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:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proinflammatory cytokine IL-4 is secreted in large amounts during allergic inflammatory response in asthma and plays a pivotal role in the airway inflammation. IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. IL-4 has also been shown to up-regulate peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors in macrophages and A549 cells. In this study we demonstrate that 15(S)-HETE binds to PPARgamma nuclear receptors and induces apoptosis in A549 cells. Moreover, pretreatment of cells with nordihydroguaiaretic acid, a 15-lipoxygenase inhibitor, prevented PPARgamma activation and apoptosis. The latter was accomplished by the interaction of the 15(S)-HETE/PPARgamma complex with the adapter protein Fas-associating protein with death domain and caspase-8, as shown by transfection of Fas-associating protein with death domain dominant negative vector and cleavage of caspase 8 to active subunits p41/42 and p18. Whereas IL-4 and PPARgamma ligands failed to induce cleavage of Bid and release of cytochrome c from mitochondria, they caused translocation of the proapoptotic protein Bax from cytoplasm to mitochondria with a concomitant decrease in the Bcl-x(L) level. We therefore believe that in unstimulated cells Bcl-x(L) and Bax form a heterodimer, in which Bcl-x(L) dominates and prevents the induction of apoptosis, whereas in IL-4-stimulated cells the 15(S)-HETE/PPARgamma complex down-regulates Bcl-x(L), and the resulting overweight of Bax commits the cell to apoptosis via caspase-3. However, this pathway does not rule out the direct caspase-8-mediated activation of caspase-3. In conclusion, IL-4-induced apoptosis may contribute to severe loss of alveolar structures and infiltration of eosinophils, mononuclear phagocytes, etc., into the lung tissue of chronic asthma patients.
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PMID:IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor. 1251 54

Signal transducers and activators of transcription (STAT) were originally discovered as components of cytokine signal transduction pathways. Persistent activation of one STAT, STAT3, is a common feature of prostate cancer. Activated STAT3 was found in pathology specimens obtained from prostatectomy in the cancerous areas but not in the normal margins. Because the activation of STAT3 is mediated by the action of an upstream Janus kinase (JAK) kinase, usually JAK1 or JAK2, the activation step for STAT3 might itself be a target for therapy in prostate cancer. However, the redundancy of upstream kinases may make this strategy unreliable for therapy. To develop molecular targets for prostate cancer treatment, JAK kinase and STAT3 inhibition of two prostate cancer lines were compared. DU145 and NRP-154 cells were treated with JAK kinase inhibitors, analyzed for onset of apoptosis, and measured by annexin V binding and propidium iodide uptake. Activation of caspases in the cells was determined by measuring cleaved caspase-3 following treatment. For determining the effect on mitochondrial membrane depolarization that accompanies apoptosis, the fluorescent dye JC-1 was used. STAT3 was specifically inhibited by transfecting either a dominant-negative (DN) STAT3 plasmid or antisense STAT3 oligonucleotides into the cells. To look for reduction in STAT3 levels within cells, fixed and permeabilized prostate cancer cells were stained with antibody to STAT3. We found that more than one JAK kinase is involved in STAT3 activation in prostate cancer lines. AG490 (JAK2 specific) induced apoptosis in DU145 but not in NRP-154 prostate cancer lines, whereas piceatannol (JAK1 specific) induced apoptosis in NRP-154 but not in DU145 cells. Next, we demonstrated efficacy of specific STAT3 inhibitors in prostate cancer lines. Both induction of apoptosis and reduction in intracellular STAT3 protein were observed following treatment with antisense STAT3 oligonucleotides, while transfection of a DN-STAT3 plasmid into both prostate cancer cell lines resulted in loss of viability and onset of apoptosis. We conclude that STAT3-specific inhibitors, rather than JAK kinase-specific inhibitors, should be more useful therapeutically in treating androgen-resistant prostate cancer and that STAT3 is an appropriate target in the treatment of prostate cancer.
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PMID:Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. 1474 71

Many factors regulate nervous system development, including complex cross-talk between local neuroendocrine systems. The adipocyte-secreted hormone leptin, mainly known for its key roles in nutrition and reproductive balance, may also be involved in neuroanatomical organization, myelination processes, and neuronal/glia maturation. SK-N-SH-SY5Y neuroblastoma cells were employed as an in vitro model of human neuronal cells to determine whether leptin exerts neuroprotective activities. We show that SH-SY5Y cells express leptin, the long and short isoforms of the leptin receptor (ObRl, ObRs). In SH-SY5Y cells, leptin induced signal transducer and activator of transcription (STAT)-3 phosphorylation and suppressor of cytokine signaling-3 mRNA expression. Leptin dose-dependently increased cell number (up to 200% at 1 microm by 48 h, P < 0.01), and at 24-48 h, leptin at 100 nm increased SH-SY5Y cell number by 30-50%, respectively. SH-SY5Y cell viability was reduced in serum-free conditions at 24 h, and addition of leptin at 100 nm significantly reduced apoptosis by approximately 20% (P < 0.001). Leptin's antiapoptotic activity required Janus kinase/STAT, MAPK, and phosphatidylinositol-3-kinase activation because the antiapoptotic effects of leptin were abolished, and caspase-3 immunoreactivity increased in the presence of the specific blockers AG490, U0126, or LY294002. Gene array demonstrated that leptin inhibits apoptosis via potent down-regulation of caspase-10 and TNF-related apoptosis-inducing ligand. Our data thus demonstrate, for the first time, that leptin stimulates, in a time- and dose-dependent manner, neuroblastoma cell proliferation and that the underlying mechanisms involve suppression of apoptosis via the Janus kinase-STAT, phosphatidylinositol-3 kinase, and MAPK pathways that culminate altogether in the down-regulation of the apoptotic factors caspase-10 and TNF-related apoptosis-inducing ligand.
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PMID:Antiapoptotic effects of leptin in human neuroblastoma cells. 1516 21

The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1), STAT3, and STAT6 as well as ERK, whereas enhanced neither phosphorylation of Akt nor nuclear translocation of nuclear factor kappaB (NF-kappaB) p65. Janus kinase (JAK)-induced phosphorylation of STAT1/3/6, which acts at translational regulation, seemed to be crucial because chemical inhibition of JAK as well as cycloheximide (CHX) abolished both the phosphorylation of STAT1/3/6 and the IFN-gamma-induced inhibitory effect. Although ERK was phosphorylated through IFN-gamma, chemical inhibition of ERK by PD98059 did not abolish the IFN-gamma-induced inhibitory effect. The authors tried to determine the responsible molecules; however, expression of TRAIL receptors; pro-caspase-3/-8/-9; Fas-associated death domain protein (FADD); tumor necrosis factor receptor 1-associated death domain protein (TRADD); silencer of death domain (SODD); FLICE inhibitory protein (FLIP); and Bcl-2, Bcl-xL, and Bax in FLS was not modulated by IFN-gamma. Although the authors have not yet clarified the precise mechanism, these data suggest that IFN-gamma/JAK/STAT pathway, which is supposed to be activated in inflammatory rheumatoid arthritis (RA) synovial tissues, contributes to form apoptosis resistance phenotype of the cells in situ, leading to a marked increase in cellularity of synovial cells.
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PMID:Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation. 1658 46

Granulocyte colony-stimulating factor (G-CSF) is known to have various functions such as induction of survival, proliferation and differentiation of hematopoietic cells. Recently, this factor has also been shown to exhibit neuroprotective effects in rat ischemic brain. In the present study, we first demonstrated that both G-CSF and G-CSF receptor were expressed in dopaminergic neurons in the adult substantia nigra and mesencephalic cultures, suggesting that G-CSF might exert its neuroprotective effects in dopaminergic neurons. Pretreatment with G-CSF protected dopaminergic neurons from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Investigation of the underlying mechanisms showed that the extracellular-regulated kinase (ERK), but not Janus kinase/signal transducer(s) and activator(s) of transcription (JAK/STAT), was activated following G-CSF treatment. Moreover, G-CSF also increased phosphorylation of Bad, and restored 6-OHDA-induced decrease in Bcl-xL level. The 6-OHDA-caused caspase-3 activation in dopaminergic neurons was inhibited by G-CSF. Inhibition of ERK abrogated G-CSF-mediated Bad phosphorylation, Bcl-xL expression, activated caspase-3 reduction, and the protection of dopaminergic neurons. Taken together, G-CSF prevents dopaminergic neurons from 6-OHDA-induced toxicity via ERK pathway followed by inhibiting the apoptosis-execution process. These results suggest that G-CSF might have a therapeutic potential in Parkinson's disease.
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PMID:G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway. 1683 44

Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 muM or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3-DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-1 and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.
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PMID:Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. 1734 59

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.
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PMID:Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. 1760 94

Leptin (Ob), the peripheral signal produced by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may work as an autocrine hormone. Recently, we have demonstrated that leptin promotes proliferation and survival of trophoblastic cells. In the present work we aimed to study the signal transduction pathways that mediate the trophic effect of leptin in placenta, by using the human placenta choriocarcinoma JEG-3 cell line, as well as trophoblastic cells from human placenta. We have assayed the early phase of apoptosis, triggered by serum deprivation, by using Annexin V-propidium iodide (PI) labeling and flow cytometric analysis, as well as the late phase of apoptosis by studying the activation of caspase-3. We have studied the major signalling pathways known to be triggered by the leptin receptor, and we have investigated the relative importance of these pathways in the effect of leptin by using pharmacological inhibitors. We have found that leptin stimulates Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway by promoting JAK-2 and STAT-3 tyrosine phosphorylation. We have also demonstrated the activation of mitogen-activated protein kinase (MAPK) pathway by studying phosphorylation of extracellular-signal regulated kinase (Erk) kinase (MEK) and Erk1/2. PI3K pathway is also triggered by leptin stimulation as assessed by the study of protein kinase B (PKB) phosphorylation. These signaling pathways were confirmed in trophoblastic cells obtained from placenta of healthy donors. The effect of leptin on JEG-3 survival was completely reversed by blocking Erk1/2 activation employing the MEK inhibitor PD98059, whereas it was not affected by PI3K inhibition using wortmannin. These data suggest that the leptin antiapoptotic effect in placenta is mediated by the MAPK pathway.
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PMID:Leptin prevents apoptosis of trophoblastic cells by activation of MAPK pathway. 1861 12

Cytokine interleukin-6 (IL-6) has been well shown to be elevated in brain injury and diseases. However, the significance of IL-6 production in such neuropathologic states remains controversial, and the intracellular signal-transduction pathways involved in the brain IL-6 action are primarily unclear. We previously indicated that exogenous IL-6 protected neurons against glutamate and N-methyl-d-aspartate (NMDA) attacks and the effects of IL-6 was blocked by anti-gp130 antibody. Here, we provide further evidence for the IL-6 neuroprotection and show signal molecules transducing the IL-6 message. The cerebellar granule neurons from postnatal 8-day infant rats were exposed to IL-6 for 8 days, and also pretreated chronically with Janus kinase (JAK) inhibitor AG490 and mitogen-activated protein kinase (MAPK) inhibitor PD98059. NMDA stimulated the cultured neurons for 30 min to induce neuronal injury and death. Cell counting kit-8 assay and Western blot were employed to measure neuronal vitality and cleaved caspase-3 expression, respectively. The chronic IL-6 exposure prevented the suppression of the neuronal vitality and the enhancement of the cleaved caspase-3 level induced by NMDA. The neuroprotective effect of IL-6 depended on IL-6 concentration and neuronal damaged degree. IL-6-induced STAT3 phosphorylation was inhibited by AG490 but not by PD98059; and IL-6-induced ERK1/2 activation was blocked by PD98059 but not by AG490. Either AG490 or PD98059 blocked the IL-6 protection against the NMDA-elicited neuronal vitality decrease and caspase-3 activation increase. These findings suggest that IL-6 protects neurons from NMDA-induced excitoxicity and the IL-6 neuroprotection may be transduced by both JAK/STAT3 and RAS/MAPK pathways.
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PMID:Neuroprotection of interleukin-6 against NMDA attack and its signal transduction by JAK and MAPK. 1906 39

Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is one of the major pathways for cytokine signal transduction. However, the role of the JAK/STAT pathway in liver ischemia/reperfusion is not clear. This study focuses on Janus kinase-2 (JAK2), which functions upstream of signal transducer and activator of transcription 1 (STAT1) in JAK/STAT, and its role in the mechanism of liver ischemia/reperfusion injury (IRI). Partial warm ischemia was produced in the hepatic lobes of C57BL/6 mice for 90 minutes, and this was followed by 6 hours of reperfusion. Mice were treated with a JAK2 inhibitor (tyrphostin AG490; 40 mg/kg intraperitoneally) or vehicle 60 minutes prior to ischemic insult. JAK2 blockade resulted in a significant reduction of hepatocyte apoptosis and liver injury. Macrophage and neutrophil infiltration, as assessed by immunohistochemistry, was markedly decreased in AG490-treated livers in comparison with controls. The expression of pro-inflammatory cytokines [tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-1beta] and chemokines [chemokine (C-X-C motif) ligand 10 (CXCL-10) and CXCL-2] was also significantly reduced in the AG490-treated group in comparison with controls. AG490-treated livers showed fewer cells positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and reduced cleaved caspase-3 protein expression in parallel with increased B-cell lymphoma extra large expression. We employed AG490 (75 mM) in primary bone marrow-derived macrophage (BMM) and hepatoma cell (CRL1830) cultures, which were both stimulated with lipopolysaccharide (LPS; 10 ng/mL). In BMM cultures, AG490 depressed otherwise LPS-induced pro-inflammatory gene expression programs (IL-6, IL-12p40, IL-1beta, CXCL-10, and inducible nitric oxide synthase). In hepatoma cells, AG490 reduced cleaved caspase-3 expression. Moreover, JAK2 blockade inhibited STAT1 and STAT3 phosphorylation. This is the first report documenting that JAK2 signaling is essential in the pathophysiology of liver IRI, as its selective blockage ameliorated the disease process and protected livers from inflammation and apoptosis.
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PMID:Blockade of Janus kinase-2 signaling ameliorates mouse liver damage due to ischemia and reperfusion. 2111 57


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