Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the Bcl-2 protein family fall into two categories on the basis of their ability to either promote or suppress apoptosis. Recent findings have linked these proteins to caspases, the cysteine proteases that effect the collapse of the cell via binding to CED-4. It seems that Bcl-2 proteins influence cell survival by regulating the activation of key caspases.
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PMID:The Bcl-2 family and cell death regulation. 952 8

Beta-Lapachone a novel topoisomerase inhibitor, has been found to induce apoptosis in various human cancer cells. In this study we report that a dramatic elevation of hydrogen peroxide (H2O2) in human leukemia HL-60 cells following 1 microM beta-lapachone treatment and that this increase was effectively inhibited by treatment with antioxidant N-acetyl-L-cysteine (NAC), ascorbic acid, alpha-tocopherol. NAC strongly prevented beta-lapachone-induced apoptotic characteristics such as DNA fragmentation and apoptotic morphology. However, treatment of HL-60 cells with another topoisomerase inhibitor camptothecin (CPT) did not induce H2O2 production as compared to untreated cells. NAC also failed to block CPT-induced apoptosis. Correlated with these findings, we found that cancer cell lines K562, MCF-7, and SW620, contained high level of intracellular glutathione (GSH), were not elevated in H2O2 and were resistant to apoptosis after treatment with beta-lapachone. In contrast, cancer cell lines such as, HL-60, U937, and Molt-4 which have lower level of GSH, were readily increased of H2O2 and were sensitive to this drug. Furthermore, ectopic overexpression of Bcl-2 in HL-60 cells also attenuated beta-lapachone-induced H2O2 and conferred resistance to beta-lapachone-induced cell death. Beta-Lapachone at the concentration as low as 0.25 microM effectively induced HL-60 cells to undergo monocytic differentiation, as evidenced by CD14 antigenicity and alpha-naphthyl acetate esterase activity. Again, the beta-lapachone-induced monocytic differentiation was suppressed by NAC. These results suggest that intracellular H2O2 generation plays a crucial role in beta-lapachone-induced cell death and differentiation.
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PMID:Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone-induced apoptosis and differentiation in human leukemia cells. 955 79

Physiological cell deaths occur ubiquitously throughout biology and have common attributes, including apoptotic morphology with mitosis-like chromatin condensation and prelytic genome digestion. The fundamental question is whether a common mechanism of dying underlies these common hallmarks of death. Here we describe evidence of such a conserved mechanism in different cells induced by distinct stimuli to undergo physiological cell death. Our genetic and quantitative biochemical analyses of T- and B-cell deaths reveal a conserved pattern of requisite components. We have dissected the role of cysteine proteases (caspases) in cell death to reflect two obligate classes of cytoplasmic activities functioning in an amplifying cascade, with upstream interleukin-1beta-converting enzyme-like proteases activating downstream caspase 3-like caspases. Bcl-2 spares cells from death by punctuating this cascade, preventing the activation of downstream caspases while leaving upstream activity undisturbed. This observation permits an operational definition of the stages of the cell death process. Upstream steps, which are necessary but not themselves lethal, are modulators of the death process. Downstream steps are effectors of, and not dissociable from, actual death; the irreversible commitment to cell death reflects the initiation of this downstream phase. In addition to caspase 3-like proteases, the effector phase of death involves the activation in the nucleus of cell cycle kinases of the cyclin-dependent kinase (Cdk) family. Nuclear recruitment and activation of Cdk components is dependent on the caspase cascade, suggesting that catastrophic Cdk activity may be the actual effector of cell death. The conservation of the cell death mechanism is not reflected in the molecular identity of its individual components, however. For example, we have detected different cyclin-Cdk pairs in different instances of cell death. The ordered course of events that we have observed in distinct cases reflects essential thematic elements of a conserved sequence of modulatory and effector activities comprising a common pathway of physiological cell death.
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PMID:Commitment and effector phases of the physiological cell death pathway elucidated with respect to Bcl-2 caspase, and cyclin-dependent kinase activities. 956 10

The vanilloid compounds, capsaicin and resiniferatoxin, are quinone analogues that inhibit the NADH-plasma membrane electron transport system and induce apoptosis in transformed cells. Because disruption of the mitochondrial transmembrane potential (deltapsi(m)) is a common metabolic alteration in all apoptotic processes, we have evaluated the role of mitochondrial permeability transition in apoptosis induced by vanilloids in Jurkat cells. Using a cytofluorimetric approach, we have determined that DNA nuclear loss induced by vanilloids is preceded by an increase of the production of reactive oxygen species (ROS) and by a subsequent deltapsi(m) dissipation in T-cell lines. Overexpression of Bcl-2 and pretreatment with either the immunosuppressant cyclosporin A or the glutathione precursor N-acetyl-L-cysteine blocked deltapsi(m) disruption and apoptosis, but not the generation of ROS induced by these compounds. Capsaicin and resiniferatoxin were found to activate both isoforms of c-jun-NH2-kinase (JNK), with a maximal activity after 30 min of treatment. Despite the activation of JNK, there was no induction of activator protein 1 (AP-1) activity as determined by gel shift assay or of induction of an AP-1-responsive reporter. On the other hand, vanilloids did not signal for c-Raf kinase and extracellular signal-regulated kinases 1 and 2. We suggest that ROS generation by inhibition of the NADH-dependent plasma membrane electron transport system resulted in the oxidation of mitochondrial megachannel pores that allows for the disruption of deltapsi(m) and apoptosis, and that AP-1 activation is not required for vanilloid-induced apoptosis.
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PMID:Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. 958 Mar 28

To search for a Bcl-2 family homologue in the posterior silk gland of Bombyx mori, Western blot analysis was performed with the anti-rat Bcl-XL antiserum preabsorbed with a XL1-Blue MRF' lysate. The antiserum was shown to cross-react specifically with a silkworm protein of 80000 mol. wt (BmP80). The level of BmP80 increased dramatically during the spinning stage and decreased rapidly after the formation of a cocoon, implying that the silkworm protein was involved in histolysis of posterior silk gland as a stimulator. Screening a B. mori cDNA library with the same preabsorbed antiserum, a cDNA clone contaiing a cDNA fragment that is presumably large enough to encode the entire BmP80 protein was identified. The cDNA fragment contained 127 nucleotides (nt) of untranslated sequence at the 5' end, 2895nt of presumptive coding sequence and 625nt of untranslated sequence including a poly(A) tail at the 3' end. The calculated mol. wt of the presumptive protein (BmP109) was 108800. BmP109 shared sequence homology with the antiapoptotic proteins within the four conserved regions, BH1, BH2, BH3 and BH4, which were located at the C-terminal half of the protein and resided in the same characteristic order as Bcl-2 family proteins. Comparison of amino acid content revealed that BmP109 contained much more cysteine and lysine but less glycine and arginine than the antiapoptotic proteins. Northern blot analysis indicated that the mRNA for BmP109 is about 4.0kb. Reverse transcription-polymerase chain reaction experiments showed that the mRNA level for BmP109 increased dramatically during the spinning stage and decreased rapidly after formation of a cocoon, suggesting the involvement of transcriptional regulation.
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PMID:Molecular cloning of a cDNA encoding a silkworm protein that contains the conserved BH regions of Bcl-2 family proteins. 961 Dec 71

Caspases are aspartate-specific cysteine proteases that play a pivotal role in drug-induced cell death. We designed RT-PCR assays to analyse the expression of CASP-3, CASP-4, CASP-6 and the long and short isoforms of CASP-2 genes in human cells. These genes heterogeneously coexpress in leukemic cell lines and bone marrow samples from patients with de novo acute myelogenous leukemia at diagnosis. Treatment of U937 and HL60 leukemic cells and HT29 colon carcinoma cells with the topoisomerase II inhibitor etoposide upregulates CASP-2 and CASP-3 genes in these cells before inducing their apoptosis. This effect of etoposide is not observed in K562 cells and bcl-2-transfected U937 cells which are less sensitive to drug-induced apoptosis. Nuclear run-on experiments demonstrate that etoposide increases CASP gene transcription in U937 cells, an effect that is prevented by Bcl-2 overexpression. Upregulation of CASP genes is associated with an enhanced synthesis of related procaspases that precedes the appearance of apoptosis markers including caspase-3 activation, poly(ADP-ribose) polymerase cleavage and internucleosomal DNA fragmentation. These results suggest that the ability of tumor cells to upregulate CASP-2 and CASP-3 genes in response to cytotoxic drugs could be predictive of their sensitivity to drug-induced apoptosis.
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PMID:Upregulation of CASP genes in human tumor cells undergoing etoposide-induced apoptosis. 967 9

Numerous studies have demonstrated an association between polycyclic aromatic hydrocarbons (PAHs) and lymphocyte toxicity. The present study shows that, consistent with its effects on Ca2+ homeostasis, benzo[a]pyrene (BaP) induces apoptosis in Daudi cells. Terminal deoxynucleotidal transferase-mediated dUTP-biotin nick end labeling (TUNEL) analysis at 18 h revealed a significant increase in the number of cells undergoing apoptosis in response to BaP (75%), BaP-7, 8-dihydrodiol (110%), and BaP-7,8-9,10-diol epoxide (BPDE) (215%) over DMSO vehicle control cultures. By 36 h, the trend toward increasing numbers of apoptotic cells continued with the parent compound producing a 125% increase over control values and the 7, 8-dihydrodiol and BPDE metabolites producing 195% and 370% increases over controls, respectively. DNA fragmentation assays demonstrated the presence of internucleosomal cleavage products consistent with the increasing numbers of TUNEL-positive cells responding to PAHs at 18 and 36 h. Analysis of poly(ADP-ribose) polymerase (PARP) protein in BaP- and BaP-7,8-dihydrodiol-treated cells strongly suggested the involvement of cysteine proteases by the appearance of an 85-kD fragment derived from hydrolytic cleavage of PARP, a phenomenon that has been associated with apoptosis in many systems. Immunoblot analysis demonstrated that both BaP and its 7,8-dihydrodiol metabolite affected a pathway involving Bcl-2 and Bax cytosolic proteins. Daudi cells undergoing apoptosis at 36 h in response to 10 microM BaP, the parent compound, expressed moderately reduced amounts of Bcl-2 (78% of vehicle controls). At the same time point, the 7,8-dihydrodiol and BDPE metabolites at 3 microM resulted in Bcl-2 protein expression that was 52% of that seen in vehicle controls. Parallel samples analyzed for expression of Bax protein displayed a 130% increase over vehicle control in Bax expression in response to the parent compound, while the 7,8-dihydrodiol metabolite produced a 257% increase in Bax. Furthermore, the effects on increased Bax expression were observed as early as 3 h after PAH exposure. The apoptotic response to PAHs in Daudi cells was sensitive to 4-h pretreatment with 0.3 microM alpha-naphthoflavone (ANF), a known inhibitor of cytochrome P450. In TUNEL assays of cells exposed to PAHs following pretreatment with ANF, at 18 h there was a significant reduction in the number of cells undergoing apoptosis in response to ANF compared to cells that were not pretreated with the compound. The effect of the parent compound at 18 h was completely blocked with ANF pretreatment, while ANF exerted a relatively weaker, but significant, effect on BaP-7, 8-dihydrodiol-induced apoptosis. With regard to modulation of expression of apoptosis-related proteins, Bax expression was restored to that observed in vehicle-control cultures at all time points tested (3, 18, and 36 h). Bcl-2 expression was most responsive to ANF at later time points following PAH exposure (18 and 36 h); however, Bcl-2 appeared to be more sensitive to the effects of ANF alone. Taken together, these data suggest that modulation of Bcl-2 family proteins, perhaps secondary to altered Ca2+ homeostasis, plays an important role in human B cell apoptosis induced by BaP.
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PMID:Apoptosis in Daudi human B cells in response to benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol. 970 13

Activation of proteolytic enzymes, including the caspase family of proteinases, is a feature characteristic of the apoptotic program. In the present study, we examined a potential role of intracellular proteinases in the death of neuronal PC12 and primary cultured rat microglial cells induced by 6-hydroxydopamine (6-OHDA). In both neuronal PC12 and microglial cells, 6-OHDA (10-200 microM) induced apoptosis in a dose-dependent manner as judged by the DNA break. The 6-OHDA was ineffective in Bcl-2-overexpressing neuronal PC12 cells. Pretreatment of these cells with two caspase inhibitors, acetyl-Try-Val-Ala-Asp-aldehyde and acetyl-Asp-Glu-Val-Asp-aldehyde, prevented the 6-OHDA-induced apoptosis. Pepstatin A and leupeptin, potent inhibitors of aspartic and cysteine proteinases, respectively, partly inhibited the apoptosis of microglia but not neuronal PC12 cells. In contrast, GBR12935, a dopamine uptake inhibitor, significantly inhibited the apoptotic death of neuronal PC12 cells but not microglia. These results suggest that mechanisms by which 6-OHDA induces apoptosis in these two cell types are distinct; 6-OHDA incorporated into neuronal PC12 cells and its metabolites may activate the caspase-like enzymes, whereas oxidative metabolites of the agent produced extracellularly may activate the caspase and the endosomal/lysosomal proteolytic systems in microglia.
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PMID:Involvement of caspase-like proteinases in apoptosis of neuronal PC12 cells and primary cultured microglia induced by 6-hydroxydopamine. 978 80

We have defined an in vitro model for the study of microvascular endothelial cell (EC) apoptosis mediated by plasma from patients with various forms of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). This system reproduces a variety of histopathologic and ultrastructural features of tissue EC involved in TTP/sporadic HUS, suggesting that apoptotic EC injury is a primary pathophysiologic event in the thrombotic microangiopathies. We now document the ability of tetrapeptide-based inhibitors of interleukin 1beta-converting enzyme (ICE)-like caspase 1 and cysteine protease protein (CPP)-32-like caspase 3, two members of a novel class of cysteine proteases involved in final pathways to apoptosis, to block TTP/sporadic HUS plasma-mediated apoptosis. Overexpression of Bcl-X(L) via gene transfer suppressed this apoptosis by 70%. Transduction of EC with the Bcl-2 homolog A1 had a more limited protective effect. These findings support a role for apoptosis-linked cysteine proteases in the pathophysiology of TTP and sporadic HUS, and raise the possibility that specific apoptosis inhibitors may have a role in the experimental therapeutics of these syndromes.
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PMID:Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies. 984 Sep 8

The purpose of the present study was to study the mechanisms involved in the induction of apoptosis and by tributyltin (TBT) in rainbow trout hepatocytes, and to examine the role of intracellular Ca2+, protein kinase C (PKC) and proteases in the apoptotic process. The intracellular Ca2+ chelator BAPTA-AM has a suppressive effect on TBT-mediated apoptosis. However, exposure to the ionophore A23187 is not sufficient to induce apoptosis in trout hepatocytes. The results obtained also show that TBT stimulates PKC gamma and delta translocation from cytosol to the plasma membrane in trout hepatocytes after 30 min of exposure. However, PKC gamma translocation is down-regulated after 90 min of treatment. The addition of protein kinase inhibitors (staurosporine and H-7) not only fails to inhibit apoptosis induced by TBT, but also leads to enhancement of DNA fragmentation. These inhibitors also afford a remarkable protection against the loss of plasma membrane integrity caused by TBT exposure. PMA, a direct activator of PKC, fails to stimulate DNA fragmentation. In addition, Z-VAD.FMK is an extremely potent inhibitor of TBT-induced apoptosis in trout hepatocytes, indicating that the activation of ICE-like proteases is a key event in this process. The cysteine protease inhibitor N-ethylmaleimide also prevented TBT-induced DNA fragmentation. Taken together, these data allow for the first time to suggest a mechanistic model of TBT-induced apoptosis. We propose that TBT could trigger apoptosis through a step involving Ca2+ efflux from the endoplasmic reticulum or other intracellular pools and by mechanisms involving cysteine proteases, such as calpains, as well as the phosphorylation status of apoptotic proteins such as Bcl-2 homologues.
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PMID:Tributyltin triggers apoptosis in trout hepatocytes: the role of Ca2+, protein kinase C and proteases. 999 Feb 99


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