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)

Cytochrome C is a mitochondrial protein that induces apoptosis when released into the cytosol or when added to cell-free extracts. Here we show that cells that overexpress the Bcl-2-related protein Bcl-xL fail to accumulate cytosolic cytochrome C or undergo apoptosis in response to genotoxic stress. Coimmunoprecipitation studies demonstrate that Bcl-xL associates with cytochrome C. Cytochrome C binds directly and specifically to Bcl-xL and not to the proapoptotic Bcl-xs protein. The results also demonstrate that Bcl-xs blocks binding of cytochrome C to Bcl-xL. Our findings support a role for Bcl-xL in protecting cells from apoptosis by inhibiting the availability of cytochrome C in the cytosol.
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PMID:Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. 919 70

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

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A-sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.
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PMID:Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. 976 33

The inhibition of protein tyrosine phosphatases by pervanadate, a potent activator of B- and T-cells through the induction of tyrosine phosphorylation and downstream signaling events in different activation cascades, efficiently induced apoptosis in lymphoid cell lines. Pervanadate-elicited apoptosis could be blocked by the tyrosine kinase inhibitor herbimycin A. This apoptotic process involved the activation of caspases 3, 8 and 9, the induction of mitochondrial permeability transition, the release of cytochrome C and the fragmentation of chromosomal DNA. T-cells lacking the CD95 receptor or caspase-8 and T-cells stably overexpressing a transdominant negative form of the adaptor protein FADD were still susceptible to pervanadate-induced apoptosis, excluding the involvement of the CD95 system or other FADD-dependent death receptors. The apoptotic program initiated by the inhibition of tyrosine phosphatases did not require the presence of the tyrosine kinase p56lck or phosphatase CD45, whereas Bcl-2 overexpression protected T-cells from pervanadate-induced cytochrome C release, caspase-8 cleavage and apoptosis.
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PMID:Inhibition of tyrosine phosphatases induces apoptosis independent from the CD95 system. 1051 Apr 65

Despite the capacity for antigen-specific activation and rapid clonal expansion, homeostatic mechanisms ensure that the mature immune system contains a relatively stable number of T cells. In recent years, it has become apparent that this stability is a consequence of apoptotic death of most of the specific T cells generated during an immune response. Clearly this process must be tightly regulated in order to retain sufficient T-cell progeny to mediate an effective response, whilst allowing the rapid deletion of these cells at the end of the response to prevent lymphadenopathy and cross-reactive autoimmunity. In this study, the factors that regulate the sensitivity of T cells to apoptosis were investigated in vitro after the induction of primary T-cell activation within a mixed lymphocyte reaction (MLR). It was found that activated T cells rapidly acquire the expression of both Fas and Fas ligand (FasL) on their surface and contain high levels of the precursor form of the pro-apoptotic enzyme, caspase 8 (FLICE). However, these T cells were resistant for up to 5 days to apoptosis following the stimulation of Fas; a maximal apoptotic response was observed after 7 days. This time point coincided with a marked reduction in expression of the FLICE inhibitory protein (FLIP) and maximal activity of caspase 8. At time points beyond day 7, the number of viable cells in the MLR decreased further despite a reduction in the expression of FasL. However, the expression of interleukin-2 (IL-2) at these late time points was low, resulting in a decrease in expression of the anti-apoptotic protein Bcl-2. This can produce apoptosis by allowing leakage of cytochrome-c from mitochondria resulting in direct activation of the caspase cascade. In this study, it is shown that T cells are resistant to apoptosis for the first 5 days after activation as a consequence of insensitivity of the Fas pathway and the presence of intracellular Bcl-2. After between 5 and 7 days, the cells become sensitive to Fas-mediated apoptosis while retaining Bcl-2 expression. At later time points, Fas ligation is reduced but the cells respond to a decreased availability of IL-2 by reducing Bcl-2 expression; this encourages further apoptosis by allowing the direct activation of caspase enzymes.
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PMID:Regulation of T-cell apoptosis: a mixed lymphocyte reaction model. 1092 50

Previously, we reported that chelation of intracellular zinc with N, N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN)-induced macromolecule synthesis-dependent apoptosis of cultured cortical neurons. According to the current theory of apoptosis, release of mitochondrial cytochrome C into the cytosol is required for caspase activation. In the present study, we examined whether cytochrome C release is dependent on macromolecule synthesis. Exposure of cortical cultures to 2 microM TPEN for 24 hr induced apoptosis as previously described. Fluorescence immunocytochemical staining as well as immunoblots of cell extracts revealed the release of cytochrome C into the cytosol 18-20 hr after the exposure onset. The cytochrome C release was completely blocked by the addition of cycloheximide or actinomycin D. Addition of the caspase inhibitor zVAD-fmk did not attenuate the cytochrome C release, whereas it blocked TPEN-induced apoptosis. Because Bcl-2 has been shown to block cytochrome C release potently, we exposed human neuroblastoma cells (SH-SY5Y) to TPEN. Whereas Bcl-2 overexpression completely blocked both cytochrome C release and apoptosis induced by staurosporine, it attenuated neither induced by TPEN. The present results suggest that, in neurons, macromolecule synthesis inhibitors act upstream of cytochrome C release to block apoptosis and that, in addition to the classical Bcl-2 sensitive pathway, there may exist a Bcl-2-insensitive pathway for cytochrome C release.
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PMID:Protein synthesis-dependent but Bcl-2-independent cytochrome C release in zinc depletion-induced neuronal apoptosis. 1095 20

Apoptosis or programmed cell death, is essential for the normal functioning and survival of most multi-cellular organisms. The morphological and biochemical characteristics of apoptosis, however, are highly conserved during the evolution. It is currently believed that apoptosis can be divided into at least three functionally distinct phases, i.e. induction, effector and execution phase. Recent studies have demonstrated that reactive oxygen species (ROS) and the resulting oxidative stress play a pivotal role in apoptosis. Antioxidants and thiol reductants, such as N-acetylcysteine, and overexpression of manganese superoxide (MnSOD) can block or delay apoptosis. Bcl-2, an endogenously produced protein, has been shown to prevent cells from dying of apoptosis apparently by an antioxidative mechanism. Taken together ROS, and the resulting cellular redox change, can be part of signal transduction pathway during apoptosis. It is now established that mitochondria play a prominent role in apoptosis. During mitochondrial dysfunction, several essential players of apoptosis, including pro-caspases, cytochrome C, apoptosis-inducing factor (AIF), and apoptotic protease-activating factor-1 (APAF-1) are released into the cytosol. The multimeric complex formation of cytochrome C, APAF-1 and caspase 9 activates downstream caspases leading to apoptotic cell death. All the three functional phases of apoptosis are under the influence of regulatory controls. Thus, increasing evidences provide support that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in pathophysiology of some of the chronic diseases including AIDS, autoimmunity, cancer, diabetes mellitus, Alzheimer's and Parkinson's and ischemia of heart and brain.
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PMID:Oxidative stress and apoptosis. 1099 8

Previous studies have shown that alpha-adrenergic activation reduces myocardial damages caused by ischemia/reperfusion. However, the molecular mechanisms of how alpha-adrenergic activation protects the myocardium are not completely understood. The objective of this study was to test the hypothesis that alpha-adrenergic activation protects the myocardium by, at least in part, inhibiting apoptosis in cardiomyocytes. The current data has shown that apoptosis in neonatal rat cardiomyocytes, induced by 24 h treatment with hypoxia (95% N2 and 5% CO2) and serum deprivation, was inhibited by co-treatment with phenylephrine. Pre-treatment with phenylephrine for 24 h also protected cardiomyocytes against subsequent 24 h treatment with hypoxia and serum deprivation. Exposure of cardiomyocytes to phenylephrine for up to 9 days under normoxic conditions did not cause apoptosis. The phenylephrine-mediated cytoprotection was blocked by an alpha-adrenergic antagonist, phentolamine. beta-adrenergic activation with isoproterenol did not protect cardiomyocytes against hypoxia and serum deprivation-induced apoptosis. Under hypoxic conditions, phenylephrine prevented the down-regulation of Bcl-2 and Bcl-X mRNA/protein and induced hypertrophic growth. Phenylephrine-mediated protection was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin and was mimicked by the caspase-9 peptidic inhibitor LEHD-fmk. These results suggest that alpha-adrenergic activation protects cardiomyocytes against hypoxia and serum deprivation-induced apoptosis through regulating the expression of mitochondrion-associated apoptosis regulatory genes, preventing activation of mitochondrial damage-induced apoptosis pathway (cytochrome C-caspase-9), and activating hypertrophic growth.
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PMID:Phenylephrine protects neonatal rat cardiomyocytes from hypoxia and serum deprivation-induced apoptosis. 1104 72

We hypothesized that diabetic sensory neuropathy is associated with activation of apoptosis and concomitant mitochondrial dysfunction. Studies were performed in excised intact and acutely dissociated dorsal root ganglion (DRG) neurons from control and streptozotocin-induced diabetic rats with decreased peripheral nerve conduction velocities (NCV). Apoptosis was increased in acutely dissociated DRG neurons from 3- to 6-week-old diabetic rats. Basal mitochondrial membrane potential (deltapsi) was significantly more positive in DRG neurons from diabetic rats. Depolarization with glutamate resulted in significantly more positive deltapsi and delayed recovery of deltapsi in neurons from diabetic rats. Restoration of euglycemia for 2 weeks with insulin implants normalized NCV, deltapsi, and apoptosis. Intact and acutely dissociated neurons from diabetic rats demonstrated decreased Bcl-2 levels and translocation of cytochrome C from the mitochondria to the cytoplasm. Neither levels of Bax nor levels of Bcl-XL were altered in diabetic neuropathy. Apoptosis associated with mitochondrial dysfunction may contribute to the pathogenesis of diabetic sensory neuropathy.
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PMID:Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. 1107 62

Avian spinal motoneurons have been well characterized with regard to developmental programmed cell death (PCD). Approximately 50% of the neurons originally generated undergo cell death as they innervate their target muscles, and target derived trophic support plays an important role in regulating survival of these neurons. To investigate events mediating motoneuron PCD, we have examined the role of Bcl-2 family proteins, cytochrome C, and caspase-9 in this process. We report that while protein levels of Bcl-2, Bcl-xL, and Bax do not change within motoneurons as they become committed to die, a translocation of Bax from the cytosol to organelle membranes and the nucleus occurs coincident with the time when motoneurons become committed to cell death. In addition, cytochrome C is released from mitochondria to the cytosol in dying cells prior to the activation of caspases. Consequently, an enhanced caspase-9-like activity was detected in dying cells, and this activity was upstream and necessary for the appearance of a caspase-3-like activity. These results allow us to further define some of the critical events that mediate the execution phase of motoneuron death following trophic factor deprivation.
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PMID:Characterization of the execution pathway of developing motoneurons deprived of trophic support. 1118 Jan 53


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