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)

Recent reports have implicated a possible role of reactive oxygen species (ROS) in the induction and mediation of apoptosis and DNA damage. Oxidative DNA base modification induced by cupric nitrilotriacetate (Cu-NTA) and the following apoptosis were observed in human promyelocytic leukemia HL-60 cells. We measured the level of ROS in the cells by using a fluorescence probe, 2',7'-dichlorofluorescein diacetate (DCFH-DA), and the amount of a modified DNA base, 8-hydroxydeoxyguanosine (8-OHdG) by HPLC-ECD. It was found that Cu-NTA exposure significantly enhanced ROS and 8-OHdG formation in the cells. Meanwhile, we observed both DNA fragmentation and morphological changes characteristic of apoptosis, which was also determined quantitatively by flow cytometry and showed dose- and time-dependent manners. Furthermore, several antioxidants such as dimethyl sulfoxide (DMSO), superoxide dismutase (SOD), and catalase were used to detect whether the apoptosis could be blocked. Only DMSO protected against this form of cell death. To elucidate molecular events in the apoptosis, expressions of Bcl-2 protein family members, such as Bcl-2, Bcl-X and Bax, and heat shock protein 70 (HSP-70) were measured by western blotting using specific antibodies. The levels of Bax and Bcl-Xs remained largely unchanged, but the Bcl-2 and Bcl-XL expression showed down-regulation. After 24 h incubation in the presence of copper, the levels of Bcl-2 and Bcl-XL reduced about 33.8% and 51.1% compared with untreated cells, respectively. Furthermore, after 16 h incubation, the level of HSP-70 expression was about 3.4-fold greater than that in untreated cells, suggesting that HSP-70 is important in increasing resistance to oxidative stress induced by Cu-NTA. But overexpression of HSP-70 failed to protect HL-60 cells from apoptosis induced by Cu-NTA. We inferred that Cu-NTA may induce oxidative DNA damage through free radical injuries, which may turn on the apoptosis in HL-60 cells.
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PMID:Cupric nitrilotriacetate induces oxidative DNA damage and apoptosis in human leukemia HL-60 cells. 974 94

Electroporation is a widely applied method for gene or protein transfer into cells, and it is also used for electrochemotherapy of cancer. During gene transfection studies, electroporation was found to decrease transiently susceptibility of some tumor cell lines to alloreactive cytotoxic T lymphocytes (CTL) or lymphokine-activated killer (LAK) cells. In each cell line electroporation induced c-fos mRNA. In K562 cells HSP70 mRNA induction also occurred. Expression of Grp78, Bcl-2, CD95/Fas, or major histocompatibility complex class I molecules was not affected by electroporation.
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PMID:Reduced susceptibility of electroporated tumor cell lines to killing by cytotoxic lymphocytes. 975 17

Tobacco smoke (TS) has been implicated as a major risk factor in human pulmonary diseases including cancer. In this study, we used TS as a model of oxidative stress. TS-mediated oxidative stress has been shown to induce protein oxidation, DNA damage, and cell death. Here we investigated, in human and rodent cell lines, whether TS induces cell death by apoptosis or by necrosis. As described for classic oxidants, TS induced apoptosis at low concentrations and necrosis at higher concentrations. We have previously described the induction of heat shock (HS) protein (HSP) (in particular, HSP70) in human monocytes exposed to TS. HSP70 is implicated in the regulation of cell injury and cell death and, in particular, modulates apoptosis, as does the antiapoptotic oncoprotein Bcl-2. At both apoptotic and necrotic concentrations, TS induced a dose-dependent HSP70 expression, whereas Bcl-2 was induced only at necrotic concentrations. TS- or HS-induced HSP had no protective effects either on apoptosis or on necrosis, but HSP70 overexpression prevented TS-induced necrosis and consequently led to increased apoptosis. These results might reconcile the apparently contradictory data previously reported on the effects of HSP on apoptosis.
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PMID:Tobacco smoke induces both apoptosis and necrosis in mammalian cells: differential effects of HSP70. 975 10

Food restriction can extend life span in rodents and was recently reported to increase the resistance of neurons in the brain to excitotoxic and metabolic insults. In principle, administration to ad libitum fed rodents of an agent that reduces glucose availability to cells should mimick certain aspects of food restriction. We now report that administration of 2-deoxy-D-glucose (2DG), a non-metabolizable analog of glucose, to adult rats results in a highly significant reduction in seizure-induced spatial memory deficits and hippocampal neuron loss. Pretreatment of rat hippocampal cell cultures with 2DG decreases the vulnerability of neurons to excitotoxic (glutamate) and oxidative (Fe2+) insults. The protective action of 2DG is associated with decreased levels of cellular oxidative stress and enhanced calcium homeostasis. 2DG treatment increased levels of the stress-responsive proteins GRP78 and HSP70 in hippocampal neurons, without affecting levels of Bcl-2 or GRP75, suggesting that mild reductions in glucose availability can increase neuronal resistance to oxidative and metabolic insults by a mechanism involving induction of stress proteins. Our findings establish cell culture and in vivo models of "chemical food restriction" which may prove useful in elucidating mechanisms of neuroprotection and in developing preventive approaches for neurodegenerative disorders that involve oxidative stress and excitotoxicity.
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PMID:2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins. 1039 35

Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
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PMID:Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. 1041 43

GRP94 is a 94-kDa chaperone glycoprotein with Ca(2+)-binding properties. We report here that during apoptosis induced by the topoisomerase II inhibitor etoposide, a fraction of GRP94 associated with the endoplasmic reticulum membrane undergoes specific proteolytic cleavage, coinciding with the activation of the caspase CPP32 and initiation of DNA fragmentation. In vivo, inhibitors of caspases able to block etoposide-induced apoptosis can only partially protect GRP94 from proteolytic cleavage, whereas complete inhibition is observed with calpain inhibitor I but not with the proteasome inhibitor. In vitro, GRP94 is not a substrate for CPP32; rather, it can be completely cleaved by calpain, a Ca(2+)-regulated protease. The cleavage of GRP94 by calpain is Ca(2+)-dependent and generates a discrete polypeptide of 80 kDa. In contrast, calpain has no effect on other stress proteins such as GRP78 or HSP70. Further, immunohistochemical staining reveals specific co-localization of GRP94 with calpain in the perinuclear region following etoposide treatment. We further showed that reduction of GRP94 by antisense decreased cell viability in etoposide-treated Jurkat cells. Our studies provide new evidence that the cytoprotective GRP94, as in the case of the antiapoptotic protein Bcl-2, can be targets of proteolytic cleavage themselves during the apoptotic process.
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PMID:The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. 1049 10

Fas-induced apoptosis is one form of programmed cell death responsible for hepatocyte demise. However, the role of this cell surface receptor in the death of tumoral hepatic cells is still being debated. It has been shown that some hepatoma cell lines may escape apoptosis because of abnormal Fas localization correlated with non-functionality of the Fas protein or dysfunctionality in the Fas pathway cascade. The aim of this study was to investigate the behaviour of four hepatoma cell lines, HepG2, Hep3B, SKHep1 and Chang-Liver and two extrahepatic cell lines, MCF7, a mammary tumoral cell line and OVCAR-3, an ovarian tumoral cell line, when they were treated with an agonistic anti-Fas antibody alone, with interferon gamma (IFNgamma), an up-regulator of Fas protein expression, alone or with a combination of both agents. We first performed immunofluorescence and flow cytometry to confirm that Fas was present on the cell surface of each cell line in the normal state. Apoptosis was then investigated after induction with the various treatments, by DAPI staining, agarose gel DNA electrophoresis and PARP cleavage. Caspase 8 and 3 expression, as well as two anti-apoptotic proteins Bcl-2 and HSP70, and one proapoptotic protein Bax were also investigated by immunoblot allowing identification of several apoptotic pathways based on the behaviour of the different studied proteins. HepG2 and OVCAR-3 cells were sensitive to the anti-Fas antibody alone. Hep3B was resistant to Fas-induced apoptosis but sensitive to IFNgamma-induced apoptosis. MCF7 was resistant to anti-Fas antibody and IFNgamma Chang-Liver and SKHep1 were sensitive to IFNgamma and anti-Fas antibody but at different degrees. Chang-Liver used the Fas and IFNgamma pathways, while SKHep1 involved mostly the Fas pathway. These results show that each tumor cell line is characterized by different apoptotic behaviour in relation to Fas and/or IFNgamma-induced apoptosis. In addition, despite the high level of Bcl-2 and HSP70 proteins in the tumoral cells investigated here, they were not fully protected against apoptosis, except for MCF7. This emphasizes the necessity to analyse the different proteins responsible for apoptosis to adapt anti-tumoral therapeutics.
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PMID:Apoptotic behaviour of hepatic and extra-hepatic tumor cell lines differs after Fas stimulation. 1072 68

Dysregulation of normal programmed cell death mechanisms plays an important role in the pathogenesis and progression of breast cancer, as well as in responses of tumors to therapeutic intervention. Overexpression of anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-X(L) has been implicated in cancer chemoresistance, whereas high levels of pro-apoptotic proteins such as Bax promote apoptosis and sensitize tumor cells to various anticancer therapies. Though the mechanisms by which Bcl-2 family proteins regulate apoptosis are diverse, ultimately they govern decision steps that determine whether certain caspase family cell death proteases remain quiescent or become active. To date, approximately 17 cellular homologs of Bcl-2 and at least 15 caspases have been identified in mammals. Other types of proteins may also modulate apoptotic responses through effects on apoptosis-regulatory proteins, such as BAG-1-a heat shock protein 70 kDa (Hsp70/Hsc70)-binding protein that can modulate stress responses and alter the functions of a variety of proteins involved in cell death and division. In this report, we summarize our attempts thus far to explore the expression of several Bcl-2 family proteins, caspase-3, and BAG-1 in primary breast cancer specimens and breast cancer cell lines. Moreover, we describe some of our preliminary observations concerning the prognostic significance of these apoptosis regulatory proteins in breast cancer patients, contrasting results derived from women with localized disease (with or without node involvement) and metastatic cancer.
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PMID:Prognostic significance of apoptosis regulators in breast cancer. 1073 84

Oxidized low density lipoproteins (OxLDLs) are believed to play a central role in atherogenesis and to possess a wide variety of biological properties; among them, OxLDLs are cytotoxic to cultured vascular cells in that they induce necrosis and apoptosis. Moreover, OxLDLs are known to induce the expression of heat shock protein 70 (Hsp70), a protein that protects cells from several cytotoxic stimuli. To determine whether Hsp70 can protect cells against OxLDL-induced cytotoxicity, COS-1 cells were transfected with a construct containing human Hsp70. A number of cell lines permanently expressing Hsp70 were obtained, 1 of which (cos-Hsp70/10, with high Hsp70 expression) was selected for further studies. Hsp70 overexpression protected cells from toxic stimuli, such as H(2)O(2), UV irradiation, and heat shock, suggesting that the overexpressed protein was functional. When incubated with OxLDLs, however, the clone overexpressing Hsp70 showed a significant decrease in viability, as determined by the [(3)H]adenine release assay (319.8+/-3.16% of control for transfected cells versus 217.6+/-6.08% for control cells exposed to 100 microgram protein/mL of OxLDL), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (12.5+/-0.9% versus 28.9+/-1.99% of control, respectively), and LDH release (48.4+/-0.04% versus 15.2+/-0.06% of control cells). The increased expression of BAX and the decreased expression of Bcl-2 (a proapoptotic and an antiapoptotic protein, respectively) in cos-Hsp70/10 cells and in control cells on incubation with OxLDLs suggested that overexpression of Hsp70 did not confer protection against apoptosis induced by OxLDLs. The analysis of nucleosome content and the nuclear staining with Hoechst 33258 confirmed this finding. These data suggest that overexpression of Hsp70 not only fails to protect COS-1 cells against OxLDL-induced apoptosis but rather confers a higher sensitivity to the cytotoxic action of these lipoproteins. Thus, the Hsp70 response, although induced by OxLDLs, cannot protect cells from lipoprotein toxicity.
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PMID:Overexpression of inducible heat shock protein 70 in Cos-1 cells fails to protect from cytotoxicity of oxidized ldls. 1123 13

Myocardial ischemia and reperfusion injury (MI/R) represents important sequelae of clinical events. Historically, a number of approaches including, surgical intervention, pharmacological therapy and physical exercise regimes have been prescribed for the treatment of patients with cardiovascular disease. Recently, however, attention has focused upon more novel approaches using gene-based therapies to treat cardiovascular and MI/R. This mini-review will examine the role that heat shock proteins (HSP), in particular the HSP70 family, and the antiapoptotic protein Bcl-2 play in myocardial protection. Also examined in this review are several techniques including adenovirus and Japan-Liposomal method for delivering genes into the myocardium.
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PMID:Gene therapy: a novel method for the treatment of myocardial ischemia and reperfusion injury--mini-review. 1139 69


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