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)

Treatment of U937 cells with an IkappaBalpha phosphorylation inhibitor, Bay 11-7085, induced a rapid phosphorylation of p38 mitogen-activated protein (MAP) kinase, significant apoptosis, extensive necrosis, and a weak phosphorylation of MAP kinase kinase. Bay 11-7085 had no effect on the basal levels of phosphorylated IkappaBalpha but completely inhibited phorbol 12-myristate 13-acetate-induced phosphorylation of IkappaBalpha. Although Bay 11-7085 prevented phorbol 12-myristate 13-acetate-induced NF-kappaB nuclear translocation, SN50, a specific inhibitor of nuclear translocation and function of NF-kappaB, did not induce any significant nuclear/DNA fragmentation, caspase 3 activation, or cell death. The p38 MAP kinase-specific inhibitor, SB203580, completely inhibited the phosphorylation of p38 MAP kinase and significantly decreased Bay 11-7085-induced apoptosis. In contrast, the MAP kinase kinase-specific inhibitor PD98059 had no effect on Bay 11-7085-induced apoptosis. Caspase-specific inhibitor, z-Val-Ala-Asp-fluoromethyl ketone prevented Bay 11-7085-induced activation of caspase 3 but was not able to block Bay 11-7085-induced phosphorylation of p38 MAP kinase. These data suggest that Bay 11-7085 induces apoptosis through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.
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PMID:An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism. 2763 47

Rho family GTPases are critical molecular switches that regulate the actin cytoskeleton and cell function. In the current study, we investigated the involvement of Rho GTPases in regulating neuronal survival using primary cerebellar granule neurons. Clostridium difficile toxin B, a specific inhibitor of Rho, Rac, and Cdc42, induced apoptosis of granule neurons characterized by c-Jun phosphorylation, caspase-3 activation, and nuclear condensation. Serum and depolarization-dependent survival signals could not compensate for the loss of GTPase function. Unlike trophic factor withdrawal, toxin B did not affect the antiapoptotic kinase Akt or its target glycogen synthase kinase-3beta. The proapoptotic effects of toxin B were mimicked by Clostridium sordellii lethal toxin, a selective inhibitor of Rac/Cdc42. Although Rac/Cdc42 GTPase inhibition led to F-actin disruption, direct cytoskeletal disassembly with Clostridium botulinum C2 toxin was insufficient to induce c-Jun phosphorylation or apoptosis. Granule neurons expressed high basal JNK and low p38 mitogen-activated protein kinase activities that were unaffected by toxin B. However, pyridyl imidazole inhibitors of JNK/p38 attenuated c-Jun phosphorylation. Moreover, both pyridyl imidazoles and adenoviral dominant-negative c-Jun attenuated apoptosis, suggesting that JNK/c-Jun signaling was required for cell death. The results indicate that Rac/Cdc42 GTPases, in addition to trophic factors, are critical for survival of cerebellar granule neurons.
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PMID:An essential role for Rac/Cdc42 GTPases in cerebellar granule neuron survival. 1150 62

Mitochondria play a central role in many apoptotic reactions. Although mitochondrial apoptotic changes and caspase activation have been demonstrated in the apoptotic thymocytes, cell death signal through mitochondria in TCR-stimulated thymocytes has not been fully understood. In this study, we show that TCR stimulation induced disruption of mitochondrial transmembrane potential (Delta Psi(m)), the cytochrome c release from mitochondira, capase-3 activation, and the cell death of thymocytes. Bongkrekic acid, an inhibitor of Delta Psi(m) disruption, blocked the cytochrome c release from mitochondria and the following caspase-3-mediated cell death. Furthermore, a pro-apoptotic Bcl-2 family protein, Bax, but not Bad or Bid, was translocated from cytosol to mitochondria in TCR-stimulated thymocytes. This translocation and the following apoptotic changes were inhibited by SB203580, a p38 kinase inhibitor, in a specific manner. These results suggest that activated p38 kinase pathway by TCR stimulation induces translocation of Bax to mitochondria, causing Delta Psi(m) disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes.
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PMID:Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR- and dexamethasone-stimulated thymocytes. 1153 68

The mitogen-activated protein kinase (MAPK) cascades are thought to be important mediators in the transduction of extracellular signals into cellular responses. The p38 kinase, a member of the MAPK superfamily, is activated by a wide variety of extracellular stimuli and has been implicated in neuronal apoptosis induced by glutamate. In this study we have examined the role of p38 kinase in the potassium deprivation model of apoptosis in rat cerebellar granule neurons (CGN). An increase in p38 kinase activity was observed with a 15-minute potassium deprivation when compared to the basal level. We also found that SB203580 and PD169316, specific p38 kinase inhibitors, significantly attenuated apoptosis in potassium-deprived cells in a dose dependent manner. A decrease in caspase-3 mediated DEVD-MCA, substrate hydrolysis and the appearance of the 120 kDa-spectrin breakdown product in cells treated with SB203580 further suggests that the p38 kinase acts upstream of caspase-3 in the apoptosis cascade. The data provides evidence for an essential role of p38 kinase in mediating apoptotic cell death in CGN and the inhibition of p38 kinase mimics the suppression of apoptosis provided by natural survival signals.
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PMID:Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons. 1154 39

Neural progenitor cells (NPC) can proliferate, differentiate into neurons or glial cells, or undergo a form of programmed cell death called apoptosis. Although death of NPC occurs during development of the nervous system and in the adult, the underlying mechanisms are unknown. Here we show that nitric oxide (NO) can induce death of C17.2 NPC by a mechanism requiring activation of p38 MAP kinase, poly(ADP-ribose) polymerase, and caspase-3. Nitric oxide causes release of cytochrome c from mitochondria, and Bcl-2 protects the neural progenitor cells against nitric oxide-induced death, consistent with a pivotal role for mitochondrial changes in controlling the cell death process. Inhibition of p38 MAP kinase by SB203580 abolished NO-induced cell death, cytochrome c release, and activation of caspase-3, indicating that p38 activation serves as an upstream mediator in the cell death process. The anti-apoptotic protein Bcl-2 protected NPC against nitric oxide-induced apoptosis and suppressed activation of p38 MAP kinase. The ability of nitric oxide to trigger death of NPC by a mechanism involving p38 MAP kinase suggests that this diffusible gas may regulate NPC fate in physiological and pathological settings in which NO is produced.
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PMID:p38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. 1155 60

Exposure of insulin-secreting RINm5F cells to the chemical nitric oxide donor sodium nitroprusside (SNP) resulted in apoptotic cell death, as detected by cytochrome c release from mitochondria and caspase 3 activation. SNP exposure also leads to phosphorylation and activation of enzymes involved in cellular response to stress such as signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase 46 (JNK46). Both cytochrome c release and caspase 3 activation were abrogated in cells exposed to MEK and p38 inhibitors. Treatment of cells with the NO donors SNP, DETA-NO, GEA 5024, and SNAP resulted in phosphorylation of the antiapoptotic protein Bcl-2, which was resistant to blockade of MEK, p38, and JNK pathways and sensitive to phosphoinositide 3-kinase (PI3K) inhibition. In addition, transient transfection of cells with the wild-type PI3K gamma gene mimics the increased rate of Bcl-2 phosphorylation detected in NO-treated cells. The generation of phosphoinositides seems to participate in the process since Bcl-2 phosphorylation was not observed in cells overexpressing lipid-kinase-deficient PI3Kgamma. The potential of SNP toxicity directly from NO was supported by our finding that the NO scavenger carboxy-PTIO prevented cell death. We found no evidence to support the contention that oxygen radicals generated during cellular SNP metabolism mediate cell toxicity in RINm5F cells, since neither addition of catalase/superoxide dismutase nor transfection with superoxide dismutase prevented SNP-induced cell death. Thus, we propose that exposure to apoptotic concentrations of NO triggers ERK- and p38-dependent cytochrome c release, caspase 3 activation, and PI3K-dependent Bcl-2 phosphorylation.
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PMID:Sodium nitroprusside-induced mitochondrial apoptotic events in insulin-secreting RINm5F cells are associated with MAP kinases activation. 1157 Aug 14

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, have been examined following intracortical injection of the glutamate analogue quinolinic acid (QA). Increased JNK(P) and p38(P) immunoreactivity has been found in the core at 1 h following QA injection, whereas increased MAPK(P) immunoreactivity occurs in neurons and glial cells localised around the lesion and in neurons in remote cortical regions. This is accompanied by strong phosphorylated Ser63 c-Jun (c-Jun(P)) immunoreactivity in the core at 3 h, and by strong phosphorylated CREB, Elk-1 and ATF-2 (CREB(P), Elk-1(P) and ATF-2(P)) immunoreactivity mainly in neurons around the core at 24 h following QA injection. Examination with the method of in situ end-labelling of nuclear DNA fragmentation has revealed large numbers of positive cells with no apoptotic morphology in the core at 24 h, thus indicating that JNK(P), p38(P) and c-Jun(P) over-expression precedes cell death. In contrast, MAPK(P), CREB(P), Elk-1(P) and ATF-2(P), but not phosphorylated c-Myc (c-Myc(P)), over-expression correlates with cell survival. Examination of cleaved, active caspase-3 has shown specific immunoreactivity restricted to a few hematogenous cells in the area of injection. Since cleaved caspase-3 is not expressed by dying cells in the present paradigm, JNK(P), p38(P) and c-Jun(P) expression is not associated with caspase-3 activation. The present results demonstrate selective activation of specific MAPK signals which are involved either in cell death or cell survival triggered by excitotoxic insult.
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PMID:Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. 1159 64

On binding to its receptor, transforming growth factor beta (TGFbeta) induces apoptosis in a variety of cells, including human B lymphocytes. We have previously reported that TGFbeta-mediated apoptosis is caspase-dependent and associated with activation of caspase-3. We show here that caspase-8 inhibitors strongly decrease TGFbeta-mediated apoptosis in BL41 Burkitt's lymphoma cells. These inhibitors act upstream of the mitochondria because they inhibited the loss of mitochondrial membrane potential observed in TGFbeta-treated cells. TGFbeta induced caspase-8 activation in these cells as shown by the cleavage of specific substrates, including Bid, and the appearance of cleaved fragments of caspase-8. Our data show that TGFbeta induces an apoptotic pathway involving sequential caspase-8 activation, loss of mitochondrial membrane potential, and caspase-9 and -3 activation. Caspase-8 activation was Fas-associated death domain protein (FADD)-independent because cells expressing a dominant negative mutant of FADD were still sensitive to TGFbeta-induced caspase-8 activation and apoptosis. This FADD-independent pathway of caspase-8 activation is regulated by p38. Indeed, TGFbeta-induced activation of p38 and two different inhibitors specific for this mitogen-activated protein kinase pathway (SB203580 and PD169316) prevented TGFbeta-mediated caspase-8 activation as well as the loss of mitochondrial membrane potential and apoptosis. Overall, our data show that p38 activation by TGFbeta induced an apoptotic pathway via FADD-independent activation of caspase-8.
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PMID:p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGFbeta-induced apoptosis in human Burkitt lymphoma B cells BL41. 1159 98

Apoptosis is considered to be the final common pathway of photoreceptor cell death in different inherited retinal diseases. However, apoptosis encompasses diverse pathways of molecular interactions culminating in cellular demise. To begin dissecting these interactions, we have investigated key participants in the rd (retinal degeneration) model of retinal neurodegeneration. By Western blot analysis and immunocytochemistry, we found that cytochrome c release occurs in rd retinas concurrently with the activation of the proapoptotic protein Bid. Active forms of caspase-8 and the mitogen-activated protein kinase p38, both of which are capable of cleaving Bid, were detected in rd retinas at the peak time of photoreceptor death. In addition, the activated form of the cell death effector caspase-3 was detectable particularly at the photoreceptors in parallel with this peak degenerative phase. These data suggest that activation of both major apoptotic pathways occurs during photoreceptor degeneration in the rd mouse model of inherited blindness.
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PMID:Characterization of cell death pathways in murine retinal neurodegeneration implicates cytochrome c release, caspase activation, and bid cleavage. 1164 Aug 92

Caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. Here, we cloned the rat homolog of caspase-11, and investigated its inducibility by inflammatory stimuli and signal transduction pathways involved. Deduced amino acid sequence of rat caspase-11 showed 88.7% similarity to mouse caspase-11, and in vitro translation of rat caspase-11 cDNA yielded approximately a 43 kDa polypeptide, which was in agreement with predicted protein size generated from full-length rat caspase-11 cDNA. The expression of caspase-11 was strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumor necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes. LPS induced activation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) in C6 cells. However, SB203580 (specific inhibitor of p38 kinase), but not PD98059 (specific inhibitor of ERK kinase), inhibited LPS induction of caspase-11, indicating that induction of caspase-11 by LPS in astrocytes was mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites.
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PMID:Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway. 1168 90


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