Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxol is an antineoplastic agent with significant activity against ovarian as well as breast cancer. To investigate mechanisms by which taxol exerts its cytotoxic action, taxol-induced apoptosis, characterized by morphologic changes and internucleosomal DNA fragmentation, was examined in a human ovarian tumor cell line. Time-dependent morphologic changes, characteristic of apoptosis, were observed over the same time as the appearance of internucleosomal DNA fragmentation. The specific protein tyrosine kinase inhibitors genistein and herbimycin A, and the ATP depletion agent sodium azide, interfered with taxol-induced DNA fragmentation and clonal cell death. Based on a quantitative reverse transcription-polymerase chain reaction technique, bcl-2 alpha oncogene expression was decreased in conjunction with taxol-induced DNA fragmentation, and this decrease could be blocked by genistein. These results strongly implicate protein tyrosine phosphorylation as an event that mediates apoptosis and, thus, the antitumor activity of taxol in ovarian cancer.
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PMID:Evidence for involvement of tyrosine phosphorylation in taxol-induced apoptosis in a human ovarian tumor cell line. 794 20

Intact nuclei derived from murine metastatic large-cell lymphoma and human chronic myelogenous leukemia cells were digested to discrete subchromatin deoxyribonucleoprotein/ribonucleoprotein precursor complexes by treatment with Msp-I. The resultant complexes were composed of nucleoproteins (NPs) that were isolated and purified by two-dimensional isoelectric focusing/sodium dodecylsulfate polyacrylamide gel electrophoresis (2D-SDS-PAGE), electroelution from the gel, and removal of SDS by extractigel chromatography. Various NPs purified by 2D-SDS-PAGE were examined for the presence of oncogenes and tissue-specific genes using a dot-blot hybridization technique. The RNA polymerase products of NPs were labeled, purified, and subsequently used in a back-hybridization assay to identify transcripts for particular genes. By utilizing a 2D-SDS-PAGE Southwestern technique in parallel with the dot-blot and RNA back-hybridization assays, we assessed whether it is possible to "track" a gene and its associations in particular NPs. In patients with chronic myelogenous leukemia, we screened approximately 1000 NPs for bcl-2 sequences and found them present in a single NP of apparent M(r) approximately 19,000, pI approximately 5.5. In murine RAW117-H10 cells transformed by the abl oncogene, we found by Western analysis that an antigen cross-reacting with abl antigen was localized to a p53 gene-containing NP of apparent M(r) approximately 22,000, pI approximately 7.2. A coincident Southwestern experiment using the same blot showed that the abl gene was bound by the same NP. The techniques described present the basis for "tracking" a particular gene to individual NPs and studying its relationship to other genes, their respective gene products, and its binding properties with particular NPs.
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PMID:Nucleoprotein complexes from metastatic cells containing oncogenes and tissue-specific genes: a novel method to track genes associated with specific nucleoproteins. 816 4

1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl-2 can frequently prevent apoptotic changes and/or delay cell death. 2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl-2 can control. Our hypothesis is that apoptosis is used as an anti-viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself. 3. Experiments on the effect of sodium azide upon growth factor-dependent cells support this idea. Bcl-2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells. 4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub-lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.
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PMID:Hypothesis: apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular pathogens. 859 45

Cell death is an important physiological process, but it can be triggered by both physiological and nonphysiological stimuli. The product of the bcl-2 gene has the ability to inhibit a physiological cell death process that can be activated by a variety of physiological signals, such as growth factor deprivation. This report describes the use of electron microscopy to examine the effects of two cytotoxic drugs on factor-dependent cells that constitutively express the human bcl-2 gene. Although all cells treated with sodium azide showed changes typical of necrosis, in the absence of Bcl-2 the cells died more rapidly and also displayed features of apoptosis. The fact that Bcl-2 could delay cell death argues that cells can activate internal cell death mechanisms to commit suicide before they are killed by a cytotoxin. Northern analysis showed that growth factor did not preserve viability of the cells through induction of bcl-2. However, growth factor may prevent activation of the physiological cell death mechanisms that bcl-2 can control. This process may constitute a primitive defense response, and blocking it may provide a means of limiting damage caused by otherwise sublethal injuries.
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PMID:Activation of physiological cell death mechanisms by a necrosis-causing agent. 874 13

The Fas/Apo-1 molecule is a member of tumor necrosis factor/nerve growth factor (TNF/NGF) receptor family and is able to induce apoptosis in various type of malignant cells, including most of the human leukemia T-cells. We previously demonstrated that the Fas-resistant variants may exist in highly Fas-sensitive human leukemia T-cell lines. The surface expression of Fas antigen was unchanged in the variant cells, suggesting the requirement of the cytoplasmic mechanism to exert apoptosis. In the present study, we examined the changes in cytoplasmic proteins of the Fas-sensitive and Fas-resistant cells after stimulation with anti-Fas antibody, 2D1. In Western blotting analysis, we found that the stimulation of Fas-sensitive cells with 2D1, but not resistant variants, induced a repression of cyclin-dependent kinases (cdks), p34cdc2 and p33cdk2, along with apoptosis. There was no alteration in the expression of bcl-2, HSP70, HSP90, and cyclin proteins examined. This observation seemed specific to Fas-mediated apoptosis, because calcium ionophore A23187 or sodium azide failed to repress the expression of cdks. These results indicate that the specific depletion of cdks, most likely due to proteolysis, may play a role in Fas-mediated apoptosis.
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PMID:Selective depletion of cyclin-dependent kinases is associated with Fas-mediated apoptosis in human leukemia T-cell lines. 878 21

Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 micrograms/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 micrograms/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W7 (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death.
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PMID:Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. 895 Jan 93

Cytokine-mediated cell death in tumor cells can be achieved through endogenous nitric oxide (NO) from within tumor cells or exogenous NO from either activated macrophages or endothelial cells. The purpose of this study was to determine the role of Bcl-2 in NO-mediated apoptosis. The incubation of murine L929 and NIH3T3 cells with interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma) induced high endogenous NO production only in the L929 cells that also underwent apoptosis. NIH3T3 cells were not resistant to NO-mediated apoptosis. In fact, the incubation of L929 and NIH3T3 cells with exogenous NO derived from NO donors, sodium nitroprusside, or S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced death, characterized by typical apoptotic morphology and DNA fragmentation, in both cell types, but to a higher degree in NIH3T3 cells than in the L929 cells. We then measured the effect of Bcl-2 expression on exogenous NO-induced apoptosis. At both the mRNA and protein levels, L929 fibroblasts expressed higher levels of endogenous mouse Bcl-2 than did NIH3T3 cells. At the same time, L929 cells were much more resistant to exogenous NO-induced cell death than were NIH3T3 cells. The inverse correlation between mouse Bcl-2 expression and sensitivity to exogenous NO-mediated cell death was also found in the murine K-1735 melanoma C-23 and X-21 clonal populations. Transfection of both NIH3T3 cells and L929 cells with the human bcl-2 gene led to resistance to both exogenous and endogenous NO-mediated apoptosis. These data demonstrate that NO-mediated apoptosis can be suppressed by expression of Bcl-2, suggesting that abnormal expression of Bcl-2 may influence the efficacy of tumor immunotherapy.
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PMID:Bcl-2 protects cells from cytokine-induced nitric-oxide-dependent apoptosis. 895 45

The aim of this study was to determine the antiproliferative activity of sodium phenylacetate (NaPa) against ovarian carcinoma cell lines. NaPa induced a dose-dependent inhibition (IC50 from 12 mM to >20 mM) of all ovarian carcinoma cell lines, although the sensitivity of individual lines to NaPa varied. Both cisplatin-sensitive and -resistant cell lines responded to NaPa, and growth-inhibitory activity was also detected against cells freshly isolated from malignant ascites of previously treated patients. The growth inhibitory effects that were produced by NaPa were time dependent, showing a maximum effect at 72 h, and were not associated with cytotoxic action. Growth inhibitory effects of NaPa were also reversible. After 48- and 72-h exposures to NaPa, a reduction in the percentage of cells in the S-phase was detected, with a concomitant recruitment of cells in the G0-G1 phase. Treatment with NaPa after different exposure times did not significantly increase the proportion of cells undergoing apoptosis. NaPa also produced a significant reduction in the percentage of cyclin-D1- and p21/ras-positive cells and in the percentage of cells positive for bcl-2, whereas the percentages of bax/p21-positive cells increased. NaPa produced minimal, if any, alterations of expression of HLA class I and transforming growth factor beta1 antigens. In contrast, the percentage of transforming growth factor beta2-positive cells decreased after exposure to NaPa. The combination of NaPa with cisplatin resulted in an additive inhibitory effect. Our results show, for the first time, that NaPa inhibits the growth of ovarian carcinoma cell lines and the cells from malignant ascites of chemotherapy-treated patients with ovarian carcinoma. The growth-inhibitory properties of NaPa suggest that this molecule could represent a prototype of a new class of compounds with possible therapeutic potential in patients with ovarian carcinoma.
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PMID:Growth inhibitory effects of sodium phenylacetate (NSC 3039) on ovarian carcinoma cells in vitro. 933 Oct 92

Aberrant expression of apoptosis-related genes, including the "cell death suppressor gene" bcl-2, may play an important pathogenetic role in cancer and autoimmune diseases, In vivo upregulation of bcl-2 mRNA in synovial lining cells of patients with rheumatoid arthritis but not in patients with osteoarthritis has been recently found. In the present study we investigated whether agents exerting beneficial effects in patients with rheumatoid arthritis, namely the long used Gold Sodium Thiomalate (GST) and the novel immunosuppressive, purine analogue 2-chlorodeoxyadenosine (2-CdA), a lymphocyte apoptosis-inducing agent interfere directly with induction of bcl-2 mRNA expression. The phytohemagglutinin (PHA)-induced in vitro proliferation of normal human peripheral blood lymphocytes was significantly inhibited by non-toxic concentrations of 2-CdA and GST which are within the range of in vivo plasma concentrations in patients receiving the respective treatment. Using mRNA dot-blot analysis and hybridization with an IL-2-specific probe we found that GST, similarly to dexamethasone that served as control, suppressed the PHA-induced IL-2 mRNA accumulation dose-dependently. In contrast, 2-CdA (0.1 microgram/ml) at concentrations that inhibit by 80-90% the PHA-induced proliferative responses of lymphocytes did not affect IL-2 mRNA accumulation. Hybridization with a bcl-2-specific probe showed that the activation-induced accumulation and kinetics of bcl-2 mRNA were not changed in the presence of a wide range of concentrations of either GST or 2-CdA. Similarly, the mRNA accumulation of the "house-keeping" control gene beta-action remained unchanged by both agents. These findings indicate that biosynthesis of bcl-2 is not specifically affected by GST and CdA, suggesting that the immunomodulating effects of these agents, including their efficacy in suppressing chronic arthritis, are not related with a bcl-2-dependent mechanism.
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PMID:Effects of 2-chlorodeoxyadenosine and gold sodium thiomalate on human bcl-2 gene expression. 954

We have demonstrated that sodium butyrate induces differentiation in human hepatoma cells; however, recent studies have shown that this agent causes apoptosis in some types of cancer cells. In this study, we examined whether sodium butyrate causes apoptosis in the human hepatoma cell lines, HCC-M and HCC-T. The growth of human hepatoma cells was dose-dependently reduced by sodium butyrate. Flow cytometric analysis showed cell-cycle arrest at the G1 phase in the sodium butyrate-treated cells. Apoptotic change was never found in treated cells at concentration levels of less than 5 mmol/L. Sodium butyrate decreased p53 expression and increased p21WAF-1 expression in HCC-T and HCC-M cells having the wild-type p53 gene. Western blot analysis showed that Bcl-2 was expressed in the HCC-T and HCC-M cells, and its expression was increased after exposure to sodium butyrate. Antisense oligodeoxynucleotide against bcl-2 easily caused apoptosis. These results indicate that sodium butyrate hardly induces apoptotic change in the human hepatoma cell lines, HCC-T and HCC-M, with the increase of Bcl-2 expression. Cell-cycle arrest in the G1 phase caused by sodium butyrate was suggested to be induced by the increase in p21WAF-1 expression, but this change did not link with the p53 increase.
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PMID:Loss of butyrate-induced apoptosis in human hepatoma cell lines HCC-M and HCC-T having substantial Bcl-2 expression. 958 76


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