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)

Mitochondrial cytochrome c, which functions as an electron carrier in the respiratory chain, translocates to the cytosol in cells undergoing apoptosis, where it participates in the activation of DEVD-specific caspases. The apoptosis inhibitors Bcl-2 or Bcl-xL prevent the efflux of cytochrome c from mitochondria. The mechanism responsible for the release of cytochrome c from mitochondria during apoptosis is unknown. Here, we report that cytochrome c release from mitochondria is an early event in the apoptotic process induced by UVB irradiation or staurosporine treatment in CEM or HeLa cells, preceding or at the time of DEVD-specific caspase activation and substrate cleavage. A reduction in mitochondrial transmembrane potential (Deltapsim) occurred considerably later than cytochrome c translocation and caspase activation, and was not necessary for DNA fragmentation. Although zVAD-fmk substantially blocked caspase activity, a reduction in Deltapsim and cell death, it failed to prevent the passage of cytochrome c from mitochondria to the cytosol. Thus the translocation of cytochrome c from mitochondria to cytosol does not require a mitochondrial transmembrane depolarization.
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PMID:Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. 942 39

The Bcl-2-sensitive release of proteins such as cytochrome c from the mitochondrial intermembrane space into the cytosol is a critical early event in apoptosis. The mitochondrial permeability transition is also an important event in many forms of apoptotic cell death. To determine whether the permeability transition led to the release of apoptogenic proteins from mitochondria we induced the permeability transition in isolated rat liver mitochondria and characterised the proteins which were released. The permeability transition led to a generalised, non-specific release of proteins, including cytochrome c, from the mitochondrial intermembrane space which was prevented by an inhibitor of the permeability transition. To determine the mechanism of this protein release we measured both mitochondrial matrix swelling and protein release during the permeability transition in media of different osmolarities. Protein release correlated with mitochondrial matrix swelling, therefore the permeability transition causes release of proteins from the intermembrane space by rupturing the mitochondrial outer membrane. Supporting an apoptotic role for the proteins released by this mechanism, supernatants from mitochondria undergoing the permeability transition caused apoptotic changes in isolated nuclei. These data support the proposal that the mitochondrial permeability transition can induce apoptosis by releasing apoptogenic proteins into the cytoplasm [Skulachev, V.P., FEBS Lett. 397 (1996) 7-10].
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PMID:Release of apoptogenic proteins from the mitochondrial intermembrane space during the mitochondrial permeability transition. 942 28

Resistance to apoptosis is a frequent characteristic of cancer cells and participates both in the initial phase of carcinogenesis and in the development of chemotherapy resistance. Recently, it has become clear that a disruption in mitochondrial membrane function is a decisive event of the apoptotic process leading to the disposal of chemotherapy-treated cells. Opening of the mitochondrial megachannel (also called permeability transition pore) is at least in part responsible for the disruption of mitochondrial membrane integrity in apoptosis. The megachannel is regulated by numerous endogenous effectors including members of the Bcl-2/Bax family, the redox status of the cell, cytosolic Ca2+ levels, ceramide, and amphipathic peptides. Chemotherapeutic agents may induce opening of the megachannel by modulating some of these endogenous effectors. The disruption of mitochondrial membrane integrity involves a loss of metabolic functions and the liberation of intermembrane proteins into the cytosol. Such proteins, which normally are well secluded in mitochondria, include cytochrome c and AIF (apoptosis inducing factor), which both activate caspases and endonucleases upon release into the cytosol. Strategies for the development of chemotherapeutic agents acting on mitochondria are discussed.
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PMID:Mitochondria in chemotherapy-induced apoptosis: a prospective novel target of cancer therapy (review). 945 98

Following exposure of cells to stimuli that trigger programmed cell death (apoptosis), cytochrome c is rapidly released from mitochondria into the cytoplasm where it activates proteolytic molecules known as caspases that specifically cleave the amino-acid sequence DEVD and are crucial for the execution of apoptosis. The protein Bcl-2 interferes with this activation of caspases by preventing the release of cytochrome c. Here we study these molecular interactions during apoptosis induced by the protein Bax, a pro-apoptotic homologue of Bcl-2. We show that in cells transiently transfected with bax, Bax localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Caspase inhibitors do not affect Bax-induced cytochrome c release but block caspase-3 activation and nuclear fragmentation. Unexpectedly, Bcl-2 also fails to prevent Bax-induced cytochrome c release, although it co-localizes with Bax to mitochondria. Cells overexpressing both Bcl-2 and Bax show no signs of caspase activation and survive with significant amounts of cytochrome c in the cytoplasm. These findings indicate that Bcl-2 can interfere with Bax killing downstream of and independently of cytochrome c release.
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PMID:Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. 946 Dec 8

Bcr-Abl expression in leukemic cells is known to exert a potent effect against apoptosis due to antileukemic drugs, but its mechanism has not been elucidated. Recent reports have indicated that a variety of apoptotic stimuli cause the preapoptotic mitochondrial release of cytochrome c (cyt c) into cytosol, which mediates the cleavage and activity of caspase-3 involved in the execution of apoptosis. Whether Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and activation of caspase-3 or acts downstream by blocking the ensuing degradation of substrates resulting in apoptosis, has been the focus of the present studies. In these, we used (1) the human acute myelogenous leukemia (AML) HL-60 cells that are stably transfected with the bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2) the chronic myelogenous leukemia (CML)-blast crisis K562 cells, which have endogenous expression of p210 Bcr-Abl. Exposure of the control AML HL-60 cells to high-dose Ara-C (HIDAC), etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the cytosol, loss of mitochondrial membrane potential (MMP), and increase in the reactive oxygen species (ROS). These preapoptotic events were associated with the cleavage and activity of caspase-3, resulting in the degradation of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), internucleosomal DNA fragmentation, and morphologic features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells, these apoptotic stimuli failed to cause the cytosolic accumulation of cyt c and other associated mitochondrial perturbations, as well as the failure to induce the activation of caspase-3 and apoptosis. While the control HL-60 cells showed high levels of Bcl-2 and barely detectable Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of Bcl-xL and undetectable levels of Bcl-2, a pattern of expression similar to the one in K562 cells. Bax and caspase-3 expressions were not significantly different between HL-60/Bcr-Abl or K562 versus HL-60 cells. These findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis.
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PMID:Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. 947 36

Caspase-3-mediated proteolysis is a critical element of the apoptotic process. Recent studies have demonstrated a central role for mitochondrial proteins (e.g., Bcl-2 and cytochrome c) in the activation of caspase-3, by a process that involves interaction of several protein molecules. Using antibodies that specifically recognize the precursor form of caspase-3, we demonstrate that the caspase-3 proenzyme has a mitochondrial and cytosolic distribution in nonapoptotic cells. The mitochondrial caspase-3 precursor is contained in the intermembrane space. Delivery of a variety of apoptotic stimuli is accompanied by loss of mitochondrial caspase-3 precursor staining and appearance of caspase-3 proteolytic activity. We propose that the mitochondrial subpopulation of caspase-3 precursor molecules is coupled to a distinct subset of apoptotic signaling pathways that are Bcl-2 sensitive and that are transduced through multiple mitochondrion-specific protein interactions.
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PMID:The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. 950 80

Recent progress in studies on apoptosis has revealed that cytochrome c is a pro-apoptotic factor. It is released from its places on the outer surface of the inner mitochondrial membrane at early steps of apoptosis and, combining with some cytosolic proteins, activates conversion of the latent apoptosis-promoting protease pro-caspase-9 to its active form. Cytochrome c release can be initiated by the pro-apoptotic protein Bax. This process is blocked by the anti-apoptotic proteins Bcl-2 and Bcl-xL. The role of cytochrome c in apoptosis may be understood within the framework of the concept assuming that the evolutionary primary function of apoptosis was to purify tissues from ROS-overproducing cells. In this context, the pro-apoptosis activity of cytochrome c might represent one of the anti-oxidant functions inherent in this cytochrome. Among other cytochrome c-linked antioxidant mechanisms, the following systems can be indicated. (1) Cytochrome c released from the inner mitochondrial membrane to the intermembrane space can operate as an enzyme oxidizing O2.- back to O2. The reduced cytochrome c is oxidized by cytochrome oxidase (or in yeasts and bacteria, by cytochrome c peroxidase). (2) The intermembrane cytochrome c can activate the electron transport chain in the outer mitochondrial membrane. This bypasses the initial and middle parts of the main respiratory chain, which produce, as a rule, the major portion of ROS in the cell. (3) The main respiratory chain losing its cytochrome c is inhibited in such a fashion that antimycin-like agents fail to stimulate ROS production.
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PMID:Cytochrome c in the apoptotic and antioxidant cascades. 951 23

In several different cell lines, Bcl-2 prevents the induction of apoptosis (DNA fragmentation, PARP cleavage, phosphatidylserine exposure) by the pro-oxidant ter-butylhydroperoxide (t-BHP) but has no cytoprotective effect when apoptosis is induced by the thiol crosslinking agent diazenedicarboxylic acid his 5N,N-dimethylamide (diamide). Both t-BHP and diamide cause a disruption of the mitochondrial transmembrane potential delta psi(m) that is not inhibited by the broad spectrum caspase inhibitor z-VAD.fmk, although z-VAD.fmk does prevent nuclear DNA fragmentation and poly(ADP-ribose) polymerase cleavage in these models. Bcl-2 stabilizes the delta psi(m) of t-BHP-treated cells but has no inhibitory effect on the delta psi(m) collapse induced by diamide. As compared to normal controls, isolated mitochondria from Bcl-2 overexpressing cells are relatively resistant to the induction of delta psi(m) disruption by t-BHP in vitro. Such Bcl-2 overexpressing mitochondria also fail to release apoptosis-inducing factor (AIF) and cytochrome c from the intermembrane space, whereas control mitochondria not overexpressing Bcl-2 do liberate AIF and cytochrome c in response to t-BHP. In contrast, Bcl-2 does not confer protection against diamide-triggered delta psi(m) collapse and the release of AIF and cytochrome c. This indicates that Bcl-2 suppresses the permeability transition (PT) and the associated release of intermembrane proteins induced by t-BHP but not by diamide. To further investigate the mode of action of Bcl-2, semi-purified PT pore complexes were reconstituted in liposomes in a cell-free, organelle-free system. Recombinant Bcl-2 or Bcl-X(L) proteins augment the resistance of reconstituted PT pore complexes to pore opening induced by t-BHP. In contrast, mutated Bcl-2 proteins which have lost their cytoprotective potential also lose their PT-modulatory capacity. Again, Bcl-2 fails to confer protection against diamide in this experimental system. The reconstituted PT pore complex itself cannot release cytochrome c encapsulated into liposomes. Altogether these data suggest that pro-oxidants, thiol-reactive agents, and Bcl-2 can regulate the PT pore complex in a direct fashion, independently from their effects on cytochrome c. Furthermore, our results suggest a strategy for inducing apoptosis in cells overexpressing apoptosis-inhibitory Bcl-2 analogs.
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PMID:The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition. 951 79

Programmed cell death serves as a major mechanism for the precise regulation of cell numbers and as a defense mechanism to remove unwanted and potentially dangerous cells. Despite the striking heterogeneity of cell death induction pathways, the execution of the death program is often associated with characteristic morphological and biochemical changes, and this form of programmed cell death has been termed apoptosis. Genetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential for cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activation of the death program. Caspases (cysteine aspartases) are the mammalian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the first discovered mammalian cell death regulator. In both worm and mammalian cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processing into active killers. Two main mechanisms of action have been proposed to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2s would maintain cell survival by dragging caspases to intracellular membranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosis protease-activating factor 1) could be the mammalian equivalent of CED-4 and could be the physical link between Bcl-2s and caspases. In the second one, Bcl-2 would act by regulating the release from mitochondria of some caspases activators: cytochrome c and/or AIF (apoptosis-inducing factor). This crucial position of mitochondria in programmed cell death control is reinforced by the observation that mitochondria contribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, we examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the maintenance of the symbiosis between the bacterial ancestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival.
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PMID:Mitochondria and apoptosis. 952 6

We identified and cloned a novel murine member of the pro-apoptotic Bcl-2 family. This protein, designated Blk, is structurally and functionally related to human Bik and localized to the mitochondrial membrane. Blk contains a conserved BH3 domain and can interact with the anti-apoptotic proteins Bcl-2 and Bcl-xL. Ectopic expression of Blk in mammalian cells induces apoptosis, which can be inhibited by mutations in the BH3 domain and by overexpression of Bcl-2 or Bcl-xL but not by CrmA. The apoptotic activity of Blk is also inhibited by a dominant negative caspase-9, suggesting that Blk induces apoptosis through activation of the cytochrome c-Apaf-1-caspase-9 pathway.
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PMID:Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. 952 67

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