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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-lapachone, an o-naphthoquinone, induces various carcinoma cells to undergo apoptosis, but the mechanism is poorly understood. In the present study, we found that the beta-lapachone-induced apoptosis of DU145 human prostate carcinoma cells was associated with endoplasmic reticulum (ER) stress, as shown by increased intracellular calcium levels and induction of GRP-78 and GADD-153 proteins, suggesting that the endoplasmic reticulum is a target of beta-lapachone. Beta-Lapachone-induced DU145 cell apoptosis was dose-dependent and accompanied by cleavage of procaspase-12 and phosphorylation of p38, ERK, and JNK, followed by activation of the executioner caspases, caspase-7 and calpain. However, pretreatment with the general caspase inhibitor, z-VAD-FMK, or calpain inhibitors, including ALLM or ALLN, failed to prevent beta-lapachone-induced apoptotic cell death. Blocking the enzyme activity of NQO1 with dicoumarol, a known NQO1 inhibitor, or preventing an increase in intracellular calcium levels using BAPTA-AM, an intracellular calcium chelator, substantially inhibited MAPK phosphorylation, abolished the activation of calpain, caspase-12 and caspase-7, and provided significant protection of beta-lapachone-treated cells. These findings show that beta-lapachone-induced ER stress and MAP kinase phosphorylation is a novel signaling pathway underlying the molecular mechanism of the anticancer effect of beta-lapachone.
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PMID:Involvement of endoplasmic reticulum stress and activation of MAP kinases in beta-lapachone-induced human prostate cancer cell apoptosis. 1878 11

HL-37, a novel anthracene derivative, exhibited potent anticancer activity in many kinds of cancer cells. However, the exact mechanism and signaling pathway involved in HL-37-induced apoptosis have not been fully elucidated. Therefore, we explored the mechanisms of HL-37-mediated apoptosis in MCF-7 and MDA-MB-435 human breast cancer cells. When MCF-7 cells or MDA-MB-435 cells were co-incubated with HL-37, the percentage of apoptotic cell and S phase of cell cycle was markedly increased. In addition, a rise in intracellular calcium levels, ROS production, phosphorylation of JNK and activation of calpain were found in both MCF-7 cells and MDA-MB-435 cells after exposure to HL-37. With the HL-37-mediated reduction of mitochondrial membrane potential, cytochrome c was released from mitochondria to cytosol. Moreover, HL-37 strongly induced cleavage of caspase-4, caspase-9, as well as caspase-3 in MDA-MB-435 cells, whereas, activation of caspase-4, caspase-9 and caspase-7 but not caspase-3 was detected in MCF-7 cells. These results suggested that HL-37 induced MDA-MB-435 and MCF-7 cells apoptosis via oxidative stress and Ca(2+)/calpain/caspase-4 pathway.
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PMID:HL-37, a novel anthracene derivative, induces Ca(2+)-mediated apoptosis in human breast cancer cells. 1894 64

Peroxisome proliferators (PPs) are a class of compounds that exert their nominal effects through the peroxisome proliferator-activated receptors. PPs, among which clofibrate (CF), have been extensively studied for their hepatocarcinogenic properties in rodents, generally ascribed to their antiapoptotic action. However, previous results demonstrated that various PPs may also have apoptogenic properties. CF, in particular, promptly induces a massive apoptotic death in cell lines established from murine or human hepatomas and from breast or lung cancers as well. The present study was aimed at elucidating the apoptotic pathway(s) triggered by CF in AH-130 cells. The results show that CF-induced cell death is completely blocked by the poly-caspase inhibitor z-VAD-fmk and that caspases 3, 8, and 9 are early activated. Consistently, cytochrome c is released from mitochondria, and CF cytotoxicity is inhibited by cyclosporine A, partially at least. In addition, the occurrence of endoplasmic reticulum (ER) stress is suggested by the observation that the levels of phosphorylated eIF2alpha and JNK increase in CF-treated cells, while the caspase 2 precursor protein levels are concurrently reduced. Finally, some degree of calpain activation also takes place, as suggested by the appearance of fodrin cleavage products. The present findings demonstrate that CF-induced apoptosis in the Yoshida AH-130 cells basically is a caspase-dependent process that involves more than a single mechanisms. Activation of the intrinsic apoptotic pathway and ER stress both play a major and concurrent role, while calpain activation seems to have only a marginal part in the process.
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PMID:Mechanisms of clofibrate-induced apoptosis in Yoshida AH-130 hepatoma cells. 1898 31

This article reviews what our colleagues have found as to how ischemic injury or cell death develop in myocardium through Ca(2+)-dependent protease calpain and how compensatory responses evolve through activation of intracellular signaling molecules including PKC isoforms, MAP kinase family enzymes and PI3 kinase. We also addressed how restraint or other psychological stress evokes hypertension and cardiovascular responses in signaling molecules or genes. Unexpectedly, carbon monoxide protects heart and cardiogenic cells against ischemia-resperfusion injury. When I think back, the unresolved cases of autopsies provided ideas for experimental study, which then taught us how the other cases died.
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PMID:Pursuing enigmas on ischemic heart disease and sudden cardiac death. 1904 46

Mechanical conditioning of mesenchymal stem cells (MSCs) has been adopted widely as a biophysical signal to aid tissue engineering applications. The replication of in vivo mechanical signaling has been used in in vitro environments to regulate cell differentiation, and extracellular matrix synthesis, so that both the chemical and mechanical properties of the tissue-engineered construct are compatible with the implant site. While research in these areas contributes to tissue engineering, the effects of mechanical strain on MSC apoptosis remain poorly defined. To evaluate the effects of uniaxial cyclic tensile strain on MSC apoptosis and to investigate mechanotransduction associated with strain-mediated cell death, MSCs seeded on a 2D silicone membrane were stimulated by a range of strain magnitudes for 3 days. Mechanotransduction was investigated using the stretch-activated cation channel blocker gadolinium chloride, the L-type voltage-activated calcium channel blocker nicardipine, the c-jun NH(2)-terminal kinase (JNK) blocker D-JNK inhibitor 1, and the calpain inhibitor MDL 28170. Apoptosis was assessed through DNA fragmentation using the terminal deoxynucleotidyl transferase mediated-UTP-end nick labeling method. Results demonstrated that tensile strains of 7.5% or greater induce apoptosis in MSCs. L-type voltage-activated calcium channels coupled mechanical stress to activation of calpain and JNK, which lead to apoptosis through DNA fragmentation. The definition of the in vitro boundary conditions for tensile strain and MSCs along with a proposed mechanism for apoptosis induced by mechanical events positively contributes to the development of MSC biology, bioreactor design for tissue engineering, and development of computational methods for mechanobiology.
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PMID:Mechanisms of strain-mediated mesenchymal stem cell apoptosis. 1904 33

D-JNKI1, a cell-permeable peptide inhibitor of the c-Jun N-terminal kinase (JNK) pathway, has been shown to be a powerful neuroprotective agent after focal cerebral ischemia in adult mice and young rats. We have investigated the potential neuroprotective effect of D-JNKI1 and the involvement of the JNK pathway in a neonatal rat model of cerebral hypoxia-ischemia (HI). Seven-day-old rats underwent a permanent ligation of the right common carotid artery followed by 2 h of hypoxia (8% oxygen). Treatment with D-JNKI1 (0.3 mg/kg intraperitoneally) significantly reduced early calpain activation, late caspase 3 activation and, in the thalamus, autophagosome formation, indicating an involvement of JNK in different types of cell death: necrotic, apoptotic, and autophagic. However, the size of the lesion was unchanged. Further analysis showed that neonatal HI induced an immediate decrease in JNK phosphorylation (reflecting mainly JNK1 phosphorylation) followed by a slow progressive increase (including JNK3 phosphorylation 54 kDa), whereas c-jun and c-fos expression were both strongly activated immediately after HI. In conclusion, unlike in adult ischemic models, JNK is only moderately activated after severe cerebral HI in neonatal rats and the observed positive effects of D-JNKI1 are insufficient to give neuroprotection. Thus, for perinatal asphyxia, D-JNKI1 can only be considered in association with other therapies.
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PMID:Limited role of the c-Jun N-terminal kinase pathway in a neonatal rat model of cerebral hypoxia-ischemia. 1904 6

Compared with adults, immature metallothionein I and II knockout (MT(-/-)) mice incur greater neuronal loss and a more rapid rate of microglia accumulation after target deprivation-induced injury. Because minocycline has been proposed to inhibit microglial activation and associated production of neuroinflammatory factors, we investigated its ability to promote neuronal survival in the immature, metallothionein-deficient brain. After ablation of the visual cortex, 10-day-old MT(-/-) mice were treated with minocycline or saline and killed 24 or 48 hr after injury. By means of stereological methods, the number of microglia and neurons were estimated in the ipsilateral dorsal lateral geniculate nucleus (dLGN) by an investigator blinded to the treatment. No effect on neuronal survival was observed at 24 hr, but 48 hr after injury, an unanticipated but significant minocycline-mediated increase in neuronal loss was detected. Further, while failing to inhibit microglial accumulation, minocycline treatment increased the proportion of amoeboid microglia in the ipsilateral dLGN. To understand the molecular mechanisms underlying this neurotoxic response, we identified minocycline-mediated changes in the expression of three potentially proapoptotic/inflammatory genes: growth arrest- and DNA damage-inducible gene 45gamma (GADD45gamma); interferon-inducible protein 1 (IFI1), and cytokine-induced growth factor. We also observed increased mitogen-activated protein kinase p38 phosphorylation with minocycline treatment. Although minocycline inhibited calpain activity at 12 hr after injury, this effect was not sustained at 24 hr. Together, these results help to explain how minocycline has a deleterious effect on neuronal survival in this injury model.
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PMID:Deleterious effects of minocycline after in vivo target deprivation of thalamocortical neurons in the immature, metallothionein-deficient mouse brain. 1911 4

Autophagy is a self-eating process to eradicate damaged proteins or organelles in cells. This process begins with formation of a double-membrane structure, called an autophagosome, which can sequester soluble proteins and organelles eventually degraded by lysosomal proteases after fusion with the lysosome. Autophagy was initially identified as a cell survival mechanism under stress conditions such as nutrient deprivation. More recently, it is also considered as type-II programmed cell death. In our recent report, we observed that overexpression of TrkA caused massive cell death via both apoptosis and autophagy. Overexpression of TrkA abated catalase activity and subsequently resulted in the production of a large amount of reactive oxygen species in cells. These consequences led to autophagic cell death. The autophagic cell death in TrkA-overexpressing cells was validated by GFP-LC3 dot formation, production of autophagosomes or acidic vacuoles, LC3 lipidation, and depletion of autopahgy-related genes. In addition, we also observed some evidence for apoptosis in TrkA-expressing cells. Many cells expressing TrkA exhibited annexin V-positive staining, activation of caspase-7 and BAX. Moreover, TrkA activated the JNK pathway, leading to phosphorylation of H2AX. In this report, we suggest that two cell death mechanisms occur simultaneously and interlink with each other. The JNK-calpain pathway might be a central process to mediate the two processes in TrkA-overexpressing cells, although further study still remains to prove the interplay between autophagy and apoptosis.
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PMID:Interplay between autophagy and apoptosis in TrkA-induced cell death. 1911 84

Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.
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PMID:Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion. 1914 24

Synaptic facilitation and post-tetanic potentiation (PTP) are believed to necessitate active regeneration of the release machinery and supply of synaptic vesicles to a ready-releasable site. The prevailing hypothesis assumes that synapsins play pivotal roles in these processes. Using a cholinergic synapse formed between cultured Aplysia neurons (B2 and MCn), we demonstrate here that the calcium-activated protease-calpain serves as a major regulating element in the cascade that links electrical activity, elevation of the free intracellular calcium concentration, and short-term synaptic enhancements such as facilitation and PTP. Our study revealed that calpain inhibitors (calpeptin and MG132) transform a facilitating synapse into a depressing one, and reduce its PTP by 80.6%. Inhibition of CaM kinases, PKA, and MAPK also reduced PTP at this synapse. When inhibitors of these kinases were applied together with calpeptin, tetanic stimuli led to synaptic depression. We concluded that at this synapse facilitation and PTP are mediated mainly by the calpain-dependent processes and to a smaller extent by the CaMKs/PKA/MAPK-dependent cascades.
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PMID:Activity-dependent calpain activation plays a critical role in synaptic facilitation and post-tetanic potentiation. 1918 19


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