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)

By GenBank database searches and PCR, we have identified a novel human Bcl2-like gene, Bcl2-L-10, which contains conserved BH4, BH1 and BH2 domains but lacks BH3 domain. The Bcl2-L-10 gene has been assigned to chromosome 15q21.2. Transfection experiments demonstrated that Bcl2-L-10 can block apoptosis induced by interleukin-3 withdrawal and Bax expression, by prevention of cytochrome C release, caspase-3 activation and mitochondrial membrane potential collapse. Bcl2-L-10 cannot block TNFalpha-induced apoptosis. Furthermore, both the BH4 domain and the transmembrane domain of Bcl2-L-10 are necessary for its suppressive action on cell death. Our results demonstrated that Bcl2-L-10 is a newly detected anti-apoptotic member of the Bcl-2 family and that it blocks apoptosis in the mitochondrial death pathway but not in the death receptor pathway.
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PMID:Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. 1168 80

Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable. Mitochondrial cytochrome c release and activation of caspase-9 accompanied DN-HNF-1 alpha-induced apoptosis, suggesting the involvement of the mitochondrial apoptosis pathway. Activation of caspases was preceded by mitochondrial hyperpolarization and decreased expression of the anti-apoptotic protein Bcl-xL. Transient overexpression of Bcl-xL was sufficient to rescue INS-1 cells from DN-HNF-1 alpha-induced apoptosis. Both WT- and DN-HNF-1 alpha-expressing cells demonstrated similar increases in apoptosis when cultured at high glucose (25 mm). In contrast, induction of DN-HNF-1 alpha highly sensitized cells to ceramide toxicity. In cells cultured at low glucose, DN-HNF-1 alpha induction also caused up-regulation of the cell cycle inhibitor p27(KIP1). Therefore, our data indicate that increased sensitivity to the mitochondrial apoptosis pathway and decreased cell proliferation may account for the progressive loss of beta-cell function seen in MODY 3 subjects.
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PMID:Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. 1172 85

The aim of this study was to determine whether hypoxic-ischemia from asphyxial cardiac arrest activates brain caspases-1 and -3, and the anti-apoptotic protein, XIAP. Asphyxial cardiac arrest in rats was used to induce hypoxic-ischemia. A pan-caspase inhibitor (zVAD) was given in the treatment group. At 72 h after reperfusion, caspase-3 and XIAP expression were present in multiple vulnerable brain regions, whereas caspase-1 was predominantly found in the CA1 hippocampus. zVAD significantly reduced expression of caspases and XIAP and the number of ischemic neurons in the CA1 hippocampus while neurological deficit scores were improved. We conclude that hypoxic-ischemia increases caspases-1 and-3, and XIAP expression. Treatment with zVAD significantly decreases caspase and XIAP expression in these brain regions and improves neurological outcome.
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PMID:Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats. 1172 87

We studied the effect of DW2282-,[(S)-(+)-4-phenyl-1-[N-(4-aminobenzoyl)-indoline-5-sulfonyl-4,5-dihydro-2-imidazolone].hydrochloride], a newly developed anti-cancer agent, on cell proliferation, cell cycle progression, and induction of apoptosis in human promyelocytic leukemia (HL-60) cells. DW2282, a diarylsulfonylurea compound, was cytotoxic to HL-60 cells, with an IC(50) of 1.0 microg/mL. Treatment with DW2282 fragmented DNA in a concentration- and time-dependent manner, suggesting that these cells underwent apoptosis. Flow cytometric analysis further confirmed that DW2282-treated HL-60 cells were hypodiploid, in terms of DNA content, and were arrested at the G(2)/M phase. The cell cycle arrest was reversible upon the removal of DW2282. HL-60 cells also underwent distinct morphological changes in response to DW2282 treatment, including the appearance of elongated cells with conical tails and other apoptotic characteristics. G(2)/M phase cell cycle arrest was accompanied by a decrease in the levels of cdc2, a protein that plays a critical role for progression through the G(2)/M phase. Treatment of HL-60 cells with DW2282 was also associated with decreased levels of the anti-apoptotic protein Bcl-2, activation of caspase-3, and proteolytic cleavage of poly(ADP-ribose) polymerase. Taken together, these results demonstrate that DW2282 dramatically suppressed HL-60 cell growth by inducing apoptosis after G(2)/M phase arrest. These findings are consistent with the possibility that G(2)/M phase arrest was mediated by the down-regulation of cdc2 levels in HL-60 cells. The data also suggest that DW2282 triggered apoptosis by decreasing Bcl-2 levels and activating caspase-3 protease. These results provide important new information towards understanding the mechanisms by which DW2282 and other diarylsulfonylureas mediate their therapeutic effects.
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PMID:Induction of G(2)/M phase arrest and apoptosis by a new synthetic anti-cancer agent, DW2282, in promyelocytic leukemia (HL-60) cells. 1172 80

Seven structurally related flavonoids including luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin were used to study their biological activities on the human leukemia cell line, HL-60. On MTT assay, wogonin, baicalein, apigenin, myricetin and fisetin showed obvious cytotoxic effects on HL-60 cells, with wogonin and fisetin being the most-potent apoptotic inducers among them. The cytotoxic effects of wogonin and fisetin were accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including DNA fragmentation, apoptotic bodies and the sub-G1 ratio. Treatment with an apoptosis-inducing concentration of wogonin or fisetin causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity. Further, cleavage of poly(ADP-ribose) polymerase (PARP) and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated HL-60 cells. An increase in the pro-apoptotic protein, bax, and a decrease in the anti-apoptotic protein, Mcl-1, were detected in fisetin- and wogonin-treated HL-60 cells. However, Bcl-2, Bcl-XL, and Bad all remained unchanged in wogonin- and fisetin-treated HL-60 cells. In vitro chromatin digestion revealed that endonuclease activity was profoundly enhanced in wogonin- and fisetin-treated HL-60 cells, and the addition of ethylenediaminetetraacetic acid (EDTA) or ethyleneglycoltetraacetic acid (EGTA) into the reaction blocked endonuclease activation and at an optimum pH of 7.5. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated wogonin- and fisetin-induced DNA ladders, PARP cleavage, and endonuclease activation. Pretreatment of HL-60 cells with N-acetyl-cysteine or catalase efficiently inhibited H(2)O(2) (200 microM)-induced apoptosis, but showed no inhibitory effect on wogonin- and fisetin-induced DNA ladders, caspase 3 activation, or bax protein induction. Decrease in endogenous ROS production was detected in wogonin- and fisetin-treated HL-60 cells by DCHF-DA assay. In conclusion, our experiments indicate that a decrease in intracellular peroxide level was involved in wogonin- and fisetin-induced apoptosis; activation of caspase 3 and endonuclease, induction of bax protein and suppression of Mcl-1 protein were detected in the process.
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PMID:Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. 1184 97

Senescent or aged endothelial cells in culture remain metabolically active after cessation of division, and are generally believed to eventually die. However, mechanisms underlying the terminal aging of cultured cells, i.e. from senescence to death, are poorly understood. Here, we report that culturing of replicative senescent endothelial cells for a prolonged period of time without passaging leads to enhanced programmed cell death or apoptosis. Senescent (passage 45) and young (passage 3) porcine pulmonary artery endothelial cells (PAEC) were cultured for 0-42 days post confluence. The cells attached to culture dishes and floating in medium were collected at 0, 7, 14, 21, 28, 35 and 42 days post confluence and were assessed for markers of apoptosis. Morphology studies showed that ratios between senescent and young cells attached to dishes declined to 45% after 42 days postconfluence. Apoptotic cells in prolonged cultures of senescent PAEC increased from 5 to 35% as determined by protein mass, DNA breakage, and caspase-3 activation. Steady state levels of Bcl-2, an anti-apoptotic protein, in senescent prolonged cultures decreased to less than 20% for all time points compared with young cells. Relative levels of Bad, a pro-apoptotic protein, in senescent cells were elevated from 60 to 130% during prolonged culturing. These results indicate that terminal cellular aging enhances apoptosis and the levels of Bcl-2/Bad may be associated with the apoptotic process in porcine lung endothelial cells.
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PMID:Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. 1185 25

Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of pro-caspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acid-mediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras.
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PMID:The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. 1198 84

We have investigated the expression and function of a novel protein encoded by open reading frame (ORF) K7 of Kaposi's sarcoma-associated herpesvirus (KSHV). Computational analyses revealed that K7 is structurally related to survivin-DeltaEx3, a splice variant of human survivin that protects cells from apoptosis by an undefined mechanism. Both K7 and survivin-DeltaEx3 contain a mitochondrial-targeting sequence, an N-terminal region of a BIR (baculovirus IAP repeat) domain and a putative BH2 (Bcl-2 homology)-like domain. These suggested that K7 is a new viral anti-apoptotic protein and survivin-DeltaEx3 is its likely cellular homologue. We show that K7 is a glycoprotein, which can inhibit apoptosis and anchor to intracellular membranes where Bcl-2 resides. K7 does not associate with Bax, but does bind to Bcl-2 via its putative BH2 domain. In addition, K7 binds to active caspase-3 via its BIR domain and thus inhibits the activity of caspase-3. The BH2 domain of K7 is crucial for the inhibition of caspase-3 activity and is therefore essential for its anti-apoptotic function. Furthermore, K7 bridges Bcl-2 and activated caspase-3 into a protein complex. K7 therefore appears to be an adaptor protein and part of an anti-apoptotic complex that presents effector caspases to Bcl-2, enabling Bcl-2 to inhibit caspase activity. These data also suggest that survivin-DeltaEx3 might function by a similar mechanism to that of K7. We denote K7 as vIAP (viral inhibitor-of-apoptosis protein).
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PMID:Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin. 1203 73

We studied the effect of momordin I, a compound purified from a plant, Ampelopsis japonica, on cell proliferation and induction of apoptosis in human promyelocytic leukemia (HL-60) cells. Momordin I was cytotoxic to HL-60 cells with an IC50 of 19.0 microg/ml. The antiproliferative effects of momordin I appear to be attributable to its induction of apoptotic cell death, as momordin I induced nuclear morphology changes and internucleosomal DNA fragmentation and it increased the proportion of hypodiploid cells. Momordin I treatment also gradually decreased the expression of.the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic protein Bax. In addition, momordin I treatment increased the activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase. In this study we showed that momordin I induced apoptosis of HL-60 cells by reduction of the Bcl-2:Bax ratio and by activation of caspase-3. These results provide important information towards understanding the mechanism by which momordin I induces apoptosis.
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PMID:Induction of apoptosis by momordin I in promyelocytic leukemia (HL-60) cells. 1216 88

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in our daily diet, induces apoptosis in cultured immunocytes. In this study, Trp-P-1 (1 mg/kg) was injected intraperitoneally into male Wistar rats to investigate whether Trp-P-1 induces apoptosis in immune tissues in vivo. In the thymus, Trp-P-1 induced DNA fragmentation and morphological changes. Trp-P-1 also activated the initiator and executioner caspases, caspase-8 and -3, respectively, and activated caspase-3 in turn cleaved its intracellular substrate poly(ADP-ribose) polymerase 1 hr after injection. On the other hand, Trp-P-1 upregulated anti-apoptotic factors Bcl-2 and Bcl-XL and downregulated pro-apoptotic factor Bax in mitochondria 1 hr after injection, indicating that Trp-P-1 also stimulated anti-apoptotic signals. Trp-P-1 activated the serine-threonine protein kinase Akt, which is known to be an anti-apoptotic protein, and increased the DNA binding activities of apoptosis-associated transcription factors NF-kappaB and AP-1. In addition to the thymus, increases in the activities of these transcription factors were also observed in the spleen and in mononuclear cells from the blood. Therefore, Trp-P-1 activates both pro- and anti-apoptotic signals in vivo in the immune system, particularly in the thymus, and the former signal overcomes the latter.
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PMID:Apoptosis in the thymus after intraperitoneal injection of rats with Trp-P-1. 1235 51


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