Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroquinone (a major marrow metabolite of the leukemogen, benzene) induces incomplete granulocytic differentiation of mouse myeloblasts to the myelocyte stage, and also causes an increase in the number of myelocytes. This was confirmed using the normal interleukin 3 (IL-3)-dependent mouse myeloblastic 32D cell line. The hydroquinone-induced twofold increase in the number of IL-3-treated myelocytes does not result from stimulation of IL-3-induced proliferation. Hydroquinone's ability to effect this increase through an inhibition of apoptosis was investigated using mouse 32D and human HL-60 myeloblasts. Apoptosis induced by staurosporine treatment (0.5-1.0 microM) of HL-60 cells (50%) and 32D cells (15%) or by IL-3 withdrawal from 32D myeloblasts was determined by monitoring the development of characteristic morphological features and confirmed by the appearance of a typical nucleosomal DNA ladder upon agarose gel electrophoresis. Concentrations of hydroquinone (1-6 microM) that induce differentiation in 32D myeloblasts caused a concentration-dependent inhibition of staurosporine-induced apoptosis in both cell lines, with a 50% inhibitory concentration of 3 microM, and prevented apoptosis in IL-3-deprived 32D cells. Hydroquinone inhibition of apoptosis in myeloblasts, like hydroquinone-induced granulocytic differentiation, required myeloperoxidase-mediated oxidation of hydroquinone to its reactive species, p-benzoquinone, and was inhibited 50% by the peroxidase inhibitor, indomethacin (20 microM). p-benzoquinone (3 microM) was shown to cause a 50% inhibition of CPP32, an IL-1 beta-converting enzyme/Ced-3 cysteine protease involved in the implementation of apoptosis and present in myeloid cells. The ability of hydroquinone to induce a program of differentiation in the myeloblast that proceeds only to the myelocyte stage coupled with its ability to inhibit the CPP32 protease and, thereby, apoptosis of the proliferating myelocytes, may have important implications for benzene-induced acute myeloid leukemia.
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PMID:Hydroquinone, a bioreactive metabolite of benzene, inhibits apoptosis in myeloblasts. 894 30

Hematopoietic cytokines transduce cell survival signals, which are distinct from the signals necessary for the stimulation of DNA synthesis. Recently, the Ras and phosphatidylinositol 3-kinase pathways have been shown to play important roles in preventing apoptosis in various cell types, e.g. hematopoietic cells and neuronal cells. Withdrawal of cytokine(s), in turn, results in rapid inactivation of these survival pathways and eventually leads to cell death accompanied by the hallmarks of apoptosis. However, the mechanism of cell death caused by cytokine deprivation has not been fully elucidated. In this study, we demonstrate that caspase-3/CPP32, a member of the caspase/interleukin-1beta-converting enzyme family, is activated upon interleukin (IL)-3 deprivation in IL-3-dependent cells as well as IL-2 deprivation in IL-2-dependent cells. In addition, poly(ADP-ribose) polymerase, a cellular substrate for the caspase family proteases, was degraded into apoptotic fragments in both cell lines after cytokine removal. Furthermore, inhibition of a caspase family protease by synthetic peptides suppressed apoptotic death. These results indicate that the activation of a caspase-like protease(s) is required for the progression of apoptosis following cytokine deprivation. However, readdition of IL-3 did not restore the proliferative potential of the cells that survived in the presence of the peptide inhibitor after IL-3 depletion. Therefore, cellular commitment to apoptosis appears to precede the activation of a caspase-like protease(s).
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PMID:Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells. 928 12

Apoptosis is cellular suicide functionally opposite of mitosis. It plays an important role in tissue growth control and removal of damaged and premalignant cells. The decrease in death suppressor Bcl-2 protein level was implicated in the many types of apoptotic cell death. Because Bcl-2 protein was recently found to be cleaved during apoptosis induced by Fas ligation, IL-3 withdrawal, and alphavirus infection, we assessed whether Bcl-2 protein was also cleaved during the anticancer drug (VP-16)-induced apoptotic cell death in U937 cells. We found that Bcl-2 protein was cleaved in vivo and in vitro after the treatment of VP-16. We also found that caspase-3/CPP32, which was activated after VP-16 treatment, was responsible for the direct cleavage of Bcl-2 protein. The overexpression of the cleaved Bcl-2 fragment increased the sensitivity to VP-16 and promoted apoptotic cell death. Therefore, caspase-3/CPP32 accelerates VP-16-induced U937 cell apoptosis by cleaving death suppressor Bcl-2 protein to produce a death promoter Bcl-2 fragment.
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PMID:Involvement of Bcl-2 cleavage in the acceleration of VP-16-induced U937 cell apoptosis. 961 Mar 88

IL-3 deprivation has been reported to induce apoptosis of bone marrow-derived mast cells. In order to evaluate this type of cell death further, we employed trypan blue and propidium iodide stainings, photometric enzyme immunoassay, fluorescence measurement of caspase-3, DNA electrophoresis, flow cytometry and transmission electron microscopy. In this experiment, although several evidences supporting apoptosis were demonstrated some findings were not consistent with typical apoptosis. On the other hand, electron microscopical observation demonstrated that most cells from all the time phases after IL-3 deprivation showed the morphology of typical oncosis, i.e. cell swelling, disintegration of ultrastructure and subsequent karyolysis. Only a small number of cells from the later time phases showed apoptotic morphology. We here suggest that BMMCs undergo both apoptosis and oncosis after IL-3 deprivation and that the dominant type of prelethal change is oncosis in all time phases, although apoptosis also plays a partial role in the late time phases.
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PMID:Murine bone marrow-derived mast cells exhibit evidence of both apoptosis and oncosis after IL-3 deprivation. 1070 46

The actin regulatory protein gelsolin cleaves actin filaments in a calcium- and polyphosphoinositide-dependent manner. Gelsolin has recently been described as a novel substrate of the cysteinyl protease caspase-3, an effector protease activated during apoptosis. Cleavage by caspase-3 generates an amino-terminal fragment of gelsolin that can sever actin filaments independently of calcium regulation. The disruption of the actin cytoskeleton by cleaved gelsolin is hypothesized to mediate many of the downstream morphological changes associated with apoptosis. In contrast, overexpression of full-length gelsolin has also been reported to inhibit apoptotic cell death upstream of the activation of caspase-3, suggesting that gelsolin may also act prior to commitment to cell death. The authors previously observed that actin stabilization by the cell permeant agent jasplakinolide enhanced cell death upon interleukin (IL)-2 or IL-3 withdrawal from growth-factor-dependent lymphocyte cell lines, and hypothesized that actin polymerization could alter the activity of gelsolin, thus enhancing apoptosis. Here the authors show that constitutive overexpression of gelsolin did not, however, inhibit or dramatically enhance apoptotic cell death upon growth-factor withdrawal, nor did it modify sensitivity to jasplakinolide. In contrast to previous reports, overexpression of gelsolin in Jurkat T cells did not prevent or delay apoptosis induced by Fas ligation or ceramide treatment. Overexpressed gelsolin protein was cleaved during apoptosis, as seen previously in this and other cell types. In these model systems, therefore, the level of gelsolin expression was not a rate-limiting determinant in commitment to or time to the morphological changes of apoptosis.
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PMID:Failure of gelsolin overexpression to regulate lymphocyte apoptosis. 1082 33

Apoptosis induced in the IL3-dependent murine pro-B lymphocytic (FL5.12) cell line by the 5-lipoxygenase activating protein inhibitor MK886 is accompanied by the rapid loss of the anti-apoptotic bcl-x(L) and bcl-2, but not the proapoptotic bax proteins (Datta et al., J. Biol. Chem. 273, 28163-28169, 1998). Since several reports indicate important roles for noncaspase proteases in apoptosis, the participation of lysosomes, as well as serine, cysteine, or aspartic acid proteases, in the effects of MK886 were investigated. Consistent with the involvement of various proteases, lysosomal degranulation was evident, as observed by a decrease in acridine orange fluorescence at 2 h and an increase in cytosolic beta-hexosaminidase activity at 4 h after treating FL5.12 cells with 10 microM MK886. The disappearance of bcl-x(L) from FL5.12 cells upon MK886 treatment was prevented in a dose-dependent manner by pretreatment with leupeptin, pepstatin, phenylmethylsulfonyl fluoride, or the broad-spectrum caspase inhibitor Boc-D-FMK. Each of the noncaspase protease inhibitors partially inhibited MK886-induced apoptosis as measured by phosphatidylserine externalization and DNA fragmentation. The noncaspase inhibitors also blocked about half of the increase in caspase-3-like activity. Boc-D-FMK completely inhibited this enzyme and prevented apoptosis. None of the inhibitors were able to directly inhibit activated caspase-3 in cell lysates, suggesting their effects were upstream of caspase activation. These observations suggest the involvement of various proteases, possibly originating from lysosomes, upstream of active caspase-3, in the loss of bcl-x(L) protein and in the signaling pathway of MK886-induced apoptosis in FL5.12 cells. This pathway may be unique to MK886 since these same protease inhibitors had only minimal effects on etoposide-induced apoptosis and the accompanying moderate loss of bcl-x(L) in FL5.12 cells.
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PMID:Proteolytic loss of bcl-x(L) in FL5.12 Cells undergoing apoptosis induced by MK886. 1148 88

Hormones, such as insulin-like growth factor-I (IGF-I), and cytokines, like IL-3 and IL-4, promote survival of progenitor myeloid cells. Here we demonstrate that IGF-I, IL-3 and IL-4 all significantly block activation of caspase-3 in promyeloid cells following growth factor deprivation. However, only IL-3 and IGF-I increase enzymatic activity and phosphorylation of the survival-promoting kinase Akt. IGF-I fails to reduce caspase-3 activity and cell death in the presence of the PI 3-kinase inhibitors, wortmannin and LY294002, whereas these blockers do not affect the ability of IL-3 to maintain cell survival. IL-4 inhibits caspase-3 activity and promotes promyeloid cell survival by a substrate for PI 3-kinase that is not Akt. These data establish that IGF-I inhibits activation of caspase-3 and promotes promyeloid cell survival through a PI 3-kinase-dependent pathway, whereas IL-3 does not. It therefore appears that signal transduction pathways for all three receptors converge upstream of caspase-3 to prevent apoptosis of progenitor myeloid cells, but their receptors differ in the intracellular substrates that are used to promote cell survival.
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PMID:Insulin-like growth factor-I and the cytokines IL-3 and IL-4 promote survival of progenitor myeloid cells by different mechanisms. 1257 27

In bronchial asthma, eosinophils are upregulated and their survival is suggested to be prolonged by the action of some cytokines such as Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF). We find here that the survival of eosinophils in the peripheral blood of patients with asthma is correlated with the serum levels of IL-3 but not of IL-5 and GM-CSF. Interestingly, theophylline is revealed to induce apoptosis of the prolonged survival eosinophils by IL-3, as judged by morphological changes and nucleosomal DNA fragmentation. During the apoptosis, caspase-3 in eosinophils stimulated by IL-3 is activated by theophylline. The substrate of caspase-3, poly (ADP-ribose) polymerase (PARP), is cleaved in the eosinophils after theophylline treatment. These results suggest that theophylline is able to induce apoptosis of the IL-3 activated eosinophils in patients with bronchial asthma, and that its clinical effectiveness may be due to the reduction of inflammatory cells in the airway.
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PMID:Theophylline induces apoptosis of the IL-3 activated eosinophils of patients with bronchial asthma. 1463 31

The purpose of this study was to investigate the radioprotective effect of HGFs (GM-CSF, IL-3 and SCF) in irradiated human peripheral blood mononuclear cells (PBMCs) in vitro, and the survival effect of lethally irradiated C3H mice in vivo. The irradiation of human PBMCs using a (137)Cs irradiator showed a dose-dependent inhibition of cell growth up to a dose of 5 Gy. This cell growth inhibition induced apoptosis, which was associated with the down-regulation of Bcl-2, up-regulation of Bax, depolarization of mitochondrial transmembrane potential (Delta psi m), and caspase-3 and -9 activation. Following gamma-irradiation at 2 Gy, IL-3 (10 ng/ml) alone or combined with SCF (50 ng/ml) reduced the apoptotic portion of human PBMCs by 15 and 20% of the cell population, respectively, showing no activation of caspase-3 compared to the control group. To examine the in vivo effect of gamma-irradiation and cytokines, we investigated the survival rate and recovery of peripheral blood cells in C3H mice. C3H mice subjected to total body irradiation (TBI) at a dose of 7 Gy (lethal dose 83% at 30 days) showed time-dependent decreases in RBC, WBC and platelet counts, with the nadir occurring at 12 to 15 days. However, treatment with recombinant murine (rm) SCF (2 microg/day s.c.), rmIL-3 (2 microg/day s.c.), or rmG-CSF (2.5 microg/day s.c.) 24 h before and after irradiation did not promote hematologic recovery or survival in the lethally irradiated C3H mice. These findings indicate that the combined treatment of IL-3 and SCF prevents the apoptosis induced in PBMCs by gamma-irradiation in vitro, but it does not afford any in vivo radioprotective effect in lethally irradiated C3H mice.
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PMID:Radioprotective effects of various cytokines in peripheral blood mononuclear cells and C3H mice. 1587 Sep 40

p21(waf 1/cip 1) (p21), best known for its ability to regulate the cell cycle, has been noted also to exert cell cycle-independent effects on apoptosis and differentiation. Inhibition of apoptosis by p21 has been reported in hematopoietic models, particularly in monocytes exposed to apoptogenic agents. The effect of p21 on survival has not hitherto been analyzed during the myeloblast to granulocyte transition. Using 32 Dc l3 murine myeloblasts, a cell line that proliferates in IL-3 and differentiates in G-CSF, we studied the effects of forced expression of p21 on cell survival. We hypothesized that exogenous p21 would suppress the modest levels of cell death associated with G-CSF-mediated differentiation of 32 Dc l3 cells. Contrary to expectations, we found that exogenous p21 enhanced apoptosis of cells removed from IL-3. The p21 overexpression led to decreased cell growth, caspase-3 activation and annexin positivity. These effects occurred only in the presence of G-CSF. These findings suggest that p21 is proapoptotic in granulopoiesis, and that this effect is masked by IL-3-mediated survival signals. Our results also indicate there are distinct and opposing effects of p21 on monocytic and granulocytic survival. Aberrantly high levels of p21 may contribute to disease processes involving excessive apoptosis of granulocyte precursors.
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PMID:A proapoptotic function of p21 in differentiating granulocytes. 1594 39


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