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

The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. The importance of both positive and negative regulators of cell growth has been well documented in neoplasia. Bcl-2 argues for the existence of a new category of oncogenes, regulators of cell death. The bcl-2 gene was identified at the chromosomal breakpoint of t(14; 18) bearing B cell lymphomas. Bcl-2 has proved to be unique among protooncogenes in blocking programmed cell death rather than promoting proliferation. In adults, bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress bcl-2 in the B cell lineage demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development and display relatively normal haematopoietic differentiation but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two potentially oxidation related pathologies: polycystic kidney disease and hair hypopigmentation. A family of bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with bcl-2. A pre-set ratio of Bcl-2/Bax appears to determine the survival or death of cells following an apoptotic stimulus.
 ...
PMID:Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. 814 17

The proto-oncogene bcl-2 inhibits apoptotic and necrotic neural cell death. Expression of Bcl-2 in the GT1-7 neural cell line prevented death as a result of glutathione depletion. Intracellular reactive oxygen species and lipid peroxides rose rapidly in control cells depleted of glutathione, whereas cells expressing Bcl-2 displayed a blunted increase and complete survival. Modulation of the increase in reactive oxygen species influenced the degree of cell death. Yeast mutants null for superoxide dismutase were partially rescued by expression of Bcl-2. Thus, Bcl-2 prevents cell death by decreasing the net cellular generation of reactive oxygen species.
 ...
PMID:Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. 823 59

1-beta-D-Arabinofuranosylcytosine (ara-C) is an anti-leukemic agent that incorporates into cellular DNA leading to inhibition of DNA synthesis and loss of clonogenic survival. In contrast, ionizing radiation induces DNA damage through the generation of reactive oxygen intermediates. Although little is known of the specific determinants of ara-C and ionizing radiation-induced cytotoxicity, recent work has shown that both are capable of inducing internucleosomal DNA fragmentation in a pattern consistent with programmed cell death (apoptosis). In order to assess the importance of apoptosis in drug and ionizing radiation-induced cytotoxicity in the U-937 myelomonocytic cell line, we created cell lines that constitutively express a transfected bcl-2 gene. Bcl-2 was capable of inhibiting 40-50% of the ara-C and ionizing radiation-induced internucleosomal DNA fragmentation at all tested concentrations. However, cell survival following exposure to these agents was only increased in the bcl-2 transfectants at relatively low doses of ara-C and ionizing radiation. These data demonstrate that although bcl-2 is capable of inhibiting ara-C and ionizing radiation-induced DNA fragmentation in myeloid cells, it increases cell survival only at low doses of these agents. This suggests that apoptosis may be a less important mechanism of cytotoxicity at higher doses of ara-C and ionizing radiation than it is at lower doses.
 ...
PMID:Effect of Bcl-2 on ionizing radiation and 1-beta-D-arabinofuranosylcytosine-induced internucleosomal DNA fragmentation and cell survival in human myeloid leukemia cells. 826 Jul 51

Apoptosis is a genetically encoded programme of cell death that can be activated under physiological conditions and may be an important safeguard against tumour development. Regions of low oxygen (hypoxia) and necrosis are common features of solid tumours. Here we report that hypoxia induces apoptosis in oncogenically transformed cells and that further genetic alterations, such as loss of the p53 tumour-suppressor gene or overexpression of the apoptosis-inhibitor protein Bcl-2, substantially reduce hypoxia-induced cell death. Hypoxia also selects for cells with defects in apoptosis, because small numbers of transformed cells lacking p53 overtake similar cells expressing wild-type p53 when treated with hypoxia. Furthermore, highly apoptotic regions strongly correlate with hypoxic regions in transplanted tumours expressing wild-type p53, whereas little apoptosis occurs in hypoxic regions of p53-deficient tumours. We propose that hypoxia provides a physiological selective pressure in tumours for the expansion of variants that have lost their apoptotic potential, and in particular for cells acquiring p53 mutations.
 ...
PMID:Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. 860 Mar 76

Previous studies have demonstrated that overexpression of the proto-oncogene bcl-2 can protect neuron and neuron-like cell lines from growth factor deprivation, calcium ionophores, glutamate excitotoxicity, hypoglycemia, free radicals, and lipid peroxidation. To determine whether Bcl-2 exhibits a similar protective effect in CNS neurons, we generated defective herpes simplex virus (HSV) vectors capable of overexpressing Bcl-2 in primary cultures and in the intact brain. Infection of hippocampal cultures with Bcl-2 vectors enhanced neuron survivorship after exposure to adriamycin, a potent oxygen radical generator. Furthermore, dichlorofluorescein measurements indicated that there was a significant reduction in the accumulation of oxygen radicals associated with this insult. Bcl-2 vectors also enhanced survival in cultured neurons after exposure to glutamate and hypoglycemia. Most significantly, the in vivo delivery of the vector protected neurons against adriamycin toxicity in the dorsal horn of the dentate gyrus and focal ischemia in the striatum.
 ...
PMID:Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. 855 33

Several putative functions have been attributed to the peripheral benzodiazepine receptor (PBR), but its precise physiologic role has not been elucidated. In the present study, we investigated PBR function by quantifying this receptor in leukocyte subsets from healthy donors and in leukemic blasts from lymphoid and myeloid lineages. Using a monoclonal antibody (MoAb) directed against the human PBR and a quantitative flow cytometric assay, we found that phagocytic cells from healthy donors displayed a higher level of PBRs than lymphocytes or natural killer (NK) cells. Among the lymphoid lineage, thymocytes and IgD-negative B cells expressed the lowest levels. However, because of the wide heterogeneity of PBR levels among 42 acute or chronic lymphoid and myeloid leukemias, it was not possible to assign PBR expression to a stage of maturation or a cell lineage. Although the PBR displayed a mitochondrial subcellular localization, its expression was not correlated with the mitochondrial content, suggesting a modulation of PBR density at the level of the mitochondria. This modulation was confirmed when we studied in detail the PBR expression during T-cell development by both flow cytometry and confocal microscopy. We found that the PBR was expressed with a bimodal profile during T-cell development, identical to the one observed with the proto-oncogene, Bcl-2. The high similarity in the expression of both the PBR and the Bcl-2 proto-oncogene in T-cell and B-cell subsets, their common mitochondrial localization, and the observation of high quantities of PBR in phagocytic cells, which are known to produce high levels of radical oxygen species, suggested that PBRs may participate in an antioxidant pathway. Indeed, a strong correlation was established between the ability of hematopoietic cell lines to resist H202 cytotoxicity and their level of PBR expression. Demonstration of the role of PBR in the protection against H202 was obtained by transfecting JURKAT cells with the human PBR cDNA. Transfected cells exhibited increased resistance to H202 compared with wild-type cells, suggesting that PBR may prevent mitochondria from radical damages and thereby modulate apoptosis in the hematopoietic system.
 ...
PMID:Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical damage. 860 31

Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium, salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB --> methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the beta-hydroxylase enzyme system itself.
 ...
PMID:Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells. 861 Nov 83

The C. elegans gene product ced-9 inhibits programmed cell death by negatively regulating the death-mediating protease ced-3. The mammalian homolog of ced-9 is the oncoprotein Bcl-2. Overexpression of Bcl-2 spares mammalian and nematodal cells from dying and prevents ectopic cell death in ced-9 loss-of-function mutants. Although Bcl-2 has been shown to act as an antioxidant under certain conditions, additional functions have emerged from studies under low oxygen pressure. Here we show that Bcl-2 overexpression impairs activation of the interleukin-1beta converting enzyme-related death protease CPP32/Yama/apopain, the mammalian homolog of ced-3. When U937 monocytes undergo programmed cell death in response to tumor necrosis factor alpha, the inactive CPP32 precursor is cleaved into its active forms. As a consequence poly(ADP ribose) polymerase, a major substrate of CPP32, is faithfully cleaved into a 85 kD fragment. Bcl-2 overexpressing cells are protected from tumor necrosis factor alpha-induced death and display neither CPP32 maturation nor PARP cleavage. The inhibitory effect of Bcl-2 on CPP32 activation is indirect since no physical interaction between the two proteins could be detected. These results indicate that Bcl-2 neutralizes an unknown cellular activator of CPP32 to save cells from programmed cell death.
 ...
PMID:Bcl-2 overexpression blocks activation of the death protease CPP32/Yama/apopain. 861 57

Bcl-2 overexpression has been shown to be protective against apoptosis induced by a variety of mechanistically diverse chemotherapeutic drugs. Recently, oxygen radical species have been implicated in the process of apoptosis, and Bcl-2 has been proposed to exert its protective effect by altering the redox state of the cell. Unlike most other chemotherapeutic agents, naturally occurring enediynes are rendered more cytotoxic in the presence of a higher reducing potential, because as prodrugs, they require reduction for activation. We demonstrate herein that induction of Bcl-2 expression in PC12 cells potentiates the induction of apoptosis and differentiation by the enediyne neocarzinostatin. In contradistinction, Bcl-2 abrogates the induction of apoptosis and differentiation by the autoactivating enediyne, enediyne-5, and the non-enediyne chemotherapeutic agent, cisplatin. We further demonstrate that enediyne potentiation by Bcl-2 is related to an increase in cellular glutathione. The present studies suggest that enediynes that require reductive activation might be critically useful agents in the therapy of tumors such as neuroblastomas and estrogen-responsive breast cancers, the resistance of which is related to up-regulation of Bcl-2.
 ...
PMID:Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2. 864 Jul 97

The mechanism by which Bcl-2 inhibits apoptosis is unknown. The Bcl-2 protein is localized to intracellular membranes, including the endoplasmic reticulum (ER). The ER is the major intracellular reservoir of Ca2+ in non-muscle cells, sequestering Ca2+ for use in intracellular signaling, and is a prime target of oxidative damage. Because of the recent suggestion that Bcl-2 acts in an antioxidant pathway, we wondered whether Bcl-2 might protect the ER Ca2+ pool in cells exposed to reactive oxygen species. To test this hypothesis, we assessed the effect of hydrogen peroxide (H2O2) treatment on the ER Ca2+ pool in WEH17.2 cells, which do not express Bcl-2, and two stable transfectants, W.Hb13 and W.Hb12. The Bcl-2 level by Western blotting is 4-fold higher in W.Hb12 cells compared to W.Hb13 cells. The ER Ca2+ pool in H2O2-treated and untreated cells was measured according to the amount of Ca2+ mobilized from the ER lumen into the cytoplasm by thapsigargin (TG), a selective inhibitor of the ER (Ca2+)-ATPase. H2O2 treatment produced a significant reduction in the TG-mobilizable Ca2+ pool in WEH17.2 and W.Hb13 cells, but not in W.Hb12 cells, indicating that overexpression of Bcl-2 preserves the integrity of the ER Ca2+ pool in cells exposed to reactive oxygen species.
 ...
PMID:Bcl-2 inhibits hydrogen peroxide-induced ER Ca2+ pool depletion. 866 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>