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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PS2, the chromosome 1 familial Alzheimer's disease gene, has been shown to be involved in programmed cell death by three complementary experimental approaches. Reduction of PS2 protein levels by antisense RNA protects from apoptosis, whereas overexpression of an Alzheimer's PS2 mutant increases cell death induced by several stimuli. In addition, ALG-3, a truncated PS2 cDNA, encodes an artificial COOH-terminal PS2 segment that dominantly inhibits apoptosis. Here we describe a physiological COOH-terminal PS2 polypeptide (PS2s, Met298-Ile448) generated by both an alternative PS2 transcript and proteolytic cleavage. We find that PS2s protects transfected cells from Fas- and tumor necrosis factor alpha (TNFalpha)-induced apoptosis. Furthermore, a similar anti-apoptotic COOH-terminal PS2 polypeptide (PS2Ccas) is generated by caspase-3 cleavage at Asp329. These results suggest that caspase-3 not only activates pro-apoptotic substrates but also generates a negative feedback signal in which PS2Ccas antagonizes the progression of cell death. Thus, whereas PS2 is required for apoptosis, PS2s and PS2Ccas oppose this process, and the balance between PS2 and these COOH-terminal fragments may dictate the cell fate.
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PMID:Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. 935 87

MEK kinases (MEKKs) are serine-threonine kinases that regulate sequential protein phosphorylation pathways involving mitogen-activated protein kinases (MAPKs), including members of the Jun kinase (JNK) family. MEKK1 is a 196 kDa protein that when cleaved by caspase-3-like proteases generates an active COOH-terminal kinase domain. Expression of the MEKK1 kinase domain is sufficient to induce apoptosis. Mutation of MEKK1 to prevent its proteolytic cleavage protects cells from MEKK1-mediated cell death even though the JNK pathway is still activated, indicating that JNK activation is not sufficient to induce cell death. The inducible acute expression at modest levels of the activated MEKK1 kinase domain can be used to potentiate the apoptotic response to low dose ultraviolet irradiation and cisplatin. Similarly, in L929 fibrosarcoma cells inducible acute expression of the kinase domain of MEKK1 markedly increased the cell death response to tumor necrosis factor alpha (TNF alpha). The findings demonstrate that acute expression of an active form of MEKK1 can potentiate the cell death response to external stress stimuli. Manipulation of MEKK1 proteolysis and its regulation of signal pathways involved in apoptosis has significant potential for anticancer therapies when used in combination with therapeutic agents at doses that alone have little or modest effects on cell viability.
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PMID:Potentiation of apoptosis by low dose stress stimuli in cells expressing activated MEK kinase 1. 939 40

Physiological levels of shear stress reduce endothelial cell turnover and exert a potent antiatherosclerotic effect. Here we demonstrate that oxidative stress-induced apoptosis of human endothelial cells was inhibited by shear stress exposure (15 dynes/cm2). Incubation with H2O2 (200 mumol/L) for 18 hours induced apoptosis of human umbilical venous endothelial cells as demonstrated by an enzyme-linked immunosorbent assay specific for histone-associated DNA fragments and visual analysis of fluorescence-stained nuclei. Shear stress-mediated inhibition of apoptosis was partially prevented by pharmacological inhibition of glutathione (GSH) biosynthesis with buthionine sulfoximine (BSO) or nitric oxide (NO) synthase with NG-monomethyl-L-arginine (LNMA), whereas inhibition of catalase by aminotriazol did not affect the inhibitory action of shear stress. Combined inhibition of NO synthase and GSH biosynthesis completely reversed the protective effect of shear stress, suggesting that both NO synthase and the GSH redox cycle system are involved in the apoptosis-suppressing effect of shear stress. Similar results were obtained when apoptosis was stimulated by tumor necrosis factor alpha (TNF alpha). To gain further insights into the interference of shear stress with apoptosis signal transduction, we measured caspase-3-like activity, a cysteine protease that has been shown to play a predominant role in the cell death effector pathway. Indeed, shear stress prevented the activation of caspase-3-like activity induced by H202 or TNF alpha. The inhibitory effect of shear stress was prevented by LNMA and BSO, suggesting that the reduction of oxidative flux by shear stress prevents the activation of caspase-like proteases and thereby inhibits apoptotic cell death in human endothelial cells.
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PMID:Shear stress inhibits H2O2-induced apoptosis of human endothelial cells by modulation of the glutathione redox cycle and nitric oxide synthase. 943 9

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPARalpha and PPARgamma forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARalpha is already present in undifferentiated monocytes, PPARgamma expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARalpha resides constitutively in the cytoplasm, whereas PPARgamma is predominantly nuclear localized. Transient transfection experiments indicate that PPARalpha and PPARgamma are transcriptionally active after ligand stimulation. Ligand activation of PPARgamma, but not of PPARalpha, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPARalpha and PPARgamma ligands induce apoptosis of macrophages activated with tumor necrosis factor alpha/interferon gamma. Finally, PPARgamma inhibits the transcriptional activity of the NFkappaB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFkappaB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.
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PMID:Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. 974 21

Bcl-xL, a member of the bcl-2 family of proteins is required for the survival of neurons early in development. To study the mechanism of action of Bcl-xL in a neuronal context, we generated rat PC12 cells overexpressing Bcl-xL and examined their susceptibility to apoptotic stimuli that induce apoptosis through different pathways involving trophic-factor deprivation, staurosporine, tumor necrosis factor alpha or cisplatin. Overexpression of Bcl-xL in both naive and neuronal PC12 cells inhibited apoptosis induced by the different pathways. However, the extent of this protective effect varied, suggesting that the contribution of the Bcl-xL-controlled step to apoptosis differs in the different pathways. Our findings also showed that TNF alpha-induced activation of caspase-3 is inhibited by overexpression of Bcl-xL, suggesting that Bcl-xL acts upstream of caspase activation.
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PMID:Bcl-xL inhibits different apoptotic pathways in rat PC12 cells. 975 99

This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IkappaB superrepressor, tumor necrosis factor alpha (TNFalpha) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFalpha induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFalpha treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFalpha treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFalpha-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing DeltaFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFalpha, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFalpha-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.
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PMID:The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. 977 51

It is now known that caspase-3-like protease activation can promote Bcl-2 cleavage and mitochondrial cytochrome c release and that these events can lead to further downstream caspase activation. NO has been proposed as a potent, endogenous inhibitor of caspase-3-like protease activity. Experiments were carried out to determine whether NO could interrupt Bcl-2 cleavage or cytochrome c release by the inhibition of caspase activity linking these events. NO inhibited the capacity of purified caspase-3 to cleave recombinant Bcl-2. Both Bcl-2 cleavage and cytochrome c release were inhibited in tumor necrosis factor alpha- and actinomycin D-treated MCF-7 cells exposed to NO donors. The NO-mediated inhibition of Bcl-2 cleavage and cytochrome c release occurred in association with an inhibition of apoptosis and caspase-3-like activation. Thus, NO suppresses a key step in the positive feedback amplification of apoptotic signaling by preventing Bcl-2 cleavage and cytochrome c release.
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PMID:Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release. 981 55

The hepatitis B virus-encoded HBx protein coactivates transcription of viral and cellular genes, and it is believed to play an important role in hepatitis B virus-related liver cancer. HBx has been shown to alter the coordinated balance between proliferation and programmed cell death, being able to either induce or block apoptosis. Here, we demonstrate for the first time that the HBx is a potent caspase 3 inhibitor. Rat fibroblasts (REV2) and hepatoma cells (Hep) synthesizing the HBx protein were resistant to various apoptotic stimuli such as growth factor depletion, tumor necrosis factor alpha, or anti-Fas antibodies administration. In these cells, HBx prevented DNA fragmentation and cell death in the absence of de novo protein synthesis, with a similar efficiency as the competitive caspase 3 substrates inhibitors VAD-FMK and DEVD-FMK. Protein extracts obtained from the HBx positive cells contained a very low caspase activity, and addition of anti-HBx antibody restored the endogenous caspase activity. To obtain a functional map of the anti-caspase activity of HBx, various cell lines were established that synthesized either N-terminally or C-terminally truncated HBx molecules. These gene dissection experiments revealed that the regions required for the anti-caspase activity overlap with the two known transactivation domains of HBx.
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PMID:The hepatitis B virus HBx protein inhibits caspase 3 activity. 983 9

Human erythroid progenitor cells are the main target cells of the human parvovirus B19 (B19), and B19 infection induces a transient erythroid aplastic crisis. Several authors have reported that the nonstructural protein 1 (NS-1) encoded by this virus has a cytotoxic effect, but the underlying mechanism of NS-1-induced primary erythroid cell death is still not clear. In human erythroid progenitor cells, we investigated the molecular mechanisms leading to apoptosis after natural infection of these cells by the B19 virus. The cytotoxicity of NS-1 was concomitantly evaluated in transfected erythroid cells. B19 infection and NS-1 expression induced DNA fragmentation characteristic of apoptosis, and the commitment of erythroid cells to undergo apoptosis was combined with their accumulation in the G(2) phase of the cell cycle. Since B19- and NS-1-induced apoptosis was inhibited by caspase 3, 6, and 8 inhibitors, and substantial caspase 3, 6, and 8 activities were induced by NS-1 expression, there may have been interactions between NS-1 and the apoptotic pathways of the death receptors tumor necrosis factor receptor 1 and Fas. Our results suggest that Fas-FasL interaction was not involved in NS-1- or B19-induced apoptosis in erythroid cells. In contrast, these cells were sensitized to tumor necrosis factor alpha (TNF-alpha)-induced apoptosis. Moreover, the ceramide level was enhanced by B19 infection and NS-1 expression. Therefore, our results suggest that there may be a connection between the respective apoptotic pathways activated by TNF-alpha and NS-1 in human erythroid cells.
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PMID:Possible interactions between the NS-1 protein and tumor necrosis factor alpha pathways in erythroid cell apoptosis induced by human parvovirus B19. 1048 30

The earliest observed apoptotic change in a macrophage-like cell line, J774.1, treated with lipopolysaccharide (LPS) in the presence of cycloheximide (CHX) was a selective increase in caspase-3-like activity. The addition of polymyxin B, TPCK, herbimycin A, or genistein, all of which inhibited LPS-induced tumor necrosis factor alpha (TNF-alpha) production by macrophages, suppressed the activation of the caspase-3-like protease in these macrophages treated simultaneously with CHX. However, SB202190 and SB203580, inhibitors of MAP kinase, and PD98059, an inhibitor of MAP-kinase kinase (MEK), showed no effect on the activation of the caspase-3-like protease or on the cell damage of the macrophages treated with LPS and CHX, whereas they inhibited LPS-induced TNF-alpha production. These results suggest that some of the early signals in LPS-treated macrophages are common to the subsequent pathways for TNF-alpha production and caspase-3-like protease activation, but the later signals, like MAP-kinase kinase or MAP-kinase, are not involved in the pathways for caspase-3-like protease activation.
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PMID:LPS-induced signals in activation of caspase-3-like protease, a key enzyme regulating apoptotic cell damage into a macrophage-like cell line, J774.1, in the presence of cycloheximide. 1053 27


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