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)

The Ret finger protein (RFP) is a member of the tripartite motif family, which is characterized by a conserved RING finger, a B-box, and a coiled-coil domain (together called RBCC). Although RFP is known to become oncogenic when its RBCC moiety is connected to a tyrosine kinase domain by DNA rearrangement, its biological function is not well defined. Here we show that ectopic expression of RFP in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. RFP expression activates Jun N-terminal kinase and p38 kinase and also increases caspase-3-like activity. However, RFP failed to release cytochrome c and, therefore, to increase caspase-9-like activity. RFP-induced apoptosis could be blocked by the caspase-8 inhibitor crmA and dominant negative ASK1 but not by Bcl-2. These results reveal a novel RFP death pathway that recruits mitogen-activated protein kinase and caspases independently of mitochondrial events. Domain mapping showed that the intact RBCC moiety is necessary for the pro-apoptotic function of RFP. Moreover, expression of the RBCC moiety further potentiated the pro-apoptotic activity and resulted in a 7-fold increase of caspase activation compared with that induced by full-length RFP. This suggests that a large number of tripartite motif family members sharing the RBCC moiety may participate in the control of cell survival.
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PMID:The Ret finger protein induces apoptosis via its RING finger-B box-coiled-coil motif. 1280 81

In this study, we identified whether mitogen-activated protein kinases (MAPKs) mediate the effects of angiopoietin-1 (Ang-1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang-1 (300 ng/ml) evoked within 15-30 min a 15-fold and a 5-fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI-3 kinase pathway attenuated Ang-1-induced ERK1/2 phosphorylation at a level up-stream from Raf and MEK1/2, but these inhibitors augmented Ang-1-induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang-1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase-9, -7, and -3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang-1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang-1. We conclude that both anti- (ERK1/2) and pro- (p38) apoptotic members of MAPKs are simultaneously activated by Ang-1 in endothelial cells and that activation of ERK1/2 by Ang-1 is mediated through the PI-3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI-3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang-1.
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PMID:Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases. 1282 93

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the family of programmed cell death-inducing cytokines. Apo2L/TRAIL induces apoptosis in a wide variety of tumor cells. Tumor cells that are resistant to Apo2L/TRAIL-induced apoptosis can be sensitized by chemotherapeutic drugs and other agents via an unknown mechanism. Here we report that PG490 (triptolide), a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii and used in traditional Chinese medicine, sensitizes lung cancer but not normal human bronchial epithelial cells to Apo2L/TRAIL-induced apoptosis. Sensitization was accompanied by caspase-3 and caspase-8 activation, whereas no cleavage of caspase-9 was observed. Determination of cell surface receptors by flow cytometry demonstrated no difference in Apo2L/TRAIL-R1 and -R2 expression, the two receptors with functional death domains, between resistant and sensitized cells. In cells treated with the combination of Apo2L/TRAIL and PG490, we observed activation of ERK2, a member of the mitogen-activated protein kinase family. Furthermore, sensitization could be blocked by the ERK inhibitor U0126 but not the p38 inhibitor SB203580, suggesting that activation of ERK2 is required for this effect. In addition, sensitization of lung cancer cells was also seen in ex vivo culture of lung cancer tissue from four patients who underwent surgery. Immunohistochemical staining showed a clear reduction in proliferation cell nuclear antigen (PCNA) in tissue treated with Apo2L/TRAIL and PG490. In conclusion, apoptosis induced by the combination of Apo2L/TRAIL and PG490 warrants further evaluation as a potential new strategy for the treatment of lung cancer.
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PMID:PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2. 1293 2

We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.
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PMID:Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. 1452 66

The combination of indole-3-acetic acid (IAA) and horseradish peroxidase (HRP) has recently been proposed as a novel cancer therapy. However, the mechanism underlying the cytotoxic effect involved is substantially unknown. Here, we show that IAA/HRP treatment induces apoptosis in G361 human melanoma cells, whereas IAA or HRP alone have no effect. It is known that IAA produces free radicals when oxidized by HRP. Because oxidative stress could induce apoptosis, we measured the production of free radicals at varying concentrations of IAA and HRP. Our results show that IAA/HRP produces free radicals in a dose-dependent manner, which are suppressed by ascorbic acid or (-)-epigallocatechin gallate (EGCG). Furthermore, antioxidants prevent IAA/HRP-induced apoptosis, indicating that the IAA/HRP-produced free radicals play an important role in the apoptotic process. In addition, IAA/HRP was observed to activate p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK), which are almost completely blocked by antioxidants. We further investigated the IAA/HRP-mediated apoptotic pathways, and found that IAA/HRP activates caspase-8 and caspase-9, leading to caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage. These events were also blocked by antioxidants, such as ascorbic acid or EGCG. Thus, we propose that IAA/HRP-induced free radicals lead to the apoptosis of human melanoma cells via both death receptor-mediated and mitochondrial apoptotic pathways.
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PMID:Oxidation of indole-3-acetic acid by horseradish peroxidase induces apoptosis in G361 human melanoma cells. 1460 78

Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations > or =0.75 microM for intervals > or =6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.
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PMID:Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. 1464 18

Nitric oxide(NO) induces apoptosis in human osteoblasts. Treatment with exogenous NO donors, SNAP (S-Nitroso-N-acetylpenicillamine) and SNP (sodium nitroprusside), to MG-63 osteoblasts resulted in apoptotic morphological changes, as shown by a bright blue-fluorescent condensed nuclei and chromatin fragmentation by fluorescence microscope of Hoechst 33258-staining. The activities of caspase-9 and the subsequent caspase-3-like cysteine proteases were increased during NO-induced cell death. Pretreatment with Z-VAD-FMK (a pan-caspase inhibitor) or Ac-DEVD-CHO (a specific caspase-3 inhibitor) abrogated the NO-induced cell death. The NO donor markedly activated JNK, a stress-activated protein kinase in the human osteoblasts. This study showed that the inhibition of the JNK pathway markedly reduced NO-induced cell death. But neither PD98059 (MEK inhibitor) nor SB203580 (p38 MAPK inhibitor) had any effect on NO-induced death. Taken together, these results suggest that JNK/SAPK may be related to NO-induced apoptosis in MG-63 human osteoblasts.
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PMID:JNK/SAPK is required in nitric oxide-induced apoptosis in osteoblasts. 1466 60

Acute exposure to trimethyltin (TMT) causes neuronal degeneration in the hippocampus, amygdala, pyriform cortex, and neocortex [Am. J. Pathol. 97 (1979) 59]. Despite extensive efforts elucidating neuropathological changes and behavioral deficits following TMT exposure, only a limited amount of work has examined the molecular signaling mechanisms that lead to these changes. The present paper demonstrates that TMT impairs neurite outgrowth and cell viability in an in vitro model of neuronal development. The decrease in cell viability is paralleled by a decrease in cell body size, an increase in DNA fragmentation, activation of caspase-9, and cleavage of the caspase substrate poly-ADP ribose polymerase (PARP). These results suggest that TMT induces apoptosis. Pharmacological inhibition of caspase activity, p38 stress-responsive protein kinase activity, or oxidative stress prevented TMT-induced cell death. This work provides the first evidence for a TMT-initiated apoptotic pathway requiring oxidative stress, caspase activation, and p38 protein kinase activity.
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PMID:The neurotoxicant trimethyltin induces apoptosis via caspase activation, p38 protein kinase, and oxidative stress in PC12 cells. 1470 May 29

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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PMID:Apoptosis and heart failure: mechanisms and therapeutic implications. 1472 98

Recently, we synthesized 9-hydroxypheophorbide alpha (9-HPbD), a new chlorophyll-derived photosensitizer. The photo-treatment of MCF-7 human breast cancer cells with 20 kJ/m2 of red light after 5 microM 9-HPbD pretreatment induced cell death, showed typical apoptotic features, i.e., chromatin condensation, phosphatidyl serine externalization, membrane blebbing, and apoptotic bodies with an intact plasma membrane structure. To elucidate the mechanism of 9-HPbD-induced apoptosis, various mediators of the apoptosis were investigated. Release of cytochrome c from mitochondria into the cytosol was distinct 9 h after irradiation, while the levels of most apoptosis-related molecules such as Fas, FasL, Bcl-2, Bax and p53 were unchanged. Furthermore, caspase-9 activated by released cytochrome c was not significantly activated after 9-HPbD-photosensitization. On the other hand, stress-activated protein kinases such as p38 and c-Jun N-terminal kinase (JNK) were activated 1 h after irradiation. Blocking of JNK signaling by transfecting with the dominant negative from of the JNK gene significantly reduced 9-HPbD-induced cell death. Our data show that photosensitization with the new photosensitizer 9-HPbD could induce the apoptotic death of MCF-7 breast cancer cell and that this death is mediated by stress-activated signal through JNK.
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PMID:9-Hydroxypheophorbide alpha-induced apoptotic death of MCF-7 breast cancer cells is mediated by c-Jun N-terminal kinase activation. 1473 56


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