Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two apoptotic events take place during embryonic development of Ciona intestinalis. The first concerns extra-embryonic cells and precedes hatching. The second controls tail regression at metamorphosis, occurs through a polarized wave originating from tail extremity, and is caspase dependent. This was shown by: (1) in vivo incorporation of a fluorescent marker of caspase activation in different cell types of the tail; (2) detection of an activated form of caspase 3-like protein by western blotting; and (3) failure of 30% of larvae to undergo metamorphosis after treatment of fertilized eggs with a pan-caspase inhibitor. In addition, Ciona embryos express a single ERK protein, specifically phosphorylated at metamorphosis. ERK activation was shown to be located in cells of the tail. Addition of MEK inhibitor in the culture medium prevented ERK activation and metamorphosis. In silico analysis of Ciona genome pointed to 15 caspases with high homology with humans, and a single ERK gene with high homology to both mammalian ERK1 and ERK2. It is concluded that the sequence of events leading to metamorphosis includes ERK phosphorylation followed by caspase-dependent apoptosis and tail regression.
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PMID:Tail regression in Ciona intestinalis (Prochordate) involves a Caspase-dependent apoptosis event associated with ERK activation. 1207 86

Tau phosphorylation was examined in argyrophilic grain disease (AGD) by using the phosphospecific tau antibodies Thr181, Ser202, Ser214, Ser 396 and Ser422, and antibodies to non-phosphorylated and phosphorylated mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), stress-activated kinase (SAPK), c-Jun N-terminal kinase (JNK), p38 kinase (p-38), alpha-calcium/calmodulin-dependent kinase II (alphaCaM kinase II), and glycogen synthase kinase-3 (GSK-3), all of which regulate phosphorylation at specific sites of tau. This is the first study in which the role of protein kinases in tau phosphorylation has been examined in AGD. Hyperphosphorylated tau accumulated in grains and pre-tangles in the hippocampus, dentate gyrus, entorhinal and trans-entorhinal cortices, and amygdala in all cases. Ballooned neurons in the amygdala, entorhinal, insular and cingulate cortex, and claustrum contained alphaB-crystallyn and phosphorylated neurofilament epitopes. Some astrocytes and scattered oligodendrocytes containing coiled bodies were recognized with anti-tau antibodies. A few tangles were observed in the entorhinal cortex and hippocampus corresponding to Alzheimer's disease (AD) stages I-III of Braak and Braak. None of the present cases was associated with progressive supranuclear palsy or with alpha-synuclein pathology. Two bands of phospho-tau of 64 and 68 kDa were observed in Western blots of sarkosyl-insoluble fractions enriched with abnormal filaments in AGD, a pattern that contrasts with the 4-band pattern obtained in AD. No modifications in the expression of non-phosphorylated MEK-1, ERK2 and GSK-3alpha/beta, as revealed by immunohistochemistry, were seen in AGD, but sarkosyl-insoluble fractions were particularly enriched in JNK-1 and alphaCaM kinase II. Increased expression of the phosphorylated (P) forms of MAPK/ERK, SAPK/JNK, p38 and GSK-3beta was found in grains and tau-containing cells in AGD. MAPK/ERK-P immunoreactivity was observed in pre-tangles and, diffusely, in the cytoplasm of ballooned neurons, but not in grains. Strong SAPK/JNK-P and P38-P, and moderate GSK-3b-P immunoreactivities selectively occured in grains, in neurons with pre-tangles and in the peripheral region of the cytoplasm of ballooned neurons. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. Western blots revealed kinase expression in sarkosyl-insoluble fractions but none of the phospho-kinase antibodies recognized hyper-phosphorylated tau protein. These findings indicate complex, specific profiles of tau phosphorylation and concomitant activation of precise kinases that have the capacity to phosphorylate tau at specific sites in AGD. These kinases co-localize abnormal tau in selected structures and cells, including neurons with pre-tangles, ballooned neurons, astrocytes and oligodendrocytes. Most of these kinases are involved in cell death and cell survival in certain experimental paradigms. However, double-labeling studies with the method of in situ end-labeling of nuclear DNA fragmentation and cleaved (active) caspase-3 immunohistochemistry show no expression of apoptosis and death markers in cells bearing phosphorylated kinases.
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PMID:Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease. 1258 May 46

We previously showed (Gastroenterology 123: 206-216, 2002) that lysophosphatidic acid (LPA) protects and rescues rat intestinal epithelial cells (IEC-6) from apoptosis. Here, we provide evidence for the LPA-elicited inhibition of the mitochondrial apoptotic pathway leading to attenuation of caspase-3 activation. Pretreatment of IEC-6 cells with LPA inhibited campothecin-induced caspase-9 and caspase-3 activation and DNA fragmentation. A caspase-9 inhibitor peptide mimicked the LPA-elicited antiapoptotic activity. LPA elicited ERK1/ERK2 and PKB/Akt phosphorylation. The LPA-elicited antiapoptotic activity and inhibition of caspase-9 activity were abrogated by pertussis toxin, PD 98059, wortmannin, and LY 294002. LPA reduced cytochrome c release from mitochondria and prevented activation of caspase-9. LPA prevented translocation of Bax from cytosol to mitochondria and increased the expression of the antiapoptotic Bcl-2 mRNA and protein. LPA had no effect on Bcl-xl, Bad, and Bak mRNA or protein expression. These data indicate that LPA protects IEC-6 cells from camptothecin-induced apoptosis through G(i)-coupled inhibition of caspase-3 activation mediated by the attenuation of caspase-9 activation due to diminished cytochrome c release, involving upregulation of Bcl-2 protein expression and prevention of Bax translocation.
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PMID:LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway. 1268 13

Many pro-apoptotic signals activate caspase-9, an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction. However, survival signals can impinge on this pathway and suppress apoptosis. Activation of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway is associated with protection of cells from apoptosis and inhibition of caspase-3 activation, although the targets are unknown. Here, we show that the ERK MAPK pathway inhibits caspase-9 activity by direct phosphorylation. In mammalian cell extracts, cytochrome c-induced activation of caspases-9 and -3 requires okadaic-acid-sensitive protein phosphatase activity. The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2. Caspase-9 is phosphorylated at Thr 125, a conserved MAPK consensus site targeted by ERK2 in vitro, in a MEK-dependent manner in cells stimulated with epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Phosphorylation at Thr 125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. We suggest that phosphorylation and inhibition of caspase-9 by ERK promotes cell survival during development and tissue homeostasis. This mechanism may also contribute to tumorigenesis when the ERK MAPK pathway is constitutively activated.
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PMID:Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. 1279 50

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

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-PGJ2) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR-gamma-dependent manner. PPAR-gamma was expressed in these cells, and 15-deoxy-PGJ2 increased expression, DNA binding activity, and transcriptional activity of PPAR-gamma. 15-Deoxy-PGJ2 also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G2/M phase after 15-deoxy-PGJ2 treatment with concomitant increase in the expression of G2/M phase regulatory protein cyclin B1 but decrease in the expression of cdk2, cdk4, cyclin A, cyclin D1, cyclin E, and cdc25C. Conversely, related to the growth inhibitory effect, 15-deoxy-PGJ2 increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ2 increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ2 also activated extracellular signal-regulated kinase (ERK) 2. In addition, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (2'-amino-3'-methoxyflavone) decreased 15-deoxy-PGJ2-induced ERK2 activation, and expression of PPAR-gamma, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ2-induced cell growth inhibition. We also found that PPAR-gamma antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ2-induced cell growth inhibition, PPAR-gamma expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ2 inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR-gamma-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ2 may have promising application as a therapeutic agent for neuroblastoma.
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PMID:Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway. 1296 53

Peripheral primitive neuroectodermal tumour (PNET)/Ewing's sarcoma (ES) and neuroblastoma (NB) are related tumours of neural crest origin with primitive neural characteristics. Fibroblast growth factor 2 (FGF2) is a critical signalling molecule for primitive neural crest cells. The treatment of NB cells with FGF2 variably affects biological characteristics such as growth and differentiation, while in PNET/ES, FGF2 predominantly induces apoptosis. The JK-GMS Askin tumour cell line can be induced to differentiate upon treatment with nerve growth factor (NGF), indicating the integrity of the cellular machinery necessary for differentiation. The present study assesses whether FGF2 can induce differentiation in JK-GMS cells. JK-GMS cells expressed high-affinity FGF receptors (FGFRs), and treatment with FGF2 induced phosphorylation of FGFR1 together with activation of extracellular signal-regulated kinases (ERK1/ERK2) and c-Jun N-terminal kinase (JNK). Subsequent biological effects were growth inhibition, neuronal differentiation, and apoptosis, and these changes were associated with increased expression of neurofilaments, reduction of c-myc and bcl-2 expression, and activation of caspase 3. Treatment of the cells with a specific inhibitor of the MAPK/extracellular signal-regulated kinase (MEK)-1, PD98059, predominantly inhibited the effects of FGF2 on growth, differentiation, and apoptosis, while an inhibitor of JNK reduced apoptosis, indicating that the ERK1/2 and JNK pathways are critical components of FGF2-mediated effects in JK-GMS cells. Additional comparative analyses of FGF2-mediated effects in two ES cell lines (CADO-ES, RD-ES) and a PNET cell line (SK-N-MC) showed pronounced differentiation in SK-N-MC, but not in CADO-ES or RD-ES cells. This study demonstrates that FGF2 can induce neuronal differentiation of PNET including Askin tumour. These findings clearly indicate that the FGF2-mediated signalling pathway plays a critical role in controlling the major properties of PNET cells and may provide a potential therapeutic target for PNET.
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PMID:Fibroblast growth factor 2 induces differentiation and apoptosis of Askin tumour cells. 1469 27

Quercetin is one of the most ubiquitous bioflavonoids in foods of plant origin. Although quercetin is generally considered to provide protection against oxidative injury and inflammation, recent studies have demonstrated that its cytoprotective effects occur within a narrow concentration range. We attempted to examine the concentration-dependent effect on proliferation and inflammation in the primary culture of rat aortic smooth muscle cells. We demonstrate that quercetin inhibited [3H]thymidine incorporation into rat aortic smooth muscle cells only at concentrations < or =50 microM in a concentration-dependent manner. Nevertheless, quercetin, at concentrations > or =100 microM, reduced cell viability; this was further characterized as being due to apoptosis, which occurred through the proteolytic activation of pro-caspase-3. Additionally, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) substantially increased in rat aortic smooth muscle cells exposed to 100 microM quercetin, results which differ from observations by others and ourselves of cells exposed to < or =50 microM quercetin. Unlike P-JNK and P-p38, the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/ERK2) was not significantly affected by the concentration-dependent effects of quercetin. Surprisingly, the adverse effects of higher concentrations of quercetin could be ameliorated by adding the antioxidants, catalase, and N-acetylcysteine (NAC). Furthermore, the electrophoretic mobility shift assay (EMSA) showed that rat aortic smooth muscle cells exposed to quercetin at concentrations of < or =50 microM caused concentration-dependent inhibition of nuclear factor kappa B (NF-kappaB) activity, whereas concentrations of > or =100 microM resulted in increased NF-kappaB binding activity. We demonstrate for the first time that quercetin at low concentrations has antiproliferative and antiinflammatory effects, but at concentrations of > or =100 microM, is likely to induce the opposite effects on rat aortic smooth muscle cells.
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PMID:Concentration-dependent differential effects of quercetin on rat aortic smooth muscle cells. 1528 73

The present study investigates the effect of ouabain on caspase-3 activation in human umbilical vein endothelial cells (HUVEC). Ouabain (EC(50) 20 nM) reduced caspase-3 activity in HUVEC treated for 24h in a medium deprived of fibroblast growth factor (FGF). Incubation for 5h in the absence of both FGF and serum produced an increase in caspase-3 activity that was completely abolished by 100 nM ouabain. Pretreatment with the phosphatidylinositol 3 kinase (PI-3K) inhibitor, wortmannin, prevented the protective effect of ouabain against serum deprivation. Furthermore, Western blotting analysis revealed an increase in phosphorylation of extracellular signal-regulated kinases (ERK-1 and ERK-2) induced by 100nM ouabain in serum-deprived cells. In accord, pretreatment of HUVEC with PD98059, inhibitor of the ERK pathway, abrogated the effect of ouabain. Our results show that ouabain has an antiapoptotic effect on HUVEC through the activation of PI-3K and ERK dependent pathways.
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PMID:Antiapoptotic effect of ouabain on human umbilical vein endothelial cells. 1535 65

The Jurkat T-cell line was used to study potential impact of deoxynivalenol (DON) and related 8-ketotrichothecenes on human immune function. DON (250-1000 ng/ml) readily induced caspase-3 and apoptosis in Jurkat cells. DON (62.5-500 ng/ml) also significantly upregulated IL-2 and IL-8 production following prestimulation with phorbol myristate acetate and ionomycin. DON markedly induced phosphorylation of p38, JNK 1/2, and ERK2. SB203580, a specific inhibitor of p38, reduced DON-induced apoptosis. The MEK1 inhibitor PD98059 which blocks ERK activation had only a small inhibitory effect on DON-induced apoptosis while the JNK inhibitor SP600125 was without effect. Inhibition of p38 attenuated DON-induced upregulation of IL-2 while all three MAPK inhibitors suppressed IL-8 upregulation. When effects of DON were compared to other 8-ketotrichothecenes, the concentrations of DON, 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon X (FX) causing 50% apoptosis were 0.6, 0.5, 0.5, 0.5 and 7.5 microg/ml, respectively. Relative to IL-2 upregulation, FX was suppressive whereas 3-ADON, 15-ADON and NIV had no effect at concentrations of 62.5-500 ng/ml. In contrast, 15-ADON at 62.5-500 ng/ml and 3-ADON at 625-5000 ng/ml upregulated IL-8 production but FX and NIV had no effect. Taken together, these data suggest that DON's effects on apoptosis and cytokine production were differentially regulated by MAPKs. Although DON shared its capacity to induce apoptosis and potentiate IL-8 production with other 8-ketotrichothecenes, it appeared to be unique in its capacity to upregulate IL-2.
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PMID:Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes. 1558 14


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