UNIPROT:P10415 - FACTA Search

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

The ability of Bcl-2 to inhibit cell death is well documented but its mechanism of action remains elusive. Recent reports have suggested that Bcl-2 prevents apoptosis by inhibiting the release of Ca2+ from the thapsigargin-sensitive Ca2+ store. The mobilization of Ca2+ from this store has been implicated as a signal regulating apoptotic cell death induced by glucocorticoids and by interleukin-3 withdrawal. The present study was designed to determine if Bcl-2 would still inhibit apoptosis after depletion of intracellular Ca2+ stores. We compared the response of two Chinese hamster ovary cell lines (5AHSmyc and 5A300bcl-2.2) following incubation with the calcium ionophore ionomycin to deplete intracellular Ca2+ stores. Continued incubation of 5AHSmyc cells in calcium-free media induced substantial apoptotic DNA fragmentation within 4 h and >95% loss of viability within 48 h. However, 5A300bcl-2.2 cells showed no evidence of DNA fragmentation or loss of viability over the same time period. Intracellular Ca2+ was analyzed with the Ca2+-sensitive fluorescent dye INDO-1 and confirmed that ionomycin was capable of releasing Ca2+ from intracellular stores in both cell lines. These results show that depletion of intracellular Ca2+ stores induces apoptosis and that these Ca2+ stores are not required for the protection afforded by Bcl-2.
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PMID:Intracellular calcium stores are not required for Bcl-2-mediated protection from apoptosis. 891 Mar 67

(-)-Deprenyl stereospecifically reduces neuronal death even after neurons have sustained seemingly lethal damage at concentrations too small to cause monoamine oxidase-B (MAO-B) inhibition. (-)-Deprenyl can also influence the process growth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with the earlier work of others, we showed that (-)-deprenyl alters the expression of a number mRNAs or proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial ATP production depends on mitochondrial membrane potential (MMP) and mitochondrial failure has been shown to be one of the earliest events in apoptosis, we used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl are accompanied by a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and to decrease cytoplasmic oxidative radical levels and thereby to reduce apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may contribute to the development of new therapies for neurodegenerative diseases.
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PMID:(-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. 898 61

Mcl-1 is a member of the Bcl-2 family that was identified based on increased expression in myeloblastic leukemia cells undergoing differentiation. Mcl-1 was previously found to be similar to Bcl-2 in causing a delay in apoptotic cell death in Chinese hamster ovary cells. The work described here was aimed at determining whether Mcl-1 could also exert such an effect in hematopoietic cells, because endogenous Mcl-1 expression is prominent in the hematopoietic system. A further aim was to assess the effects of Mcl-1 in cells exposed to a variety of cytotoxic stimuli, because Bcl-2 is known to have a broad spectrum of activity. To approach these aims, FDC-P1 murine myeloid progenitor cells were transfected with vectors driving either constitutive or inducible expression of Mcl-1. The introduced Mcl-1 gene was found to cause a prolongation of viability under various conditions that cause apoptotic cell death, including exposure to cytotoxic agents (the chemotherapeutic drug etoposide, calcium ionophore, or UV irradiation) and the withdrawal of required growth factors. In addition, Mcl-1 was found to interact with Bax, a member of the Bcl-2 family that promotes cell death as a homodimer but that can heterodimerize with Bcl-2 to promote cell viability. Although Mcl-1 prolonged cell viability, it did not prevent eventual cell death upon continuous exposure to a cytotoxic agent. Prolongation of viability was maximal when expression of Mcl-1 was induced before the application of the apoptotic stimulus, although some increase occurred if Mcl-1 was induced shortly thereafter and before overt apoptosis. Taken as a whole, these findings provide further parallels between Mcl-1 and Bcl-2, showing that Mcl-1 can interact with Bax in hematopoietic FDC-P1 cells and can prolong cell viability under a variety of cytotoxic conditions.
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PMID:Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. 900 67

Previous studies have shown that although the majority of rat thymic lymphocytes are sensitive to glucocorticoid-induced apoptosis in vivo, a small population of mature thymic lymphocytes remains even after high dose steroid administration. Here, we describe experiments that were performed to understand the molecular basis of the resistance of these cells to glucocorticoid-induced apoptosis. Adrenalectomized rats were treated for 72 h with a bolus dose (5 mg/kg body weight) of dexamethasone to produce a population of thymocytes that survived glucocorticoid administration. Reinjection of these animals with equivalent doses of dexamethasone failed to induce further thymic regression or apoptosis in these cells. Glucocorticoid receptor number and receptor binding affinity for dexamethasone were similar in control and resistant thymocytes. Western blot analysis using epitope-purified antiglucocorticoid receptor antibodies confirmed this observation. To delineate the mechanism of resistance, we evaluated whether cells resistant to dexamethasone in vivo showed any response to this glucocorticoid in vitro. The ability of glucocorticoid to inhibit [3H]lysine incorporation into protein in cells treated with dexamethasone in vitro was equivalent to control cells, indicating that glucocorticoid receptor function was normal in both populations. To evaluate whether in vivo glucocorticoid-resistant thymocytes retain any capacity to undergo apoptosis, in vitro studies were performed on these cells using the calcium ionophore A23187 to induce programmed cell death. Cleavage of chromatin into 30- to 50-kilobase fragments or oligonucleosomal fragments characteristic of apoptosis was observed in both sensitive and resistant thymocytes treated in vitro with A23187. Cells resistant to glucocorticoid in vivo unexpectedly exhibited internucleosomal cleavage of chromatin and apoptosis in response to dexamethasone in vitro. We examined the levels of the apoptosis suppressor Bcl-2 in thymocytes isolated from control and 72 h dexamethasone-treated rats to determine whether increased expression of this protein could explain the resistance to glucocorticoid-induced apoptosis that we observed. Both glucocorticoid-sensitive and -resistant thymocytes expressed similar levels of Bcl-2. Together, these data indicate that resistance to glucocorticoid in vivo is not due to alteration of the glucocorticoid receptor or to expression of Bcl-2, but rather to some endogenous thymic factor and/or cell-to-cell contact that probably alters glucocorticoid receptor signaling.
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PMID:In vivo resistance to glucocorticoid-induced apoptosis in rat thymocytes with normal steroid receptor function in vitro. 900 19

Suppression of apoptosis appears to contribute to the development of various diseases, including autoimmune disorders and cancer. Numerous genes that encode activators and suppressors of apoptosis have been identified; however, such genes have not been shown to be expressed in all cell types. Furthermore, the sensitivity of different cell types to induction of apoptosis varies widely. We have employed a genetic approach using somatic cell hybridization to determine if apoptosis is a dominant or a recessive process in cells. These studies have utilized cell fusion partners with differing sensitivity to induction of apoptosis. The apoptosis-sensitive cells chosen were BW5147 murine thymoma cells. These cells readily undergo apoptosis in response to glucocorticoids and calcium ionophore. The resistant fusion partners were HTC rat hepatoma cells, which possess an intact glucocorticoid signal transduction pathway but are resistant to induction of apoptosis by either agent. Neither cell type expresses detectable Bcl-2 protein. Heterokaryons were identified by their retention of fluorescent cytosolic dyes and by nuclear morphology and cell size. The three types of heterokaryons observed were intratypic HTC/HTC and BW5147/BW5147 heterokaryons and intertypic BW5147/HTC heterokaryons. Glucocorticoid receptor was shown by immunohistochemistry to undergo hormone-dependent translocation to all nuclei in intertypic heterokaryons. BW5147/BW5147 heterokaryons die after treatment with glucocorticoid and calcium ionophore, whereas both HTC/ HTC and BW5147/HTC hybrids survive. The presence of multiple BW5147 cells fused to a single HTC cell did not affect this outcome. This demonstrates that HTC cells are able to dominantly suppress apoptosis in all BW5147/HTC heterokaryons. Thus, HTC cells contain activities that can suppress apoptosis in lymphocytes.
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PMID:Dominant suppression of lymphocyte apoptosis by hepatoma cells. 901 14

Although histological data suggest that cholangiocytes die by apoptosis in human liver diseases, no information exists on the mechanisms of cholangiocyte apoptosis. Thus our aims were to establish an in vitro model of cholangiocyte apoptosis and to test the hypothesis that changes in intracellular ions would cause apoptosis in cholangiocytes by a protease-sensitive pathway. A large number of proapoptotic agents were ineffective in inducing apoptosis in rat or human cholangiocytes in culture; in contrast, beauvericin, a K+ ionophore, caused apoptosis in both cell lines, despite their expression of Bcl-2. Although beauvericin decreased intracellular K+ and increased intracellular Ca2+, abolishing the K+ gradient did not prevent beauvericin-induced apoptosis; in contrast, omission of extracellular Ca2+ inhibited apoptosis by 42%. The interleukin-1 beta-converting enzyme (ICE) family protease inhibitor, Z-Val-Ala-Asp chloromethylketone, inhibited apoptosis in a concentration-dependent manner. By Northern blot analysis, cholangiocytes expressed the mRNA for three members of the ICE protease family: ICE, ICE/ CED-3 homologue-1 (ICH-1), and cysteine protease P-32 (CPP-32). Cleavage of a substrate for CPP-32-like protease activity, but not a substrate for ICE and ICH-1, increased after beauvericin treatment. In summary, we have established an in vitro model of apoptosis in cholangiocytes. Our data suggest that beauvericin-induced apoptosis occurs by a Ca(2+)-dependent CPP-32 protease-sensitive pathway despite cholangiocyte expression of Bcl-2.
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PMID:Development and initial application of an in vitro model of apoptosis in rodent cholangiocytes. 903 83

Mammary epithelial cells (MEC) undergo programmed cell death (PCD) when deprived of serum and growth factors at high cell density but not at low density. The addition of epidermal growth factor and insulin to serum-free medium (SFM) completely restores cell survival. In this report, we examine the role of cell-cell and cell-matrix interaction. When cell attachment is prevented, PCD is markedly accelerated. This effect is observed in cells collected at low or high density and is unaffected by calcium depletion. Cells plated in SFM on purified laminin, tenascin C, or collagen IV-coated dishes, as well as on dishes coated with endogenous extracellular matrix deposited by HC11 mammary cells, show reduced PCD. The addition of soluble laminin or tenascin C to suspension cultures of MECs also partially inhibits PCD. In contrast, no effect is seen with fibronectin or collagen I. These results indicate that reduced contact with a solid substrate contributes to the induction of PCD, which might partially explain the fact that it is only observed in confluent cultures. Ectopic Bcl-2 expression in MCF-10-A and HC11 mammary cells results in a complete suppression of PCD. In MCF-10-A cells, the level of endogenous Bcl-2 increases when the survival factors epidermal growth factor and insulin are added to the SFM but is unaffected by cell density. On the contrary, Bax protein expression increases sharply with cell density but does not change upon addition of epidermal growth factor and insulin. When compared to lactating tissue, Bcl-2 protein levels decrease during mammary gland involution. Bax protein levels increase during lactation and remain high during involution. These data suggest that Bcl-2 and Bax might be intracellular mediators of signals that influence MEC apoptosis.
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PMID:Apoptosis is accompanied by changes in Bcl-2 and Bax expression, induced by loss of attachment, and inhibited by specific extracellular matrix proteins in mammary epithelial cells. 904 Sep 47

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

It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for induction of interleukin-2 expression, suggesting a mechanism by which Bcl-2 suppresses NF-AT activity. We also show that Bax, a pro-apoptotic member of the Bcl-2 family, interferes with interactions between calcineurin and Bcl-2. We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions.
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PMID:Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. 910 91

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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