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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When the mammalian proto-oncogene bcl-2 is overexpressed it can protect various types of cells both from normal and from experimentally induced apoptosis, but the molecular mechanisms involved are unknown. Although the Bcl-2 protein is membrane-associated, its subcellular location is controversial: two studies have suggested that it is mainly associated with the nuclear envelope and endoplasmic reticulum, whereas another study has suggested that it is mainly located in the inner mitochondrial membrane. The latter study has suggested that Bcl-2 might protect cells from apoptosis by altering mitochondrial function and that mitochondria may be involved in apoptosis. Here we report that human mutant cell lines that lack mitochondrial DNA (mtDNA), and therefore do not have a functional respiratory chain, can still be induced to die by apoptosis, and that they can be protected from apoptosis by the overexpression of bcl-2, suggesting that neither apoptosis nor the protective effect of bcl-2 depends on mitochondrial respiration. We also show that the Bcl-2 protein in overexpressing cells is associated with the nuclear envelope and endoplasmic reticulum, as well as with mitochondria.
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PMID:Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. 838 Dec 12

A multidisciplinary approach was taken to investigate the intracellular locations of the 26-kDa integral membrane protein encoded by the bcl-2 gene. Subcellular fractionation analysis of a t(14;18)-containing lymphoma cell line revealed the presence of Bcl-2 protein in nuclear, heavy-membrane, and light-membrane fractions but not in cytosol. Sedimentation of heavy-membrane fractions in Nycodenz and Percoll continuous gradients demonstrated comigration of p26-Bcl-2 with mitochondrial but not other organelle-associated proteins. Fractionation of light-membrane fractions using discontinuous sucrose-gradients revealed association of Bcl-2 protein primarily with lighter-density microsomes (smooth endoplasmic reticulum) as opposed to heavy-density microsomes (rough endoplasmic reticulum). Immune microscopy studies using laser-scanning microscopy, pre- and postembedding electron microscopic methods, and six different anti-Bcl-2 antibodies demonstrated Bcl-2 immunoreactivity in the nuclear envelope and outer mitochondrial membrane in a patchy distribution. Furthermore, anti-Bcl-2 antibody immunoreactivity generally appeared to directly overlie the nuclear envelope in high magnification electron microscopic studies, reminiscent of nuclear pore complexes. Addition of in vitro translated p26-Bcl-2 to isolated translocation-competent mitochondria revealed transmembrane domain-dependent association of Bcl-2 protein with mitochondria but provided no evidence for import into a protease-resistant compartment, consistent with immunomicroscopic localization to the outer mitochondrial membrane. Taken together, the findings demonstrate that p26-Bcl-2 resides primarily in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membrane in a nonuniform distribution suggestive of participation in protein complexes perhaps involved in some aspect of transport.
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PMID:Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. 840 48

The splenic marginal zone is a morphologically and perhaps immunologically distinct B-cell compartment. Lymphomas arising from cells of the splenic marginal zone are rare. Here we describe the morphologic, immunologic, and clinical features of 14 cases. Patient age ranged from 35 to 79 years (median, 68 years) with a male-to-female ratio of 1:1.8. The spleen was uniformly enlarged (median, 1,540 g; range, 388-3,845 g) in all patients, the neoplastic infiltrate had a nodular pattern in three cases, nodular and diffuse in seven cases, and diffuse in four cases. The neoplastic cells had small to medium-sized nuclei with round, oval, or slightly indented contours, small eosinophilic nucleoli, and a moderate amount of pale cytoplasm. Extrasplenic involvement was present in 12 patients. Lymph nodes often had a vaguely nodular pattern and preservation of sinuses; bone marrow was infiltrated focally (seven cases) or diffusely (one case). Five patients had hepatic involvement. Ultrastructurally, neoplastic cells differed from other small B cells and resembled normal marginal zone cells by having long, serpentine rough endoplasmic reticulum profiles. All lymphomas marked as B cells and light chain restriction was demonstrated in 12 cases. Bcl-2 protein expression was present in all cases. Most cases (70%) were negative for DBA.44 (CD72). Plasmacytic differentiation was present in three cases. In conclusion, splenic marginal zone lymphoma is a B-cell neoplasm with distinctive clinical, morphologic, immunologic, and ultrastructural characteristics.
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PMID:Splenic marginal zone lymphoma. A distinct B-cell neoplasm. 861 26

Bcl-2 expression is associated with the progression of prostate cancer from androgen-dependence to androgen-independence. Bcl-2 is an integral membrane protein which localizes to mitochondria, endoplasmic reticulum, and the nuclear envelope. Using spectrofluorometry and laser confocal microscopy, the ability of bcl-2 to modulate intracellular Ca2+ was examined in the Dunning G prostate carcinoma cell line following apoptosis induction by adriamycin. Adriamycin and thapsigargin, an endoplasmic reticulum Ca2+-pump inhibitor, were effective inducers of apoptosis in control, but not bcl-2 transfected, cells. Treatment with adriamycin was accompanied by a sustained rise in cytoplasmic Ca2+ in control and bcl-2 transfected cells. An increase in intranuclear Ca2+ was observed in control cells only. Apoptosis induction by thapsigargin was associated with an increase in cytoplasmic Ca2+ in control cells that was not detected in the resistant bcl-2 transfectants. Ca2+ was excluded from nuclei isolated from bcl-2 expressing cells, but was sequestered in control nuclei, following the addition of ATP. These findings suggest that bcl-2 may regulate levels of intranuclear Ca2+ independently of cytosolic Ca2+ levels. The ability of bcl-2 to modulate, directly or indirectly, sustained increases in both cytosolic and intranuclear Ca2+ may provide a common basis for bcl-2 function in different subcellular compartments.
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PMID:Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+. 864 65

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.
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PMID:Bcl-2 inhibits hydrogen peroxide-induced ER Ca2+ pool depletion. 866 30

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

Human Bcl-2 is located in multiple intracellular membranes when expressed in MDCK and Rat-1/myc cells. We restricted expression to the endoplasmic reticulum or mitochondria by exchanging the Bcl-2 carboxy-terminal insertion sequence for an equivalent sequence from cytochrome b5 or ActA, respectively. MDCK cells are protected from serum deprivation-induced apoptosis by both wild-type Bcl-2 and the mutant targeted to mitochondria but not by the mutant targeted to endoplasmic reticulum. In contrast, when expressed in Rat-1/myc cells, the Bcl-2 mutant located at the endoplasmic reticulum is more effective than that targeted to mitochondria. In MDCK cells both mutants bind Bax as effectively as wild-type, demonstrating that Bax binding is not sufficient to prevent apoptosis.
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PMID:Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. 886 42

Bcl-2-related proteins are critical regulators of cell survival that are localized to the outer mitochondrial, outer nuclear and endoplasmic reticulum membranes. Despite their physiological importance, the biochemical function of Bcl-2-related proteins has remained elusive. The three-dimensional structure of Bcl-xL, an inhibitor of apoptosis, was recently shown to be similar to the structures of the pore-forming domains of bacterial toxins. A key feature of these pore-forming domains is the ability to form ion channels in biological membranes. Here we demonstrate that Bcl-xL shares this functional feature. Like the bacterial toxins, Bcl-xL can insert into either synthetic lipid vesicles or planar lipid bilayers and form an ion-conducting channel. This channel is pH-sensitive and becomes cation-selective at physiological pH. The ion-conducting channel(s) formed by Bcl-xL display multiple conductance states that have identical ion selectivity. Together, these data suggest that Bcl-xL may maintain cell survival by regulating the permeability of the intracellular membranes to which it is distributed.
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PMID:Bcl-x(L) forms an ion channel in synthetic lipid membranes. 900 22

The pathways and identification of cell injury and cell death are of key importance to the practice of diagnostic and research toxicologic pathology. Following a lethal injury, cellular reactions are initially reversible. Currently, we recognize two patterns, oncosis and apoptosis. Oncosis, derived from the Greek word "swelling," is the common pattern of change in infarcts and in zonal killing following chemical toxicity, e.g., centrilobular hepatic necrosis after CC14 toxicity. In this common reaction, the earliest changes involve cytoplasmic blebbing, dilatation of the endoplasmic reticulum (ER), swelling of the cytosol, normal or condensed mitochondria, and chromatin clumping in the nucleus. In apoptosis, the early changes involve cell shrinkage, cytosolic shrinkage, more marked chromatin clumping, cytoplasmic blebbing, swollen ER on occasion, and mitochondria that are normal or condensed. Following cell death, both types undergo postmortem changes collectively termed "necrosis." In the case of oncosis, this typically involves broad zones of cells while, in the case of apoptosis, the cells and/or the fragments are often phagocytized prior to their death by adjacent macrophages or parenchymal cells. In either case, the changes converge to a pattern that involves mitochondrial swelling, mitochondrial flocculent densities and/or calcification, karyolysis, and disruption of plasmalemmal continuity. The biochemical mechanisms of cell death are currently under intense study, particularly concerning the genes involved in the process. Pro-death genes include p53, the ced-3/ICE proteases, and the Bax family. Anti-death genes include ced-9/Bcl-2 and the adenovirus protein EIB. It is clear that ion deregulation, particularly that of [Ca2+]i plays an important role in cell death following either apoptosis or oncosis. Genetic evidence strongly indicates that activation of proteases is an important step, possibly very near to the point where cell death occurs.
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PMID:The pathways of cell death: oncosis, apoptosis, and necrosis. 906 57

The Ca2+-ATPase inhibitors, thapsigargin and cyclopiazonic acid, depleted intracellular Ca2+ stores, induced large increases in intracellular Ca2+ concentration, and caused apoptosis in S49 cells. Removal of extracellular Ca2+ augmented apoptosis due to thapsigargin, indicating that depletion of Ca2+ from intracellular stores is responsible for apoptosis with this agent. Overexpression of the apoptosis suppressor, Bcl-2, inhibited apoptosis due to thapsigargin but did not affect thapsigargin-induced Ca2+ signaling. Dexamethasone induced apoptosis, diminished the size of the endoplasmic reticulum Ca2+ pool, and caused a small elevation of intracellular Ca2+. However, this elevation was not due to Ca2+ influx because the increase was similar in the presence or absence of Ca2+ in the medium. Furthermore, in contrast to the results with thapsigargin, apoptosis due to dexamethasone was unchanged in a Ca2+-free medium. These results indicate that depletion of Ca2+ stores initiates a pathway leading to apoptosis. Elevations in cytoplasmic Ca2+ appears to play a lesser role than previously thought in the actions of Bcl-2 and glucocorticoids.
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PMID:Roles of cytoplasmic Ca2+ and intracellular Ca2+ stores in induction and suppression of apoptosis in S49 cells. 914 49


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