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)

The mechanism by which Bcl-2 inhibits apoptosis is unknown. One proposal is that Bcl-2 regulates intracellular Ca2+ fluxes thought to mediate apoptosis. In the present study, we investigated Bcl-2's mechanism of action by determining the effect of Bcl-2 on intracellular Ca2+ fluxes in the WEHI7.2 mouse lymphoma cell line, which does not express Bcl-2, and its stable transfectant, W.Hb12, which expresses a high level of Bcl-2. Treatment with the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin produced marked alterations in intracellular Ca2+ homeostasis in both WEHI7.2 and W.Hb12 cells, including elevation of free cytosolic Ca2+, endoplasmic reticulum Ca2+ pool depletion, capacitative entry of extracellular Ca2+, and increased loading of Ca2+ into mitochondria. Similar changes in intracellular Ca2+ occurred spontaneously in both cell lines following exponential growth. In both situations, W.Hb12 cells maintained optimal viability despite marked alterations in intracellular Ca2+, whereas WEHI7.2 cells underwent apoptosis. Treatment with the glucocorticoid hormone, dexamethasone, induced apoptosis in WEHI7.2 cells, but not in W.HB12 cells, even though dexamethasone treatment did not alter intracellular Ca2+ homeostasis in either cell line. These findings indicate that Bcl-2 acts downstream from intracellular Ca2+ fluxes in a pathway where Ca(2+)-dependent and Ca(2+)-independent death signals converge.
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PMID:Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells. 884 14

The human T lymphoma cell line Hut78 was transfected with Bel-2 gene or with control G418 Neomycin resistance-conferring plasmid. Bcl-2 transfected and Neomycin selected Hut78 cells expressed about ten-fold greater Bcl-2 protein than the neo-transfected controls. Susceptibility of Bcl-2-transfected Hut78 cells to human NK cells, human mixed lymphocyte reaction-generated cytotoxic effector cells, and mouse cytotoxic spleen cells generated by immunization with Hut78 cells was examined. In all systems tested, Bcl-2-transfected Hut78 target cells were significantly less susceptible to lysis than the neo-transfected control target cells. These results suggest that in Hut78 cells, Bcl-2 gene product may confer partial resistance to different types of cytotoxic effector mechanisms.
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PMID:Bcl-2 transfection protects Hut78 cell line from different types of cytotoxic effector cells. 890 2

We examined the effects of a cell-permeable ceramide analog, C2-ceramide, on the growth of TNF-alpha-resistant B lymphoma Raji cells lacking TNF-alpha-receptors (TNF-R). C2-ceramide inhibited the clonal growth of not only TNF-alpha-sensitive myeloid leukemia cells (HL60 and U937) but also Raji cells. Following stimulation with C2-ceramide, HL60 and U937 cells showed apoptotic cell death, whereas Raji cells did not show a detectable level of apoptosis. However, a cell-cycle arrest in G0/G1 phase was observed in Raji cells after the treatment with C2-ceramide, which was accompanied by the dephosphorylation of retinoblastoma (RB) gene products and decreased expression of p53 proteins. Failure of C2-ceramide to induce apoptosis in Raji cells might be explained by the lack or low expression of apoptosis-inducing proteins by two lines of evidence: (1) Raji cells were resistant to apoptosis induced by ceramide even in the presence of transcription/translation inhibitors; (2) Bax protein expression was not detectable in Raji cells, although Bcl-2 protein expression in Raji cells was even less than that in HL60 and U937 cells. Moreover, protein kinase C (PKC), whose activation has been described to inhibit ceramide-induced apoptosis, inhibitor H-7 did not induce apoptotic cell death in Raji cells, suggesting that an imbalance between PKC and ceramide pathways is not the reason for the resistance of Raji cells against ceramide-induced apoptosis. Finally, ceramide-induced activation of nuclear factor kappaB (NF-kappaB) was observed in Raji cells as well as HL60 cells, indicating that activation of this molecule may not be specific for apoptosis. By using the present model, one can dissect cell-cycle arrest and apoptosis induced by ceramide.
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PMID:Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-alpha-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. 894 36

Mouse malignant T-lymphoma CS-21 cells grow in vitro in the presence of CA-12 lymph node stromal cells, but they undergo apoptotic cell death when separated from CA-12 stromal cells. In the course of examining the nursing effects of CA-12 stromal cells, we found that these cells provided some soluble factors that suppressed CS-21 cell apoptosis. We recently found that cysteine was an antiapoptotic soluble factor. In this report, we identify interleukin-7 (IL-7) as another antiapoptotic soluble factor secreted by CA-12 stromal cells. Although the activity of CPP32-like protease was increased in induction of CS-21 cell apoptosis, the addition of IL-7 suppressed the activity. The expression of Bcl-2 protein was down-regulated when CS-21 cells were cultured alone, but the addition of IL-7 recovered the expression of Bcl-2. These results indicate that CA-12 stromal cells inhibit CS-21 cell apoptosis by producing IL-7, which leads to the suppression of CPP32-like protease activation and the expression of Bcl-2 protein.
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PMID:Interleukin-7 inhibits apoptosis of mouse malignant T-lymphoma cells by both suppressing the CPP32-like protease activation and inducing the Bcl-2 expression. 895 Sep 80

The aim of this study was to investigate the changes involved in the evolution of nine cases of recurrent B-cell lymphomas. Using the polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded tissue from both the primary and the recurrent lymphoma of each case, monoclonality was demonstrated in every tumour. In all nine cases, the recurrent lymphoma was shown to belong to the same clone as the primary lymphoma. Eight of these cases were then investigated by immunohistochemistry for changes in Bcl-2 and p53 expression. Five out of eight of the primary lymphomas showed Bcl-2 overexpression. Two of the three cases initially negative for Bcl-2 expression became positive in the recurrence. One out of eight of the primary lymphomas was positive for p53 expression. Of the seven negative cases, one became positive for p53 expression in the recurrence. Both of the p53-positive cases showed high-grade histology. This study shows that Bcl-2 overexpression is probably an important early event in the development of B-cell lymphomas, although it may occur as a post-neoplastic event. p53 mutation is probably more important as a late event and may be associated with high-grade transformation.
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PMID:Changes in Bcl-2 and p53 expression in recurrent B-cell lymphomas. 895

RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) treatment of murine EL4 T lymphoma cells induced the cells to undergo apoptosis. After 48 hours of VES treatment at 20 micrograms/ml, 95% of cells were apoptotic. Evidence for the induction of apoptosis by VES treatments is based on staining of DNA for detection of chromatin condensation/fragmentation, two-color flow-cytometric analyses of DNA content, and end-labeled DNA and electrophoretic analyses for detection of DNA ladder formation. VES-treated EL4 cells were blocked in the G1 cell cycle phase; however, apoptotic cells came from all cell cycle phases. Analyses of mRNA expression of genes involved in apoptosis revealed decreased c-myc and increased bcl-2, c-fos, and c-jun mRNAs within three to six hours after treatment. Western analyses showed increased c-Jun, c-Fos, and Bcl-2 protein levels. Electrophoretic mobility shift assays showed increased AP-1 binding at 6, 12, and 24 hours after treatment and decreased c-Myc binding after 12 and 24 hours of VES treatment. Treatments of EL4 cells with VES+RRR-alpha-to-copherol reduced apoptosis without effecting DNA synthesis arrest. Treatments of EL4 cells with VES+rac-6-hydroxyl-2, 5,7,8-tetramethyl-chroman-2-carboxylic acid, butylated hydroxytoluene, or butylated hydroxyanisole had no effect on apoptosis or DNA synthesis arrest caused by VES treatments. Analyses of bcl-2, c-myc, c-jun, and c-fos mRNA levels in cells receiving VES + RRR-alpha-tocopherol treatments showed no change from cells receiving VES treatments alone, implying that these changes are correlated with VES treatments but are not causal for apoptosis. However, treatments with VES + RRR-alpha-tocopherol decreased AP-1 binding to consensus DNA oligomer, suggesting AP-1 involvement in apoptosis induced by VES treatments.
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PMID:RRR-alpha-tocopheryl succinate inhibits EL4 thymic lymphoma cell growth by inducing apoptosis and DNA synthesis arrest. 897 Jan 89

We have investigated the ability of several drugs commonly used in the treatment of human cancer to induce bcl2 phosphorylation and cell death in human cell lines derived from acute leukemia, lymphoma, breast cancer, and prostate cancer. The results of this analysis indicate that drugs affecting the integrity of microtubules induce bc12 phosphorylation, whereas anticancer drugs damaging DNA do not. Comparison of the effects of taxol and its analogue, taxotere, indicates that taxotere is capable of inducing bcl2 phosphorylation and apoptotic cell death at 100-fold lower concentrations than taxol. Induction of cancer cell death through phosphorylation of bcl2 thus provides an opportunity not only for more refined targeting of therapeutic drugs but for understanding of an important pathway leading to apoptosis. Phosphorylation of bcl2 in drug-treated cancer cells occurs in G2-M, the phase of the cell cycle in which this class of drugs is active. No induction of bcl2 phosphorylation occurs in chronic lymphocytic leukemia cells that overexpress bcl2 but are blocked at G0-G1. Thus, prevention of polymerization or depolymerization of cellular microtubules by this class of cancer therapeutic drugs causes phosphorylation of bcl2, abrogating the normal antiapoptotic function of bcl2 and initiating the apoptotic program in the cycling cancer cells; these results are consistent with a normal physiological role of bcl2 as "guardian of microtubule integrity."
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PMID:Bcl2 is the guardian of microtubule integrity. 900 May 60

Bcl-x is a Bcl-2-family protein that has been previously detected in cortical thymocytes, plasma cells, and activated lymphocytes. We report here on the high detection rate of the Bcl-x protein found in 86% of Hodgkin's disease samples and on the significance regarding its complex role among the Bcl-2-family of proteins: Bcl-x is known to heterodimerize with Bcl-2 (an anti-apoptosis protein) and with Bax, a potent inducer of cell death. Moreover, recent evidences show that Bcl-x may induce multiple drug resistance in vitro, suggesting that chemical or biological interactions with this protein may have potential therapeutic value in Hodgkin's disease.
Leuk Lymphoma 1996 Sep
PMID:Bcl-x gene expression in Hodgkin's disease. 902 97

Many factors involved in the proliferation of myelomas have been reported, and the relationship between these factors and the pathogenesis of multiple myeloma has been discussed. We found that most myeloma cells express Fas antigen/APO-1 (CD95), a cell surface antigen that mediates apoptosis. However only some cells are sensitive to anti-Fas antibody and undergo apoptosis. These data indicate that some multiple myelomas are generated not only by cell proliferation but also by cell immortalization. The mechanism by which myelomas are immortalized is still unclear, but Bcl-2, Bcl-xL, adult T cell leukemia derived factor (ADF), soluble Fas are all candidate factors for this mechanism. The possibility also exists that inducers of apoptosis, e.g. tumor necrosis factor(TNF), interleukin-1 beta-converting enzyme(ICE), Bcl-xS, or Bax, do not have a lethal effect. In this review, we focus on the system that immortalizes myeloma cells, and suggest the possibility that multiple myeloma constitutes one group of cells which cannot undergo apoptosis in the bone marrow.
Leuk Lymphoma 1996 Nov
PMID:Fas antigen/APO-1 (CD95) expression on myeloma cells. 903 Oct 82

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.
Leuk Lymphoma 1996 Oct
PMID:Chlorambucil in chronic lymphocytic leukemia: mechanism of action. 903 Oct 99


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