Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

Overexpression of the proto-oncogene bcl-2 has been shown to protect a variety of cell types from oxidative and non-oxidative injury, blocking apoptotic and necrotic types of cell death. Retroviral vectors were used to stably overexpress bcl-2 in primary murine astrocyte cultures with more than 95% efficiency. Compared to beta-galactosidase-expressing and uninfected control cells, bcl-2 overexpressing astrocytes suffered < 40% injury after 24 h glucose deprivation, while controls were essentially completely injured. After exposure to 0.2 mM hydrogen peroxide, the bcl-2 overexpressing astrocytes suffered < 40% the injury seen in controls. In contrast, when the cultures were injured by combined oxygen-glucose deprivation, no difference in the extent or time course of injury was found between cells overexpressing bcl-2 and those expressing beta-galactosidase. To investigate one possible mechanism of bcl-2 protection, we measured the levels of glutathione and three antioxidant enzymes. Astrocytes overexpressing bcl-2 had elevated glutathione levels (130-200%), increased superoxide dismutase (170%) and glutathione peroxidase (140%) activities compared with beta-galactosidase-expressing controls. Bcl-2 overexpressing astrocytes suffered less lipid peroxidation after glucose deprivation, as assessed by cis-parinaric acid fluorescence, and demonstrated more rapid removal of hydrogen peroxide from the medium. When glutathione levels were decreased 80% by pretreatment with buthionine sulfoximine, the extent of protection from glucose deprivation of bcl-2 overexpressing cells was decreased by about half. Increased antioxidant defence contributes to protection from glucose deprivation in bcl-2 overexpressing astrocytes.
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PMID:Potentiation of murine astrocyte antioxidant defence by bcl-2: protection in part reflects elevated glutathione levels. 974 79

Recent studies indicate that arsenic may generate reactive oxygen species to exert its toxicity. However, the mechanism is still unclear. In this study, we demonstrate that arsenite is able to induce apoptosis in a concentration- and time-dependent manner; however, arsenate is unable to do so. An increase of intracellular peroxide levels was accompanied with arsenite-induced apoptosis, as demonstrated by flow cytometry using DCFH-DA. N-Acetyl-L-cysteine (a thiol-containing antioxidant), diphenylene iodonium (an inhibitor of NADPH oxidase), 4,5-dihydro-1,3-benzene disulfonic acid (a selective scavenger of O2-), and catalase significantly inhibit arsenite-induced apoptosis and intracellular fluorescence intensity. In contrast, allopurinol (an inhibitor of xanthine oxidase), indomethacin (an inhibitor of cyclooxygenase), superoxide dismutase, or PDTC had no effect on arsenite-induced cell death. Activation of CPP32 activity, PARP (a DNA repair enzyme) degradation, and release of cytochrome c from mitochondria to the cytosol are involved in arsenite-induced apoptosis, and Bcl-2 antagonize arsenite-induced apoptosis by a mechanism that interferes in the activity of CPP32. These results lead to a working hypothesis that arsenite-induced apoptosis is triggered by the generation of hydrogen peroxide through activation of flavoprotein-dependent superoxide-producing enzymes (such as NADPH oxidase), and hydrogen peroxide might play a role as a mediator to induce apoptosis through release of cytochrome c to cytosol, activation of CPP32 protease, and PARP degradation.
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PMID:Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. 976 29

Bax, a member of the Bcl-2 gene family, is known to promote apoptosis in many cases but to block cell death under certain conditions. To investigate the potential role of Bax in 6-hydroxydopamine (6-OHDA)-induced cell death, we first established and characterized a dopaminergic neuronal cell line (MN9D) stably overexpressing hemagglutinin epitope-tagged Bax (MN9D/HA-Bax) as well as control clones (MN9D/Neo). Treatment of MN9D/Neo cells with 6-OHDA induced typical apoptotic cell death accompanied by shrinkage of the cell, nuclear condensation, and DNA fragmentation as demonstrated by light microscopy and agarose gel analysis. Overexpression of HA-Bax in MN9D cells was shown to attenuate 6-OHDA-induced cell death as determined by the MTT reduction assay and agarose gel analysis for DNA fragmentation. Western blot analysis revealed that cleavage of poly(ADP-ribose)polymerase induced by 6-OHDA was attenuated in MN9D/HA-Bax cells. In contrast, overexpression of a well-known cell death-inhibiting protein such as Bcl-2 or Bcl-XL did not attenuate 6-OHDA-induced cell death. Interestingly, cell death induced by hydrogen peroxide (0.25-2.0 mM) was significantly accelerated, whereas the rate of cell death induced by menadione (10-50 microM) was not affected in MN9D/HA-Bax cells. Thus, our present data suggest that the functionally diverse roles of Bax may be determined by the type of stress applied to the cell.
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PMID:Overexpression of HA-Bax but not Bcl-2 or Bcl-XL attenuates 6-hydroxydopamine-induced neuronal apoptosis. 987 80

It is now generally accepted that massive neuronal death due to oxidative stress is a regular feature of brains in neurodegenerative diseases. However, much less attention has been given to the death of glial cells. In this study, we examined p53-sensitive apoptosis of cells by using human glioblastoma A172 cells and p53-deficient mouse astrocytes. In human A172 cells, hydrogen peroxide (H2O2) caused cell death in a time- and concentration-dependent manner, accompanied by nucleosomal DNA fragmentation and chromatin condensation. After treatment with H2O2, p53 protein was highly expressed and protein levels of Bak, p21WAF1/CIP1 and GADD45 were also enhanced. However, the protein levels of Bcl-2 and Bax did not change. On the other hand, primary cultured astrocytes from p53-deficient mouse brain grew faster than wild-type and heterozygous astrocytes. In addition, p53-deficient astrocytes were more resistant to H2O2-induced apoptosis than wild-type and heterozygous astrocytes. These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53-induced p21WAF1/CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53-induced Bak.
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PMID:Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells. 989 Jun 30

Stable transfectants of PC12 cells expressing bcl-2 or crmA were generated and tested for their susceptibility to various apoptotic insults. Bcl-2 expression conferred resistance to apoptosis induced by staurosporine and by oxidative insults including hydrogen peroxide and peroxynitrite, but was less effective in inhibition of activation-induced programmed cell death induced by concanavalin A. Concanavalin A-induced apoptosis was abated, however, in cells expressing very high levels of bcl-2. In contrast, cells expressing crmA were protected from concanavalin A-induced apoptosis, but were as susceptible as control cells to apoptosis induced by staurosporine and oxidative insults. Therefore, at least two apoptotic pathways in PC12 cells can be discerned by their differential sensitivity to blockade by bcl-2 and crmA. The ability of beta-amyloid (Abeta) to induce apoptosis in these cells was assessed. CrmA transfectants were protected from apoptosis induced by Abeta1-42, but only cells expressing very high levels of bcl-2 were similarly protected. These results suggest that the apoptotic pathway activated by Abeta1-42 in PC12 cells can be differentiated from the apoptotic pathway activated by oxidative insults. Gene transfer experiments also demonstrated that expression of crmA in primary cultures of hippocampal neurons is protective against cell death induced by Abeta1-42. Together these results support the hypothesis that Abeta-induced apoptosis occurs through activation-induced programmed cell death.
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PMID:Multiple pathways of apoptosis in PC12 cells. CrmA inhibits apoptosis induced by beta-amyloid. 989 Sep 71

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p561ck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential delta psi(m) and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-kappaB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-kappaB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-kappaB-dependently upregulated in the presence of H2O2.
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PMID:Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. 998 25

Protein phosphorylation in a human glioblastoma cell line, T98G, was examined after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of focal adhesion kinase (FAK) and serine phosphorylation of Akt at 1 h after stimulation. Concommitantly, the association of FAK with phosphatidylinositide 3'-OH-kinase (PI 3-kinase) was also observed by the hydrogen peroxide stimulation. When T98G cells were incubated with wortmannin, a PI 3-kinase inhibitor, both PI 3-kinase activity and phosphorylation of Akt were inhibited, whereas apoptosis by oxidative stress was accelerated. Concomitant with apoptosis, elevated level of CPP32 protease activity (caspase-3) was observed, with decreases in Bcl-2 protein and increases in Bax protein. These results suggested that in the signal transduction pathway from FAK to PI 3-kinase, Akt promotes survival. Thus, it became apparent that FAK is the upstream signal protein of the PI 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis in T98G cells.
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PMID:FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. 1018 51

During development, excess neurons are produced about half of which die. The time of cell death (apoptosis) is limited to the period of formation of synapses with the target cells, and the neurons which fail to obtain sufficient amounts of trophic factor(s) released from the target cells are eliminated. This selection system is considered to be a mechanism to ensure formation of a physiologically relevant neuronal network. Mature neurons which correctly execute their functions, however, undergo apoptosis in response to exogenous toxic stimuli. Such stimuli may be responsible for neurodegenerative diseases. The mechanism underlying cell death has been analyzed using in vitro model systems. In the present communication, we used cultured rat cerebellar granule neurons, in which low potassium concentration (LK+) in the medium induces apoptosis, and this apoptosis is prevented by high concentration of potassium (HK+), BDNF. One of the lipid-modifying kinases, phosphatidylinositol 3-kinase (PI3-K), is also activated by trophic factors including neurotrophins. BDNF and high K+ prevented low K(+)-induced apoptosis via PI3-K. BDNF also promotes the survival of basal forebrain cholinergic neurons cultured from postnatal 2-week-old (P2w) rats. The mechanism of neuronal apoptosis induced by oxidative stress using CNS neurons and PC12 cells was investigated, and we found that generation of reactive oxygen species (ROS) is highly associated with apoptosis. High oxygen induced neuronal apoptosis, which was blocked by protein or RNA synthesis inhibitors. Neurotrophic factors and Bcl-2 prevented this apoptotic cell death. Exposure to hydrogen peroxide, lipid hydroperoxide or serum deprivation triggered apoptosis associated with increased generation of ROS as determined using a ROS-specific fluorescent probe. In cultured cerebellar granule neurons from 15-day-old wild-type and p53-deficient mice, we examine the role of p53 in regulating the life and death of CNS neurons. When exposure of gamma-ray or bleomycin to neurons died in p53 dependent manner. These neuronal deaths were partially prevented by actinomycin D or cycloheximide. The pycnotic nuclei observed in these dying neurons indicated that cell death occurs via apoptosis. Although there are many evidences that p53 is involved in apoptosis in proliferating cells, it is interesting that p53 is also involved in apoptosis in postmitotic neurons as shown in this study.
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PMID:[Neuroprotection by neurotrophic factors in apoptosis]. 1019 Jan 24

Thyrocytes, that generate and use hydrogen peroxide (H2O2) to synthesize thyroid hormones, undergo apoptosis, as do most cell types, when exposed in vitro to H2O2. We have studied 1) the kinetics and the amplitude of the apoptotic response to H2O2 and 2) the relationship between the extent of the apoptosis-inducing effect of H2O2, the H2O2 degradation activity, and the level of expression of apoptosis regulatory proteins, Bcl-2 and Bax, in pig thyrocytes in primary culture. Cells were seeded at high density to obtain confluent monolayers and were cultured in the presence of TSH to maintain the expression of differentiation. H2O2 (10-300 microM) induced the appearance of cells with fragmented DNA (terminal transferase deoxy-UTP-fluorescein isothiocyanate nick end labeling-positive cells) at a maximum of 3-4 h after H2O2 addition and then the detachment of apoptotic cells from the cell monolayer. The proportion of detached cells increased with H2O2 concentration and amounted to up to 30% of the initial cell number after 24 h. The transient effect of H2O2 was related to its rapid degradation by cells and culture medium components (rate constant, approximately 0.1 min(-1)). Iterative additions of H2O2 produced cumulative apoptotic waves. The amplitude of the apoptotic response of thyrocytes to H2O2 progressively increased with the time of culture, up to 4-fold from days 1-8. This was not related to a change in the capacity of thyrocytes to degrade H2O2. During the same period of culture, the Bcl-2 cell content progressively decreased, whereas that of Bax concomitantly increased; thus, the Bcl-2/Bax ratio varied from about 6 on day 1 to 0.5 on day 10. These data show that the susceptibility of thyrocytes to undergo apoptosis increases with the time of culture and that the pronounced changes in the apoptotic status ofthyrocytes might be linked to coordinate modifications of the level of expression of pro- and antiapoptotic regulatory proteins.
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PMID:Susceptibility of differentiated thyrocytes in primary culture to undergo apoptosis after exposure to hydrogen peroxide: relation with the level of expression of apoptosis regulatory proteins, Bcl-2 and Bax. 1021 46


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