces NF-kappaB activation. Nod1 mutants inhibited NF-kappaB activity induced by RICK, but not that resulting from tumor necrosis factor-alpha stimulation. Thus, Nod1 is a leucine-rich repeat-containing Apaf-1-like molecule that can regulate both apoptosis and NF-kappaB activation pathways.
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PMID:Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. 1032 46

We reported previously that a synthetic compound, MT-21, induced apoptosis by activating c-Jun-NH2-terminal kinase via the Krs/MST protein, which is activated by caspase-3 cleavage dependent on reactive oxygen species production. Here we examine the activation mechanism of caspase-3, an important cysteine aspartic protease, during MT-21-induced apoptosis. We found that MT-21 activated caspase-3 via caspase-9, but not via caspase-8. In addition, MT-21 induced the release of cytochrome c from the mitochondria that is necessary to activate caspase-9, and this release occurred before a change in membrane potential. This initiation process of MT-21-induced apoptosis was suppressed by overexpression of Bcl-2, which is known to prevent cells from undergoing apoptosis in response to a variety of stimuli. Moreover, when we treated mitochondria isolated from the cells with MT-21, the direct release of cytochrome c from the mitochondria was observed, whereas this effect was not observed in the mitochondria isolated from cells that overexpressed Bcl-2. Other apoptosis-inducing agents known to induce apoptosis via cytochrome c release from the mitochondria failed to release cytochrome c directly from isolated mitochondria. These findings indicate that MT-21 is a possible candidate antitumor agent that is able to induce apoptosis via the direct release of cytochrome c from the mitochondria.
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PMID:MT-21 is a synthetic apoptosis inducer that directly induces cytochrome c release from mitochondria. 1101 50

Apoptosis induction may be a mechanism mediating the anticancer activity of selenium. Our earlier work indicated that distinct cell death pathways are likely involved in apoptosis induced by the CH3SeH and the hydrogen selenide pools of selenium metabolites. To explore the role of caspases in cancer cell apoptosis induced by selenium, we examined the involvement of these molecules in the death of the DU-145 human prostate carcinoma cells induced by methylseleninic acid (MSeA), a novel penultimate precursor of the putative critical anticancer metabolite CH3SeH. Sodium selenite, a representative of the genotoxic selenium pool, was used as a reference for comparison. The results show that MSeA-induced apoptosis was accompanied by the activation of multiple caspases (caspase-3, -7, -8, and -9), mitochondrial release of cytochrome c (CC), poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. In contrast, selenite-induced apoptotic DNA fragmentation was observed in the absence of these changes, but was associated with the phosphorylation of c-Jun-NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase/stress-activated protein kinase 2. A general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone, blocked MSeA-induced cleavage of procaspases and PARP, CC release, and DNA nucleosomal fragmentation, but did not prevent cell detachment. Furthermore, PARP cleavage and caspase activation were confined exclusively to detached cells, indicating that MSeA induction of cell detachment was a prerequisite for caspase activation and apoptosis execution. This process therefore resembled "anoikis," a special mode of apoptosis induction in which adherent cells lose contact with the extracellular matrix. Additional experiments with irreversible caspase inhibitors show that MSeA-induced anoikis involved caspase-3- and -7-mediated PARP cleavage that was initiated by caspase-8 and probably amplified through CC-caspase-9 activation and a feedback activation loop from caspase-3. Taken together, the data support a methyl selenium-specific induction of DU-145 cell apoptosis that involves cell detachment as a prerequisite (anoikis) and is executed principally through caspase-8 activation and its cross-talk with multiple caspases.
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PMID:Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. 1130 88

Intracellular polyamine homeostasis is important for the regulation of cell proliferation and apoptosis and is necessary for the balanced growth of cells and tissues. Polyamines have been shown to play a role in the regulation of apoptosis in many cell types, including IEC-6 cells, but the mechanism is not clear. In this study, we analyzed the mechanism by which polyamines regulate the process of apoptosis in response to tumor necrosis factor-alpha (TNF-alpha). TNF-alpha or cycloheximide (CHX) alone did not induce apoptosis in IEC-6 cells. Significant apoptosis was observed when CHX was given along with TNF-alpha, as indicated by a significant increase in the detachment of cells, caspase-3 activity, and DNA fragmentation. Polyamine depletion by treatment with alpha-difluoromethylornithine significantly reduced the level of apoptosis, as judged by DNA fragmentation and the caspase-3 activity of attached cells. Apoptosis in IEC-6 cells was accompanied by the activation of upstream caspases-6, -8, and -9 and NH2-terminal c-Jun kinase (JNK). Inhibition of JNK activation prevented caspase-9 activation. Polyamine depletion prevented the activation of JNK and of caspases-6, -8, -9, and -3. SP-600125, a specific inhibitor of JNK activation, prevented cytochrome c release from mitochondria, JNK activation, DNA fragmentation, and caspase-9 activation in response to TNF-alpha/CHX. In conclusion, we have shown that polyamine depletion delays and decreases TNF-alpha-induced apoptosis in IEC-6 cells and that apoptosis is accompanied by the release of cytochrome c, the activation of JNK, and of upstream caspases as well as caspase-3. Polyamine depletion prevented JNK activation, which may confer protection against apoptosis by modulation of upstream caspase-9 activation.
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PMID:Polyamines are required for activation of c-Jun NH2-terminal kinase and apoptosis in response to TNF-alpha in IEC-6 cells. 1286 86

Norcantharidin (NCTD) is an anticancer drug routinely used against hepatoma in China. Previously, we reported that NCTD could induce mitotic arrest and apoptosis in human hepatoma HepG2 cells. However, the intracellular signaling pathways involved in NCTD-induced apoptotic cell death are still obscure. Caspase inhibitors were used to clarify the role of specific caspase in NCTD-triggered apoptotic process. Results showed that activation of caspase-9/caspase-3 cascade is required for NCTD-induced apoptotic death. To decipher the upstream signals for NCTD-induced apoptosis, we characterized the involvement of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38MAPK. The role of their downstream targets, transcription factors activating protein-1 (AP-1), and nuclear factor kappaB (NF-kappaB) in NCTD-induced apoptosis was also analyzed. Immunoblot analyses and in vitro kinase assay demonstrated that NCTD-induced apoptosis was accompanied by the elevations of the levels of phosphorylated form and kinase activity of ERK and JNK, but not p38MAPK. The inhibitor of ERK pathway (U0126 or PD98059) or JNK pathway (SP600125) markedly prevented kinase activation, and also greatly reduced NCTD-induced apoptotic cell death. Increased DNA-binding activity of AP-1 and NF-kappaB was also observed after NCTD treatment. Inhibition of NF-kappaB activation by PDTC or inhibition of AP-1 activation by curcumin drastically blocked NCTD-induced cell death. These results imply that activation of ERK and JNK, and modulation of downstream transcription factors NF-kappaB and AP-1, may be involved in NCTD-induced apoptosis.
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PMID:Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells. 1297 86

X-linked inhibitor of apoptosis protein (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family, plays a crucial role in the regulation of apoptosis. XIAP is structurally characterized by three baculovirus IAP repeat (BIR) domains that mediate binding to and inhibition of caspases and a RING domain that confers ubiquitin ligase activity. The caspase inhibitory activity of XIAP can be eliminated by the second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low pI (DIABLO) during apoptosis. Here we report the identification and characterization of a novel isoform of Smac/DIABLO named Smac3, which is generated by alternative splicing of exon 4. Smac3 contains an NH2-terminal mitochondrial targeting sequence required for mitochondrial targeting of Smac3 and an IAP-binding motif essential for Smac3 binding to XIAP. Smac3 is released from mitochondria into the cytosol in response to apoptotic stimuli, where it interacts with the second and third BIR domains of XIAP. Smac3 disrupts processed caspase-9 binding to XIAP, promotes caspase-3 activation, and potentiates apoptosis. Strikingly, Smac3, but not Smac/DIABLO, accelerates XIAP auto-ubiquitination and destruction. Smac3-stimulated XIAP ubiquitination is contingent upon the physical association of XIAP with Smac3 and an intact RING domain of XIAP. Smac3-accelerated XIAP destabilization is, at least in part, attributed to its ability to enhance XIAP ubiquitination. Our study demonstrates that Smac3 is functionally additive to, but independent of, Smac/DIABLO.
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PMID:Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. 1452 16

This study first investigates the anticancer effect of asiatic acid in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Asiatic acid exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclinB1, cyclinA, Cdc2, and Cdc25C in a p53-independent manner. Asiatic acid also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the level of inactivated phospho-Cdc2 and phospho-Cdc25C. Asiatic acid treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8. We also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), and p38, but not c-Jun NH2-terminal kinase (JNK), are critical mediators in asiatic acid-induced cell growth inhibition. U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], specific inhibitors of mitogen-activated protein kinase kinase and p38 kinase activities, significantly decreased or delayed apoptosis. Asiatic acid was likely to confine the breast cancer cells in the S-G2/M phase mainly through the p38 pathway, because both SB203580 and p38 small interfering RNA (siRNA) inhibition significantly attenuated the accumulation of inactive phospho-Cdc2 and phospho-Cdc25C proteins and the cell numbers of S-G2/M phase. Moreover, U0126 and ERK siRNA inhibition completely suppressed asiatic acid-induced Bcl-2 phosphorylation and Bax up-regulation, and caspase-9 activation. Together, these results imply a critical role for ERK1/2 and p38 but not JNK, p53, and Fas/Fas ligand in asiatic acid-induced S-G2/M arrest and apoptosis of human breast cancer cells.
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PMID:Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. 1562 23

The bovine viral diarrhea virus (BVDV) strains exist as two biotypes, cytopathic (cp) and noncytopathic (ncp), according to their effects on tissue culture cells. It has been previously reported that cell death associated to cp BVDV in vitro is mediated by apoptosis. Here, experiments were conducted to determine the involvement of the NS3 protein in the induction of apoptosis. The NS3- and NS3Delta50 (deleted from the NH2-terminal 50 amino acids)-cDNA encoding sequences of BVDV NADL cp reference strain were cloned into adenoviral vectors (AdV) from which the BVDV gene of interest could be expressed from a tetracycline-responsive promoter. A549tTA cells infected in vitro with NS3 or NS3Delta50-expressing AdV showed cytopathic changes characterized by cell rounding and detachment, and nucleus chromatin condensation. DNA fragmentation assays, cytochrome c release, and activation of cellular caspases performed on these infected cells clearly correlated with the observed cytopathic changes with apoptosis. The BVDV NS3Delta50-induced apoptotic process was inhibited by caspase-8- and -9-specific peptide inhibitors (Z-IETD-FMK and Z-LEHD-FMK). Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given that HSV2-R1, a specific inhibitor of the caspase-8 activation pathway, efficiently suppressed apoptosis and also prevented caspase-9 activation, the overall results indicate that the BVDV NS3/NS3Delta50 induces apoptosis initiated by caspase-8 activation and subsequent cytochrome c release-dependent caspase-9 activation.
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PMID:The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation. 1572 Sep 74

Trimidox (3,4,5-trihydroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase accompanied by growth inhibition and the differentiation of mammalian cells. Here we examine the induction of apoptosis by trimidox in several human leukaemia cell lines, focusing on the release of cytochrome c and the activation of caspase proteases in the human B cell line NALM-6. Induction of apoptosis by trimidox (300 microM) was detected in NALM-6, HL-60 (premyelocytic leukaemia cells), MOLT-4 (an acute lymphoblastic leukaemia cells), Jurkat (a T-cell leukaemia cells), U937 (expressing many monocyte-like characteristics), and K562 (erythroleukaemia). NALM-6 was most affected by trimidox among leukaemia cells; therefore, we employed NALM-6 cells in the subsequent experiments. The cells showed a time-dependent increase in DNA damage after trimidox (250 microM) treatment. A significant increase in the amount of cytochrome c release was detected after treatment with trimidox. Bcl-2 and Bax protein expressions were not changed by trimidox. Caspase-3 and -9 were activated by incubation with trimidox, whereas caspase-8 was not. Furthermore, trimidox-induced apoptosis was prevented by a broad-spectrum caspase inhibitor, a caspase-3, and a caspase-9 inhibitor, but not by a caspase-8 inhibitor. Inhibition of c-Jun NH2-terminal kinase (JNK) by SP600125 appreciably protected cells from trimidox-induced apoptosis, but no effect inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580. In contrast, extracellular signal-regulated kinase (ERK) inhibitors U0126 and PD98059 strongly potentiated the apoptotic effect of trimidox. This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c-dependent pathway, which sequentially activates caspase-3 and caspase-9.
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PMID:Trimidox induces apoptosis via cytochrome c release in NALM-6 human B cell leukaemia cells. 1643 90


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