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)

In the present study we show that N-acetylsphingosine (C2-ceramide), N-hexanoylsphingosine (C6-ceramide), and, to a much lesser extent, C2-dihydroceramide induce cytochrome c (cyto c) release from isolated rat liver mitochondria. Ceramide-induced cyto c release is prevented by preincubation of mitochondria with a low concentration (40 nM) of Bcl-2. The release takes place when cyto c is oxidized but not when it is reduced. Upon cyto c loss, mitochondrial oxygen consumption, mitochondrial transmembrane potential (Delta Psi), and Ca2+ retention are diminished. Incubation with Bcl-2 prevents, and addition of cyto c reverses the alteration of these mitochondrial functions. In ATP-energized mitochondria, ceramides do not alter Delta Psi, neither when cyto c is oxidized nor when it is reduced, ruling out a nonspecific disturbance by ceramides of mitochondrial membrane integrity. Furthermore, ceramides decrease the reducibility of cyto c. We conclude that the apoptogenic properties of ceramides are in part mediated via their interaction with mitochondrial cyto c followed by its release and that the redox state of cyto c influences its detachment by ceramide from the inner mitochondrial membrane.
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PMID:Ceramide induces cytochrome c release from isolated mitochondria. Importance of mitochondrial redox state. 1003 89

Apoptosis is a genetically programmed cell death that is required for morphogenesis during embryogenic development and for tissue homeostasis in adult organisms. In most cases, apoptosis involves cytochrome c release from mitochondria. In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3. Bcl-2 and related proteins control cytochrome c release from the mitochondria whereas IAP (for Inhibitor of APoptosis) molecules modulate the activity of caspases. Plasma membrane receptors such as Fas (CD95, APO-1), characterized by a so-called "death domain" in their cytoplasmic domain, can activate the caspase cascade through adaptator molecules such as FADD (Fas-Associated protein with a Death Domain). Dysregulation of the apoptotic machinery plays a role in the pathogenesis of various diseases and molecules involved in cell death pathways are potential therapeutic targets in immunologic, neurologic, cancer, infectious and inflammatory diseases.
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PMID:[Apoptosis: molecular mechanisms]. 1010 3

Recent studies that attempt to explore the action of pro- and anti-apoptotic proteins of the bcl2 family demonstrate the crucial role of relocalization of cytochrome c from the mitochondrial intermembrane space to the cytosol. This early event of apoptosis can be mimicked in the yeast Saccharomyces cerevisiae following expression of bax. In mammalian mitochondria, the mechanism of relocalization is thought to involve the opening of the so-called permeability transition pore. We show in this paper: (a) that bax-induced release of cytochrome c in yeast does not involve any permeability transition of the inner mitochondrial membrane but involves a general alteration of the permeability of the outer mitochondrial membrane to macromolecules. This suggests that a permeability transition of the inner mitochondrial membrane is not an event required for the relocalization of cytochrome c in yeast. (b) The outer-membrane voltage-dependent anion channel (VDAC), a putative component of the permeability transition pore, is not involved in bax-induced release of cytochrome c or in the prevention of this release by bcl-xL. (c) Bax devoid of its C-terminal putative hydrophobic alpha-helix is as efficient as full-length bax to allow the relocalization of cytochrome c, demonstrating this segment of the protein is not required for membrane-targeting. (d) We finally observe that the action of bax on the outer mitochondrial membrane requires the presence of ATP both in vitro and in vivo, and it is shown that ATP directly increases the amount of bax inserted to mitochondria.
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PMID:Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. 1010 96

Programmed cell death, apoptosis, involves very distinctive changes within the target cell nucleus, including margination of the chromatin, DNA fragmentation and breakdown of the nuclear envelope. Cytolytic granule-mediated target cell apoptosis is effected, in part, through synergistic action of the membrane-acting protein perforin and serine proteases, such as granzymes A or B. Recent work using confocal laser scanning microscopy as well as other techniques supports the idea that perforin-dependent translocation of granzymes to the nucleus of target cells plays a central role in effecting the nuclear changes associated with apoptosis. In vitro experiments indicate that granzyme nuclear import follows a novel pathway, being independent of ATP, not inhibitable by non-hydrolysable GTP analogues and involving binding within the nucleus, unlike conventional signal- dependent nuclear protein import. In intact cells, perforin-dependent nuclear entry of granzymes precedes the nuclear events of apoptosis such as DNA fragmentation and nuclear envelope breakdown; prevention of granzyme nuclear translocation through bcl2 overexpression or treatment of target cells with inhibitors of caspase activation blocks these events. Nuclear localization of granzymes thus appears to be central to induction of the nuclear changes associated with cytolytic granule-mediated apoptosis.
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PMID:Perforin-dependent nuclear targeting of granzymes: A central role in the nuclear events of granule-exocytosis-mediated apoptosis? 1036 Dec 52

We have examined interactions between the purine nucleoside analog fludarabine (9-beta-arabinofuranosyl-2-fluoroadenine) and the macrocyclic lactone bryostatin 1 in the human monocytic leukemic cell line U937. Fludarabine exerted dose-dependent effects on U937 cell viability and growth which were associated with both induction of apoptosis, as well as cellular maturation. Incubation of cells with bryostatin 1 (10 nM; 24 h) after, but not before a 6-h exposure to 10 microM fludarabine resulted in a modest but significant increase in apoptosis, and was associated with greater than a 1 log reduction in clonogenicity. Subsequent exposure to bryostatin 1 also increased the percentage of fludarabine-treated cells displaying differentiation-related features (eg plastic adherence, CD11b positivity) compared to cells exposed to fludarabine alone. Bryostatin 1 did not increase the retention of the active fludarabine metabolite, F-ara-ATP, nor did it increase 3H-F-ara-A incorporation into DNA. Despite its capacity to trigger cellular maturation, fludarabine exposure (either with or without bryostatin 1) failed to induce the cyclin-dependent kinase inhibitors (CDKls) p21WAF1/CIP1 and p27KIP1. Nevertheless, dysregulation of p21 (resulting from stable transfection of cells with a p2lWAF1/CIP1 antisense construct) reduced fludarabine-mediated differentiation, while inducing a corresponding increase in apoptosis. Enforced expression of Bcl-2 partially protected cells from fludarabine-related apoptosis, an effect that was overcome, in part, by subsequent exposure of cells to bryostatin 1. Interestingly, Bcl-2-overexpressing cells were as or in some cases, more susceptible to differentiation induction by fludarabine (+/- bryostatin 1) than their empty vector-containing counterparts. Collectively, these results indicate that the antiproliferative effects of fludarabine toward U937 leukemic cells involve both induction of apoptosis and cellular maturation, and that each of these processes may be enhanced by bryostatin 1.
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PMID:Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937): interactions with the macrocyclic lactone bryostatin 1. 1040 Apr 20

The effects of a transient exposure to hydrogen peroxide (10 min at 200 microM H(2)O(2)) on pancreatic beta cell signal transduction and insulin secretion have been evaluated. In rat islets, insulin secretion evoked by glucose (16.7 mM) or by the mitochondrial substrate methyl succinate (5 mM) was markedly blunted following exposure to H(2)O(2). In contrast, the secretory response induced by plasma membrane depolarization (20 mM KCl) was not significantly affected. Similar results were obtained in insulinoma INS-1 cells using glucose (12.8 mM) as secretagogue. After H(2)O(2) treatment, glucose no longer depolarized the membrane potential (DeltaPsi) of INS-1 cells or increased cytosolic Ca(2+). Both DeltaPsi and Ca(2+) responses were still observed with 30 mM KCl despite an elevated baseline of cytosolic Ca(2+) appearing approximately 10 min after exposure to H(2)O(2). The mitochondrial DeltaPsi of INS-1 cells was depolarized by H(2)O(2) abolishing the hyperpolarizing action of glucose. These DeltaPsi changes correlated with altered mitochondrial morphology; the latter was not preserved by the overexpression of the antiapoptotic protein Bcl-2. Mitochondrial Ca(2+) was increased following exposure to H(2)O(2) up to the micromolar range. No further augmentation occurred after glucose addition, which normally raises this parameter. Nevertheless, KCl was still efficient in enhancing mitochondrial Ca(2+). Cytosolic ATP was markedly reduced by H(2)O(2) treatment, probably explaining the decreased endoplasmic reticulum Ca(2+). Taken together, these data point to the mitochondria as primary targets for H(2)O(2) damage, which will eventually interrupt the transduction of signals normally coupling glucose metabolism to insulin secretion.
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PMID:Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. 1048 38

The toxicity of tributyltin chloride (TBT) involves Ca(2+) overload, cytoskeletal damage, and mitochondrial failure leading to cell death by apoptosis or necrosis. Here, we examined whether the intracellular ATP level modulates the mode of cell death after exposure to TBT. When Jurkat cells were energized by the mitochondrial substrate, pyruvate, low concentrations of TBT (1-2 microM) triggered an immediate depletion of intracellular ATP followed by necrotic death. When ATP levels were maintained by the addition of glucose, the mode of cell death was typically apoptotic. Glycolytic ATP production was required for apoptosis at two distinct steps. First, maintenance of adequate ATP levels accelerated the decrease of mitochondrial membrane potential, and the release of the intermembrane proteins adenylate kinase and cytochrome c from mitochondria. A possible role of the adenine nucleotide exchanger in this first ATP-dependent step is suggested by experiments performed with the specific inhibitor, bongkrekic acid. This substance delayed cytochrome c release in a manner similar to that caused by ATP depletion. Second, caspase activation following cytochrome c release was only observed in ATP-containing cells. Bcl-2 had only a minor effect on TBT-triggered caspase activation or cell death. We conclude that intracellular ATP concentrations control the mode of cell death in TBT-treated Jurkat cells at both the mitochondrial and caspase activation levels.
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PMID:Tributyltin-induced apoptosis requires glycolytic adenosine trisphosphate production. 1052 61

The present article attempts to summarize and introduce the mechanisms of hypoxia-induced cell death. Necrosis is associated with rapid metabolic collapse that leads to cell swelling, early loss of plasma membrane integrity, and ultimate cell rupture, in which cytosolic contents leak from necrotic cells causing injury to and inflammation of the surrounding tissue. In contrast, apoptosis is an energy-requiring, gene-directed process, which results in cell suicide without any injury to surrounding tissues. Although apoptosis and necrosis are conceptually distinct pathways of cell death, recent advances have revealed that hypoxic cell damage can induce both necrosis and apoptosis simultaneously. Loss of the mitochondrial membrane potential (MMP) precedes the morphological changes in cell death, and overexpression of Bcl-2 or Bcl-XL blocks apoptosis as well as hypoxia-induced necrosis by maintaining MMP. These findings indicate that apoptosis and some types of necrosis share common features in the death signaling pathway. The factors that determine whether cells undergo apoptosis or necrosis are still unclear, but intracellular ATP levels and/or their rate of decline are considered to be one possible determinant of the manifestation of cell death.
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PMID:[Mechanisms of cell death in hypoxic stress]. 1057 Jul 75

Apoptosis in response to stress signals activates effector caspases known to be regulated by the release of cytochrome c (Cyt c) from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Experiments were carried out to determine whether the release of Cyt c is evoked by NO. in RAW 264.7 macrophages and to position signaling components relative to mitochondria. S-nitrosoglutathione and spermine-NO caused a fast p53 accumulation, followed by Bcl-xL downregulation, Cyt c release, and caspase activation. These alterations were absent in p53 antisense expressing macrophages (R delta p53asn-11). In Bcl-2 overexpressing cells (Rbcl2-14) Cyt c relocation and caspase activation were abrogated although p53 accumulation remained intact. The use of caspase inhibitors revealed Cyt c release and decreased Bcl-xL expression to be caspase independent. ATP-depleted cells showed a shift from apoptosis towards necrosis and no p53 accumulation or caspase activation upon NO. addition. Conclusively, NO.-mediated apoptosis in macrophages is entirely controlled by the mitochondrial pathway with the implication that Cyt c relocation demands p53 accumulation. Moreover, pulse-chase-experiments in combination with the ATP-depletion protocol identified p53 accumulation and stabilization as an energy requiring process. This allowed to dissect two ATP-dependent steps, one is in association with Apaf-1 formation, while the other resides in p53 accumulation.
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PMID:p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide. 1059 41

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes. ANT-1 is a component of the mitochondrial permeability transition complex, a protein aggregate connecting the inner with the outer mitochondrial membrane that has recently been implicated in apoptosis. ANT-1 expression led to all features of apoptosis, such as phenotypic alterations, collapse of the mitochondrial membrane potential, cytochrome c release, caspase activation, and DNA degradation. Both point mutations that impair ANT-1 in its known activity to transport ADP and ATP as well as the NH(2)-terminal half of the protein could still induce apoptosis. Interestingly, ANT-2, a highly homologous protein could not lead to cell death, demonstrating the specificity of the signal for apoptosis induction. In contrast to Bax, a proapoptotic Bcl-2 gene, ANT-1 was unable to elicit a form of cell death in yeast. This and the observed repression of apoptosis by the ANT-1-interacting protein cyclophilin D suggest that the suicidal effect of ANT-1 is mediated by specific protein-protein interactions within the permeability transition pore.
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PMID:Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. 1061 7


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