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)

Fas-associated death domain (FADD) plays an important role as an adapter molecule in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced cytotoxicity. We treated three human prostate cancer cell lines with etoposide, a toposiomerase II inhibitor with activity against various tumors including prostate cancer. We found that the overexpression of FADD sensitizes etoposide-induced apoptosis through a rapid activation of c-Jun NH(2)-terminal kinase (JNK) and, subsequently, of caspase 3. In addition, phosphorylation of FADD at serine 194 coincided with this sensitization. Treatment with the caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), or overexpression of either mitogen-activated protein kinase kinase (MKK) 7 or Bcl-xL canceled FADD-mediated sensitization to etoposide-induced apoptosis. Moreover, treatment with the caspase 8 inhibitor, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (z-IETD-fmk), or overexpression of viral FLICE/caspase-8-inhibitory protein (FLIP) from equine herpesvirus type 2 E8 also had an inhibitory effect, supporting a major involvement of a caspase 8-dependent mitochondrial pathway. Interestingly, FADD was phosphorylated, and etoposide-induced JNK/caspase activation and apoptosis were enhanced in the cells arrested at G2/M transition, but not in those overexpressing mutant FADD, in which 194 serine was replaced by alanine. Our results demonstrate that phosphorylated FADD-dependent activation of the JNK/caspase pathway plays a pivotal role in sensitization to etoposide-induced apoptosis in prostate cancer cells.
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PMID:Phosphorylation of Fas-associated death domain contributes to enhancement of etoposide-induced apoptosis in prostate cancer cells. 1241 47

Triggering tumor necrosis factor receptor-1 (TNFR1) induces apoptosis in various cell lines. In contrast, stimulation of TNFR1 in L929sA leads to necrosis. Inhibition of HSP90, a chaperone for many kinases, by geldanamycin or radicicol shifted the response of L929sA cells to TNF from necrosis to apoptosis. This shift was blocked by CrmA but not by BCL-2 overexpression, suggesting that it occurred through activation of procaspase-8. Geldanamycin pretreatment led to a proteasome-dependent decrease in the levels of several TNFR1-interacting proteins including the kinases receptor-interacting protein, inhibitor of kappa B kinase-alpha, inhibitor of kappa B kinase-beta, and to a lesser extent the adaptors NF-kappaB essential modulator and tumor necrosis factor receptor-associated factor 2. As a consequence, NF-kappa B, p38MAPK, and JNK activation were abolished. No significant decrease in the levels of mitogen-activated protein kinases, adaptor proteins TNFR-associated death domain and Fas-associated death domain, or caspase-3, -8, and -9 could be detected. These results suggest that HSP90 client proteins play a crucial role in necrotic signaling. We conclude that inhibition of HSP90 may alter the composition of the TNFR1 complex, favoring the caspase-8-dependent apoptotic pathway. In the absence of geldanamycin, certain HSP90 client proteins may be preferentially recruited to the TNFR1 complex, promoting necrosis. Thus, the availability of proteins such as receptor-interacting protein, Fas-associated death domain, and caspase-8 can determine whether TNFR1 activation will lead to apoptosis or to necrosis.
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PMID:Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosis. 1244 46

Studies in vitro have shown that phosphorylated translation initiation factor 2 alpha (TIF 2 alpha) may have several functions, including regulation of protein synthesis, control of cell death and procurement of resistance to oxidative stress in nerve cells. These properties may have implications in certain human neurodegenerative diseases, such as Alzheimer's disease (AD) and Creutzfeldt-Jakob's disease (CJD), in which oxidative stress appears to be involved in the process of neurodegeneration and neurone death. Single and double-labelling immunohistochemistry to phosphorylated TIF 2 alpha, phosphorylated SAPK/JNK, phosphorylated p38, tau, Cu/Zn superoxide dismutase 1 (SOD 1) and cleaved caspase-3 (17 kDa), and in situ end-labelling of nuclear DNA fragmentation, was carried out in postmortem samples of 10 patients with AD (stages III and VI of Braak and Braak), seven patients with CJD (five cases with methionine/methionine and two cases with methionine/valine at the codon 129 of the PrP gene) and eight age-matched controls. No phosphorylated TIF 2 alpha immunoreactivity was found in control brains, but strong phosphorylated TIF 2 alpha expression was observed in subpopulations of neurones bearing neurofibrillary tangles (NFTs) or pretangles in the hippocampus, entorhinal cortex and isocortex in AD. Phosphorylated TIF 2 alpha is restricted to neurones with abnormal tau deposition, but only approximately 80% of neurones with NFTs in the hippocampus and 60% in the isocortex colocalize phosphorylated TIF 2 alpha, thus indicating that not all neurones with NFTs over-express phosphorylated TIF 2 alpha. Moreover, phosphorylated TIF 2 alpha immunoreactivity was found in a percentage of neurones expressing phosphorylated SAPK/JNK and p38, which, in turn, are involved in tau phosphorylation in AD. However, dystrophic neurites of senile plaques that contain abnormal tau and express SOD 1 are negative to antiphosphorylated TIF 2 alpha antibodies. Smooth muscle cells in blood vessels affected by amyloid angiopathy, which are putative targets of beta A 4 amyloid-derived oxidative stress, are not associated with phosphorylated TIF 2 alpha immunoreactivity. Double-staining with the method of in situ end-labelling of nuclear DNA fragmentation demonstrated no relationship between phosphorylated TIF 2 alpha expression and increased nuclear DNA vulnerability in individual cells. Moreover, no single caspase-3-immunoreactive cell in AD expressed phosphorylated TIF 2 alpha. Oxidative stress response, manifested as positive SOD 1 expression in Bergmann glia and in a few reactive astrocytes, has been demonstrated in CJD. No phosphorylated SAPK/JNK or phosphorylated p38 kinase immunoreactivity was observed in these cases. Moreover, neurones and glial cells do not over-express phosphorylated TIF 2 alpha in CJD. The present results demonstrate selective expression of phosphorylated TIF 2 alpha in subpopulations of nerve cells with abnormal tau deposition, and suggest that factors linked with tau deposition regulate protein synthesis throughout TIF 2 alpha phosphorylation in certain neurones sensitive to oxidative stress in AD.
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PMID:Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease. 1244 60

The ubiquitin-proteasome pathway is an intracellular protein degradation pathway responsible for degradation of many regulatory proteins that must be rapidly eliminated normally. Some recent studies reported that a proteasome dysfunction was involved in the pathogenesis of neurodegenerative diseases. Thus, there is now considerable interest in the possible role of proteasome in this regard. Here we show that inhibition of proteasomal function by Lactacystin-induced cell death in a neuronal differentiated Neuro2a (nN2a) cell line but not in an undifferentiated Neuro2a (N2a) cell line. Cell death was accompanied by both the activation of c-Jun N-terminal kinase, p38 and caspase-3. A pan-caspase inhibitor, Z-VAD-FMK, or SB203580, a p38 inhibitor could not inhibit cell death induced by Lactacystin, whereas nN2a cell lines with stable expression of the dominant negative mutant of c-Jun N-terminal kinase showed a remarkable suppression of cell death. Lactacystin-induced cell death is mediated through the c-Jun N-terminal kinase pathway but not the caspase-dependent pathway in a nN2a cell line. Our results shed light on the association among the proteasomal dysfunction, JNK pathway and neuronal cell death, leading to the elucidation of its possible role in the pathogenesis of neurodegenerative diseases.
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PMID:c-Jun N-terminal kinase pathway mediates Lactacystin-induced cell death in a neuronal differentiated Neuro2a cell line. 1248 Jan 74

1 Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects, but little is known about its molecular mechanisms of action. 2 Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 microM), and induced apoptosis at high concentrations (80-100 microM). 3 Treatment with 80 microM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. 4 Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. 5 Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the protein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. 6 These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis.
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PMID:Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. 1252 90

We investigated the mechanism of toxicity of peroxovanadium complex bpV (phen) in RINm5F cells. Treatment with bpV (phen) provoked cell death, predominantly by apoptosis. This compound induced strong and sustained JNK and p38 MAPK activation. However, ERK phosphorylation was not affected. The level of expression of MAPK phosphatase MKP-1 was suppressed after bpV (phen) treatment. In addition, this compound did not stimulate proteolytic processing of procaspase-3, suggesting that caspase-3 is not activated during the course of bpV (phen)-induced apoptosis. A correlative inhibition of JNK activation by immunosuppressive drug FK 506 induced ERK activation and MKP-1 expression, and suppressed RINm5F cell death. A specific p38 inhibitor SB 203580 also stimulated ERK activation and cell survival. Furthermore, simultaneous pretreatment with both FK 506 and SB 203580 almost completely abolished cell death. Thus, our results suggest that stress kinases and MKP-1 have a role in bpV (phen)-induced apoptosis of RINm5F cells.
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PMID:BpV (phen) induces apoptosis of RINm5F cells by modulation of MAPKs and MKP-1. 1255 54

Erythropoietin (EPO) modulates primarily the proliferation of immature erythroid precursors, but little is known of the potential protective mechanisms of EPO in the central nervous system. We therefore examined the ability of EPO to modulate a series of death-related cellular pathways during anoxia and free radical induced neuronal degeneration. Neuronal injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, protein kinase B phosphorylation, cysteine protease activity, mitochondrial membrane potential, and mitogen-activated protein (MAP) kinase phosphorylation. We demonstrate that constitutive neuronal EPO is insufficient to prevent cellular injury, but that signaling through the EPO receptor remains biologically responsive to exogenous EPO administration. Exogenous EPO is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent phagocytosis through membrane PS exposure, because neuronal protection by EPO is completely abolished by co-treatment with an anti-EPO neutralizing antibody. Through pathways that involve the initial activation of protein kinase B, EPO maintains mitochondrial membrane potential. Subsequently, EPO inhibits caspase 8-, caspase 1-, and caspase 3-like activities linked to cytochrome c release through mechanisms that are independent from the MAP kinase systems of p38 and JNK. Elucidating some of the novel neuroprotective pathways employed by EPO may further the development of new therapeutic strategies for neurodegenerative disorders.
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PMID:Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8. 1258 24

Shiga toxins made by Shiga toxin-producing Escherichia coli (STEC) are associated with hemolytic uremic syndrome. Shiga toxins (Stxs) may access the host systemic circulation by absorption across the intestinal epithelium. The effects of Stxs on this cell layer are not completely understood, although animal models of STEC infection suggest that, in the gut, Stxs may participate in both immune activation and apoptosis. Stxs have one enzymatically active A subunit associated with five identical B subunits. The A subunit inactivates ribosomes by cleaving a specific adenine from the 28S rRNA. We have previously shown that Stxs can induce multiple C-X-C chemokines in intestinal epithelial cells in vitro, including interleukin-8 (IL-8), and that Stx-induced IL-8 expression is linked to induction of c-Jun mRNA and p38 mitogen-activated protein (MAP) kinase pathway activity. We now report Stx1 induction of both primary response genes c-jun and c-fos and activation of the stress-activated protein kinases, JNK/SAPK and p38, in the intestinal epithelial cell line HCT-8. By 1 h of exposure to Stx1, mRNAs for c-jun and c-fos are induced, and both JNK and p38 are activated; activation of both kinases persisted up to 24 h. Stx1 enzymatic activity was required for kinase activation; a catalytically defective mutant toxin did not activate either. Stx1 treatment of HCT-8 cells resulted in cell death that was associated with caspase 3 cleavage and internucleosomal DNA fragmentation; this cytotoxicity also required Stx1 enzymatic activity. Blocking Stx1-induced p38 and JNK activation with the inhibitor SB202190 prevented cell death and diminished Stx1-associated caspase 3 cleavage. In summary, these data link the Stx1-induced ribotoxic stress response with both chemokine expression and apoptosis in the intestinal epithelial cell line HCT-8 and suggest that blocking host cell MAP kinases may prevent these Stx-associated events.
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PMID:Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. 1259 68

Iron is an essential element for the neoplastic cell growth, and iron chelators have been tested for their potential anti-proliferative and cytotoxic effects. To determine the mechanism of cell death induced by iron chelators, we explored the pathways of the three structurally related mitogen-activated protein (MAP) kinase subfamilies during apoptosis induced by iron chelators. We report that the chelator deferoxamine (DFO) strongly activates both p38 MAP kinase and extracellular signal-regulated kinase (ERK) at an early stage of incubation, but slightly activates c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) at a late stage of incubation. Among three MAP kinase blockers used, however, the selective p38 MAP kinase inhibitor SB203580 could only protect HL-60 cells from chelator-induced cell death, indicating that p38 MAP kinase serves as a major mediator of apoptosis induced by iron chelator. DFO also caused release of cytochrome c from mitochondria and induced activation of caspase 3 and caspase 8. Interestingly, treatment of HL-60 cells with SB203580 greatly abolished cytochrome c release, and activation of caspase 3 and caspase 8. Collectively, the current study reveals that p38 MAP kinase plays an important role in iron chelator-mediated cell death of HL-60 cells by activating downstream apoptotic cascade that executes cell death pathway.
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PMID:Involvement of p38 MAP kinase during iron chelator-mediated apoptotic cell death. 1265 44

Leptin, the Ob gene product, has emerged recently as a key regulator of bone mass. However, the mechanism mediating leptin effect remains controversial. Because the action of leptin is dependent on its receptors, we analyzed their expression in osteoblast-lineage primary human bone marrow stromal cells (hBMSC). Both the short and long forms of leptin receptors were detected in hBMSC. Leptin significantly decreased the viability of hBMSC. This cytotoxic effect was prevented by Z-Val-Ala-Asp-fluoromethylketone, a pan-caspase inhibitor, implicating that leptin-induced hBMSC death was caspase-dependent. Further investigation demonstrated that leptin activated caspase-3 and caspase-9, but not caspase-8, and increased the cleavage of poly-(ADP-ribose) polymerase and cytochrome c release into cytosol. Leptin activated ERK, but not p38 and JNK, and up-regulated cPLA2 activity; the latter was abolished by pre-treatment of cells with the MEK inhibitor (PD98059 or U0126) or cPLA2 inhibitor (AACOCF3). PD98059, U0126, and AACOCF3 also diminished the leptin-induced cytochrome c release into cytosol, cell death, and caspase-3 activation. These data indicated that leptin induced hBMSC apoptosis via ERK/cPLA2/cytochrome c pathway with activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. To our knowledge, this is the first study demonstrating the direct detrimental effect of leptin on bone cells.
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PMID:Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. 1266 5


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