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)

Although apoptosis contributes to myocardial cell death in the ischemia-reperfused heart, the molecular basis of apoptosis is poorly understood. Apoptosis-inducing factor (AIF) has been characterized as a caspase-independent death effector. Upon the induction of apoptosis, mitochondrial AIF is released to the cytoplasm and then enters the nucleus, in which it induces chromatin condensation and 50 kbp DNA fragmentation. In the present study, we examined the role of AIF in ischemia-reperfusion injury in isolated rat hearts. AIF was detected in the cytosolic and nuclear fractions of hearts subjected to ischemia-reperfusion, whereas it was detected only in the mitochondria of control hearts. Moreover, AIF release increased in a reperfusion time-dependent manner. Pulse field gel electrophoresis revealed that 50 kbp DNA fragments were produced by ischemia/reperfusion. In contrast, cytochrome c release and the activation of caspase-3 did not occur to a significant extent. Moreover, ischemic preconditioning attenuated the AIF release and the 50 kbp DNA fragmentation. These results suggest that AIF-dependent apoptosis is likely to attribute to myocardial cell death in the ischemia-reperfused heart and that it is related with the protective effect of ischemic preconditioning.
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PMID:Role of apoptosis-inducing factor in myocardial cell death by ischemia-reperfusion. 1296 35

Survivin, a member of inhibitor of apoptosis family of proteins, plays important roles in both cell proliferation and cell death. We previously observed that Survivin is overexpressed in leukemic cell lines and blasts from patients with acute myelogenous leukemia (AML). To understand the roles of Survivin in AML and search for new approaches to the treatment of AML, we inhibited Survivin expression in HL-60 cells with a Survivin anti-sense oligonucleotide (sur-AS-ODN) (ISIS 23722). This blocked significant numbers of HL-60 cells in G2/M phase, and halted cell proliferation at 24 hrs and progressing over time. There was only a slight increase in the number of apoptotic cells at 24 hrs compared with cells treated with nonsense oligonucleotide (NS-ODN). At 48 hrs, however, there were significant increases in sub-G1 phase and annexin V+ cells, suggesting that cell division defects caused cell death. This was supported by the finding that a reduction in the Survivin protein by sur-AS-ODN in cells under serum-free medium did not induce G2/M block and cell death compared to cells treated with NS-ODN. The formation of polyploid cells was observed 48 hrs after sur-AS-ODN treatment, as was the activation of caspase 3, which suggested that apoptotic cell death had occurred. The mitochondrial release of cytochrome C and Smac and the nuclear translocation of the apoptosis-inducing factor were also detected. Our results suggest that Survivin is essential for cell cycle progression in leukemic cells. Reduced Survivin expression causes a cell-cycle defect that leads to cell death through a mitochondrial pathway. This finding has potential utility for therapy of patients with AML.
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PMID:Targeting Survivin expression induces cell proliferation defect and subsequent cell death involving mitochondrial pathway in myeloid leukemic cells. 1296 50

Transient focal ischaemia by middle cerebral artery occlusion (MCAO) may produce cell death, but the mechanisms leading to cell death differ in the infarct core and in the penumbra, the immediate zone surrounding the infarct core. In the present study, transient focal ischaemia to adult rats was produced by intraluminal occlusion of the middle cerebral artery for 1 h followed by 0 h (n=6), 1 h (n=10), 4 h (n=8), 6 h (n=2) and 12 h (n=3) of reperfusion. The present model of ischaemia causes a large cortico-striatal infarct extending through the mediolateral cortex and dorsolateral striatum at 12 h. The expression and subcellular distribution of several proteins involved in apoptosis have been examined in the penumbra and in the infarct core by using combined methods of immunohistochemistry, cell subfractionation and Western blotting. Transient focal ischaemia by MCAO results in activation of complex signal pathways for cell death in the penumbra. Increased expression of Bcl-2 and Bax, but not of Bcl-x, occurs in the penumbra at the time when Bax translocates from the cytosol to the mitochondria, cytochrome c is released to the cytoplasm and active caspase-3 is expressed. Bax translocation, cytochrome c release and active caspase-3 are observed at 4 h, but not at 1 h, following reperfusion, and together indicate activation of the caspase-dependent pathway of apoptosis in the penumbra. In contrast, reduced Bax expression but not Bax translocation and cytochrome c release occurs in the infarct core, thus suggesting apoptosis signals restricted to the penumbra. In addition, increased expression of an apoptosis-inducing factor in the cytoplasm and nuclei of selected cells shows, for the first time, activation of the caspase-independent mitochondrial pathway in the penumbra following transient focal ischaemia and reperfusion.
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PMID:Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat. 1450 39

Loss of mitochondrial membrane integrity and the resulting release of apoptogenic factors may play a critical role in mediating hippocampal neurodegeneration after transient global ischemia. In the present study, the authors have cloned and characterized the rat cDNA encoding apoptosis-inducing factor (AIF), an intramitochondrial protein that promotes cell death in a caspase-independent manner upon release into nonmitochondrial compartments. In contrast to the expression patterns of a number of apoptosis-regulatory gene products during brain development, the expression of AIF protein increases gradually with brain maturation and peaks in adulthood. In a rat model of transient global ischemia, AIF was found to translocate from mitochondria to the nucleus in the hippocampal CA1 neurons after ischemia and to manifest a DNA-degrading activity that mimicked the purified AIF protein and was inhibitable by AIF immunodepletion. The temporal profile of AIF translocation after ischemia (24 to 72 hours) coincided with the induction of large-scale DNA fragmentation at the size of 50 kbp, a well-characterized hallmark of AIF-like activity but preceded the formation of internucleosomal DNA fragmentation (72 hours), a DNA degradation associated with the terminal stage of cell death. Further, the nuclear translocation of AIF after ischemia was not blocked by inhibiting caspase-3/-7 activities, but, as shown in neuronal cultures that were challenged with transient oxygen-glucose deprivation, it can be prevented by intracellular delivery of the mitochondria-associated antiapoptotic protein Bcl-xL. The results presented here strongly suggest that mitochondrial release of AIF may be an important factor, in addition to the previously reported cytochrome c and Smac, which could contribute to the selective vulnerability of CA1 neurons to transient global ischemic injury.
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PMID:Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. 1452 24

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.
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PMID:The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines. 1456 87

Enforced expression of c-myc has been shown to serve as an apoptotic stimulus in cultured cells. Prior studies have also demonstrated that several tissues expressing c-myc transgene display a large number of dead cells, although a morphologic or biochemical verification of apoptosis in these tissues has actually not been presented. In the present study, we examined the morphologic properties of cell death in the mammary tumors developed from MMTV-c-myc transgenic mice. We found that c-myc-expressing mammary tumor cells exhibited malformation of mitochondria, characterized by an amorphous matrix with very few cristae. The mitochondria were also frequently degenerated by lysis of the matrix and cristae. The protein level of cytochrome c was much lower in the areas of c-myc-expressing tumor cells compared with the adjacent tumor foci, which was previously shown to have decreased expression of c-myc, reduced frequencies of cell death, and increased frequencies of proliferating cells. In the c-myc-expressing tumor areas, there were many dying or dead cells organized in clusters, termed "dead cell islands." These cells exhibited shrinkage, DNA breakage as indicated by a positive TUNEL staining, and nuclear localization of apoptosis-inducing factor, but a lack of typical apoptotic morphology, such as nuclear condensation and formation of cell membrane blebs and apoptotic bodies. Many macrophages infiltrated into these dead cell islands, engulfing the dying or dead tumor cells. In the total tumor tissue, the protein level of caspase-3 was very low, and the poly(ADP)-ribose polymerase was present mainly as the unprocessed, inactive form. Collectively, these results suggest that programmed cell death in the c-myc transgenic mammary tumor tissue may not be typical apoptosis and may involve a caspase-independent mechanism.
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PMID:Cell death in MMTV-c-myc transgenic mouse mammary tumors may not be typical apoptosis. 1456 45

We previously demonstrated that evening primrose extract (EPE) induced apoptosis in Ehrlich ascites tumor cells, while mouse embryo fibroblast cells (NIH3T3) used as a normal cell model, showed no effect of cell viability by treatment of EPE. Furthermore, our results demonstrated the rapid increase in intracellular peroxides levels, loss of mitochondrial membrane potential and the release of cytochrome c to cytosol, suggesting that the rapid increase in intracellular peroxides levels after addition of EPE triggers off induction of apoptosis. In this study, we identified that EPE elicited the translocation of Bax to mitochondria and apoptosis-inducing factor (AIF) to nuclei, but no activation of caspase-3-like protease. We also demonstrated that the rapid EPE-induced increase in hydrogen peroxide levels caused the translocation of Bax to mitochondria, and then mitochondrial cytochrome c was released. One of the main consequences of mitochondrial cytochrome c release is the activation of caspase-3. However, no caspase-3 activation was observed. On the other hand, AIF was translocated from mitochondria to nuclei. The EPE-induced translocation of AIF was suppressed with the addition of catalase, suggesting that the rapid intracellular peroxide levels after addition of EPE triggers off induction of apoptosis, which is AIF-mediated and caspase-independent.
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PMID:Caspase-independent apoptosis induced by evening primrose extract in Ehrlich ascites tumor cells. 1458 Jun 81

Status epilepticus (SE) increases neurogenesis in the subgranular zone (SGZ) of the adult dentate gyrus, but many of the newborn cells die, partly through caspase-induced apoptosis. Here we provide immunohistochemical evidence indicating that the caspase-evoked death of the new neurons involves the mitochondrial but not the death-receptor-mediated pathway. Cytochrome c released from mitochondria was found in a subset of progenitor cell progeny, while Fas ligand and tumor necrosis factor 1 receptor-associated domain as well as the mitochondria-related, caspase-independent apoptosis-inducing factor were not detected. We also show that additional seizures, induced at different stages during neuronal differentiation of progenitor cell progeny following SE, neither potentiate cell death mechanisms in the SGZ nor compromise the survival of the new cells. Thus, we found similar expression of cytochrome c, active caspase-3, caspase-cleaved PARP, and TUNEL/Hoechst-positive DNA fragmentation, as well as numbers of new cells in the SGZ in rats exposed to additional seizures at days 6 and 7 or days 33 and 34 following SE as in control animals only subjected to SE. We propose that the degree of survival of newly generated neurons is determined primarily by the initial SE insult and the ensuing pathology in the tissue environment, whereas spontaneous seizures play a minor role.
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PMID:Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival. 1467 67

The mechanisms of apoptosis in the loss of myocytes in skeletal muscle with age and the role of mitochondrial and sarcoplasmic reticulum-mediated pathways of apoptosis are unknown. Moreover, it is unknown whether lifelong calorie restriction prevents apoptosis in skeletal muscle and reverses age-related alterations in apoptosis signaling. We investigated key apoptotic regulatory proteins in the gastrocnemius muscle of 12 and 26 month old ad libitum fed and 26 month old calorie-restricted male Fischer-344 rats. We found that apoptosis increased with age and that calorie-restricted rats showed less apoptosis compared with their age-matched cohorts. Moreover, pro- and cleaved caspase-3 levels increased significantly with age and calorie-restricted rats had significantly lower levels than the aged ad libitum group. Neither age nor calorie restriction had any effect on muscle caspase-3 enzyme activity, but the levels of X-linked inhibitor of apoptosis, particularly an inhibitor of caspase-3, increased with age and were reduced significantly in the 26 month old calorie-restricted cohort. The apoptotic inhibitor apoptosis repressor with a caspase recruitment domain (ARC), which inhibits cytochrome c release, underwent an age-associated decline in the cytosol but increased with calorie restriction. In contrast, mitochondrial ARC levels increased with age and were lower in calorie-restricted rats than in age-matched controls, suggesting a translocation of this protein to attenuate oxidative stress. The translocation of ARC may explain the reduction in cytosolic cytochrome c levels observed with age and calorie restriction. Moreover, we found a striking approximately 350% increase in the expression of procaspase-12 (caspase located at the sarcoplasmic reticulum) with age which was significantly lower in the 26 month old calorie-restricted group. The total protein level of apoptosis-inducing factor in the plantaris muscle increased with age and was reduced calorie-restricted rats compared with age-matched controls, but there were no significant changes in this pro-apoptotic protein in the isolated nuclei. Calorie restriction is able to lower the apoptotic potential in aged skeletal muscle by altering several key apoptotic proteins toward cellular survival, thereby reducing the potential for sarcopenia.
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PMID:Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. 1473 88

The functional significance of disruption of p21(WAF1/CIP1) induction by flavopiridol (FP) in human leukemia cells (Jurkat) exposed to the histone deacetylase (HDAC) inhibitor sodium butyrate (SB) was investigated. Coexposure of leukemic cells to FP blocked SB-mediated induction of p21(WAF1/CIP1) and resulted in a marked increase in mitochondrial injury, activation of procaspases-3 and -8, Bid cleavage, and PARP degradation. Enforced expression of p21(WAF1/CIP1) (i.e., in Jurkat cells inducibly expressing p21(WAF1/CIP1) under the control of a doxycycline-responsive promoter) partially but significantly reduced cytochrome c and apoptosis-inducing factor release, loss of mitochondrial membrane potential, caspase-3 and -8 activation, Bid cleavage, poly(ADP-ribose)polymerase (PARP) degradation, and apoptosis in response to SB/FP. Furthermore, increasing expression of p21(WAF1/CIP1) (i.e., by culturing cells in the presence of higher concentrations of doxycycline) rendered cells more resistant to SB/FP-mediated lethality. Enforced expression of p21(WAF1/CIP1) did not modify SB/FP-mediated JNK activation or generation of reactive oxygen species. Consistent with these results, Jurkat cells stably expressing a p21(WAF1/CIP1) nuclear localization mutant (p21DeltaNLS) were also resistant to SB/FP-mediated mitochondrial injury, activation of procaspases-3 and -8, PARP cleavage, and apoptosis. Finally, enforced expression of full-length or ectopic expression of DeltaNLS p21(WAF1/CIP1) increased the amount of p21(WAF1/CIP1) coimmunoprecipitating with procaspase-3. Together, these findings suggest that interruption of HDAC-mediated p21(WAF1/CIP1) induction by FP plays a significant functional role in potentiating apoptosis, possibly by preventing the formation of a procaspase-3/p21(WAF1/CIP1) complex.
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PMID:Evidence of a functional role for p21WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. 1497 35


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