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)

Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.
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PMID:Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death. 1558 99

Inflammatory processes and cytokine expression have been implicated in the pathogenesis of several neurodegenerative disorders. Chronic ethanol intake induces brain damage, although the mechanisms involved in this effect are not well understood. We tested the hypothesis that activation of glial cells by ethanol would induce stimulation of signaling pathways and inflammatory mediators in brain, and would cause neurotoxicity. We used cerebral cortex from control and chronic ethanol-fed rats, which received ethanol-liquid diet for 5 months and cultured of astrocytes exposed to 75 mM ethanol for 7 days. Our results demonstrate that chronic ethanol treatment up-regulates iNOS, COX-2 and IL-1beta in rat cerebral cortex and in cultured astrocytes. Under both experimental conditions, up-regulation of these inflammatory mediators and IL-1RI concomitantly occurs with the stimulation of IRAK and MAP kinases, including ERK1/2, p-38 and JNK, which trigger the downstream activation of oxidant-sensitive transcription factors NF-KB and AP-1. These effects were associated with an increased in both caspase-3 and apoptosis in ethanol-fed rats and in astrocytes exposed to ethanol. In conclusion, chronic ethanol treatment stimulates glial cells, up-regulating the production and the expression of inflammatory mediators in the brain, and activating signalling pathways and transcription factors involved in inflammatory damage and cell death.
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PMID:Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. 1560 83

Ochratoxin A (OTA) is a mycotoxin involved in the development of chronic nephropathies and a known carcinogen. As we have shown previously, OTA activates mitogen-activated protein kinases [extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-jun amino-terminal kinase (JNK), and extracellular-regulated protein kinase 38 (p38)] in proximal tubular cells (opossum kidney and normal rat kidney epithelial). ERK1/2, JNK, or p38 are thought to mediate opposite action on apoptosis, fibrosis, and inflammation. As we have already shown, OTA activates the latter processes. Here, we investigated the effect of OTA in the absence or presence of the ERK1/2 inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4bis(2-aminophenylthio)-butadiene] to test whether OTA then will exert increased toxicity. In the presence of ERK1/2 inhibition, OTA decreased cell number and protein to a significantly larger extent compared with OTA alone. The same was true for epithelial tightness, apoptosis (caspase-3 activity), and necrosis (lactate dehydrogenase release). Furthermore, simultaneous inhibition of ERK1/2 amplified the effect of OTA on markers of inflammation (nuclear factor of the kappa-enhancer in B cells activity), fibrosis (collagen secretion), and epithelial mesenchymal transition (alpha smooth muscle actin). OTA induces phenomena typical for chronic interstitial nephropathy and activates ERK1/2, JNK, and p38 in proximal tubular cells. Inhibition of ERK1/2 aggravates the effects of OTA or even induces toxicity at normally nontoxic concentrations. This is highly likely due to activation of JNK and p38. Our data indicate a new mechanistic explanation for the toxic actions induced by OTA, and they are notable with respect to a possible coexposition of the kidney to OTA and naturally occurring ERK1/2 inhibitors. Finally, our data give rise to an attractive hypothesis on the coincidence of increased OTA exposition and urinary tract tumors in humans.
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PMID:Proximal tubular toxicity of ochratoxin A is amplified by simultaneous inhibition of the extracellular signal-regulated kinases 1/2. 1562 19

The extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway plays a critical role in the anticancer action in vitro. ERK1/2 activation or phosphorylation is responsible for increased cyclooxygenase-2 (COX-2) protein expression in some cancer cells treated with selective COX-2 inhibitor NS398. We determined the effect of NS398 on ERK signaling and the synergistic effect of combined treatment with NS398 and a specific MEK inhibitor U0126 on three human endometrial cancer cell lines: Ishikawa, HEC-1A and AN3CA cells. Results showed that NS398 and U0126 individually, and especially the combination of both exhibited profound anti-proliferation of all three cell lines in a time- and concentration-dependent manner by [3-(4, 5)-dimethylthiazol-z-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay. The phosphorylated ERK1/2 was up-regulated in HEC-1A and AN3CA cells, but the COX-2 protein expression was unchanged in the three cancer cell lines treated with NS398 alone. However, both phosphorylated ERK1/2 and COX-2 protein expression were concentration-dependently decreased in all three cell types by combined treatment with NS398 and U0126 assessed by western blot analysis. Simultaneously, the combination of NS398 and U0126 resulted in 2-fold increase in apoptosis of all three lines over that by the individual alone, and enhanced G0/G1 phase arrest of Ishikawa and HEC-1A cells induced by U0126 treatment determined by flow cytometry. The synergistic and complementary effects of combining NS398 and U0126 were found to be associated with activation of caspase-3, alterations of Bcl-2 family proteins and cell cycle regulatory proteins detected by western blot analysis. Taken together, these findings correlate with blocking MEK-ERK signaling cascade and down-regulating COX-2 protein expression in endometrial cancer cells with combination treatment of NS398 and U0126, suggesting that the combinatory use of NS398 and specific MEK inhibitors may be valuable for chemotherapy or chemoprevention of human endometrial cancer.
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PMID:Significant anti-proliferation of human endometrial cancer cells by combined treatment with a selective COX-2 inhibitor NS398 and specific MEK inhibitor U0126. 1570 31

The current study investigated the phosphorylation of mitogen-activated protein kinases (MAPKs) as well as pro- and anti-apoptotic proteins in adriamycin (ADR)-induced cardiomyopathy (AIC) and heart failure in rats. Modulatory effects of antioxidant probucol on the activation of MAPKs were also examined. Male rats were administered with ADR (15 mg/kg body wt ip, over 2 wk) with and without probucol (120 mg/kg body wt for 4 wk ip). Hearts from these animals were studied at 1- to 24-h as well as at 3-wk posttreatment durations. In the 3-wk group, ADR depressed cardiac function, increased left ventricular end-diastolic pressure (LVEDP), and caused dyspnea and mortality. These changes were prevented by probucol. Phosphorylation of extracellular signal-regulated kinase (ERK)1/2, in the early stage of AIC, showed a biphasic response, with a maximum increase to 513% seen at 4 h, followed by a decrease to 66.8% at 3 wk after the last injection of ADR. Phosphorylation of p38 and c-Jun NH(2)-terminal kinases (JNKs) showed a steady increase through 2, 4, and 24 h and 3 wk (116% to 148%). In gene microarray analysis at 3 wk (heart failure stage), mRNA expression for both ERK1/2 and p38 kinases was decreased, whereas JNK mRNA was undetectable. Probucol completely prevented these MAPK changes. Activation of caspase-3 as well as the increase in the ratio of Bax to Bcl-xl were seen at early time points (1-24 h) as well as in the heart failure stage (3 wk). It is suggested that a transient increase in ERK1/2 at a shorter interval indicate an early adaptive response, and failure of this response corresponded with heart failure. In contrast, a gradual and persistent increase in p38 and JNK MAPKs as well as in caspase-3 and the Bax-to-Bcl-xl ratio may contribute in the initiation of apoptosis and progression of heart failure. Because probucol modulated changes in cellular signaling pathways and cardiac function, it is likely that oxidative stress plays a key role in AIC and heart failure.
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PMID:Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. 1577 36

Mevastatin which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, suppress cell proliferation and induce apoptosis. However, the molecular mechanism of apoptosis induction is not well understood. So, in the present study, we attempted to clarify the mechanism by which mevastatin induces apoptosis in HL60 cells. It was found that mevastatin induced apoptosis. At that time, we observed an increase in caspase-3 activity and morphological fragmentation of the nuclei. The apoptosis induced by mevastatin was not inhibited by the addition of farnesyl pyrophosphate (FPP), squalene, ubiquinone, and isopentenyladenine, but was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of mevastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals, such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38), exhibited no change. In addition, no quantitative change was observed in Bcl-2, which was an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggested that mevastatin induced apoptosis when it inhibited GGPP biosynthesis and consequently decreased the level of phosphorylated ERK, which was a survival signal; moreover, at that time, there was no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggested that mevastatin could be used as an anticancer agent.
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PMID:Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK. 1578 22

Lactoferrin, a member of the transferrin family, is iron-binding and a strongly cationic 76 kDa glycoprotein. In breast milk it is secreted in high concentrations from glandular epithelia and is also present in other exocrine fluids including saliva. In the present study, we examined the biological mechanisms of apoptosis induced by pepsin-digested-lactoferrin peptide (Lfn-p) in the human oral squamous cell carcinoma cell line SAS. We found that treatment with Lfn-p induced cell death with apoptotic nuclear changes, preceded by the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in the apoptotic cells. Treatment with Lfn-p induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), a member of the MAP kinase family, at early stages of apoptosis. Another MAP kinase, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), was also phosphorylated by treatment with Lfn-p. Pretreatment of SAS cells with SP600125, a JNK/SAPK inhibitor, diminished Lfn-induced apoptosis, as assessed by determining released lactate dehydrogenase activity. On the other hand, the MEK1 inhibitors PD98059 or U0126 showed no effect on repression of cell death, but rather an increase. These results suggest that JNK/SAPK activation may play an important role in Lfn-p-induced apoptotic cell death of human oral squamous cell carcinoma cells.
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PMID:Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. 1587 78

We investigated the molecular mechanisms involved in the anti-proliferative activity exerted by conjugated linoleic acid (CLA) on the estrogen unresponsive MDA-MB-231 human breast cancer cell line. The effects on cell proliferation, cell cycle progression and induction of apoptosis were examined. CLA caused the reduction of cell proliferation along with the accumulation of cells in the S phase of the cycle. The occurrence of apoptosis in these cells was indicated by flow cytometry data and further confirmed by the onset of cells with morphological features typical of apoptosis. ERK1/2 reduction and upregulation of pro-apoptotic protein Bak were induced. These events were associated with: (a) reduced levels of the anti-apoptotic protein Bcl-x(L), (b) the translocation of cytochrome c from the mitochondria to the cytosol, (c) the cleavage of pro-caspase-9 and pro-caspase-3. From the above data, we are induced to think that CLA may trigger apoptosis in the estrogen unresponsive MDA-MB-231 cell line via mechanisms involving above all the mitochondrial pathway.
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PMID:Conjugated linoleic acid induces apoptosis in MDA-MB-231 breast cancer cells through ERK/MAPK signalling and mitochondrial pathway. 1588 90

The cellular isoform of prion protein, PrPc, may confer neuroprotection in the brain, according to recent studies. To elucidate the role of PrPc in stroke pathology, we subjected PrPc-knockout (Prnp(0/0)), wild-type and PrPc-transgenic (tga20) mice to 30 min of intraluminal middle cerebral artery occlusion, followed by 3, 24 or 72 h reperfusion, and examined how PrPc levels influence brain injury and cell signaling. In immunohistochemical experiments and Western blots, we show that PrPc expression is absent in the brains of Prnp(0/0) mice, detectable in wild-type controls and approximately 4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by approximately 200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp(0/0)-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp(0/0)mice. Our data suggest a role of cytosolic signaling pathways in Prnp(0/0)-induced cell death.
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PMID:Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1. 1589 68

Ceramide accumulates in neurons during various disorders associated with acute or chronic neurodegeneration. In these studies, we investigated the mechanisms of ceramide-induced apoptosis in primary cortical neurons using exogenous C(2) ceramide as well as inducing endogenous ceramide accumulation using inhibitors of glucosylceramide synthetase. Ceramide induced the translocation of certain, but not all, pro-apoptotic mitochondrial proteins: cytochrome c, Omi, SMAC, and AIF were released from the mitochondria, whereas Endonuclease G was not. Ceramide also selectively altered the phosphorylation state of members of the MAPK superfamily, causing dephosphorylation of ERK1/2 and hyperphosphorylation of p38 MAP kinases, but not affecting the phosphorylation of JNK or ERK5. Inhibitors of the p38 MAP kinase pathway (SB-202190 or SB-203580) and an inhibitor of the ERK1/2 pathway (U0126) reduced ceramide-induced neuronal death. These p38 and ERK1/2 inhibitors appear to block ceramide-activated apoptotic signaling upstream of the mitochondria, as they attenuated mitochondrial release of cytochrome c, Omi, AIF, and SMAC, as well as reducing ceramide-induced caspase-3 activation.
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PMID:Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. 1590 98


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