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)

Intracellular nitric oxide levels may differ in resting and stimulated cells and contribute to the regulation of cell survival and proliferation through a variety of mechanisms and effects. We exposed two B-cell lines to a range of S-nitroso-N-acetyl-D,L-penicillamine (SNAP) concentrations in order to examine their susceptibility to exogenous nitric oxide and the participation of nitric oxide as modulator of cell proliferation. Although both FLEB and NALM-6 decreased their levels of thymidine incorporation, only NALM-6 cells were induced to undergo G1 arrest, phosphatidyl serine exposure and DNA fragmentation when cultured in the presence of 250 microm SNAP. This higher sensitivity of NALM-6 coincided with initially low cyclin E protein levels which were increased 7.8-fold after culture for 24 h with 250 microm SNAP. In contrast, there was no difference in cyclins A and D3, Bcl-2 and actin levels, neither at the beginning nor at the end of the 24 h culture. Our study reveals that FLEB and NALM-6 exhibit different response to the same concentration of nitric oxide, that nitric oxide can simultaneously induce cell cycle alterations and apoptosis, and further suggests an association between these two processes, with the involvement of cell cycle regulatory molecules.
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PMID:Nitric oxide induces apoptosis in NALM-6, a leukaemia cell line with low cyclin E protein levels. 1173 1

Reactive oxygen intermediates (ROI) and nitric oxide (NO(.)) are produced in abundance in the inflammatory muscle diseases of autoimmune origin polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). However, their role in the pathogenesis of these diseases is so far not clear. In contrast to demyelinating neuropathies, there is no convincing evidence for oxide-induced apoptosis either in myocytes or in lymphocytes and phagocytes in inflammatory myopathies. On the contrary, NO(.) released at low concentrations at target sites may even have cell-protective effects. A major mechanism of protection from apoptosis in both myocytes and inflammatory cells seems to be the upregulation of anti-apoptotic proteins like Bcl-2. Caution is warranted to apply antioxidative and anti-apoptotic agents to patients with inflammatory myopathies as long as the pathogenic role of oxides and apoptosis in the individual case is not resolved.
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PMID:Oxides and apoptosis in inflammatory myopathies. 1174 63

The NMDA-type glutamate receptor is a predominant mediator of excitotoxicity in the immature brain due to overexpression of the receptor in the developing brain. Within the development period however, the extent of NMDA receptor mediated processes including hypoxia-induced excitotoxicity may depend on the ontogeny of the NMDA receptor recognition and modulation sites, and subunits leading to altered function of the ion-channel comples. The function of the receptor may be modified by intracellular mechanisms such as phosphorylation/dephosphorylation, nitration, and generation of free radicals including nitric oxide. The susceptibility of the developing brain to hypoxia depends on several factors: the lipid composition of the brain cell membrane; the rate of membrane lipid peroxidation and the status of anti-oxidant defenses; the development and modulation of the NMDA receptor sites; the intracellular Ca(2+) influx mechanisms; expression of apoptotic and antiapoptotic genes such as Bax and Bcl-2; and the activation of initiator caspases and caspase-3, the "executioner" of cell death. The developmental status of these cellular mechanisms and their response to hypoxia determine the fate of the hypoxic cell in the developing brain in the fetus and the newborn.
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PMID:NMDA receptor and neonatal hypoxic brain injury. 1175 18

Protein A (PA) of Staphylococcus aureus has been demonstrated to possess anti-tumor activity against a wide variety of tumors. In the current study we endeavored to obtain a mechanistic insight into PA-mediated Ehrlich's ascites carcinoma (EAC) killing. Our results indicate that PA stimulates generation of nitric oxide (NO) from murine peritoneal macrophages. Nitric oxide in turn induces cytotoxic damage to the tumor cells. Analysis of the morphological features and cell cycle phase distribution pattern of nuclear DNA revealed an induction of apoptosis (appearance of sub-G0/G1 population) in EAC after PA treatment. We have further elaborated the alterations in the expressions of the proto-oncoproteins p53 and Bax, together with a change in the ratio of Bcl-2/Bax in the treated tumor cells, which favor apoptosis. PA-induced apoptosis and changes in the expression of oncoproteins in the tumor cells was prevented by the suppression of NO release by the addition of L-NAME, the competitive NOS inhibitor, suggesting a possible mechanism by which PA exerts its anti-tumor activities involving nitric oxide through the alteration in the expressions of pro-apoptotic proteins.
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PMID:Protein A-activated macrophages induce apoptosis in Ehrlich's ascites carcinoma through a nitric oxide-dependent pathway. 1177 5

Previous studies have shown that cerebral tissue hypoxia results in increased expression of Bax protein, thereby altering the ratio of Bax to Bcl-2 or formation of Bax/Bcl-2 heterodimer. Hypoxia also induces the generation of nitric oxide free radicals in the cerebral cortex of newborn animals. The present study tests the hypothesis that tissue hypoxia will result in nitration of Bax and Bcl-2 proteins in the neuronal nuclei of newborn piglets. Studies were performed in 22 piglets, 3-5 days old, divided into normoxic (n = 7), hypoxic (n = 9) and hypoxic + NNLA (n = 6) groups. Hypoxia was induced by decreasing the FiO(2) (5-7%) for 60 min and cerebral hypoxia documented by determining tissue ATP and phosphocreatine (PCr) levels. The density of protein bands was expressed as absorbance (OD x mm(2)). PCr levels were 3.03 +/- 0.85 micromol/g brain in the normoxic group and 0.88 +/- 0.32 micromol/g brain in the hypoxic group (p < 0.001 vs. normoxia) and 0.55 +/- 0.13 (p < 0.001 vs. normoxia) in the NNLA-treated hypoxic group. There was increased nitration of Bax protein in hypoxic neuronal nuclei as compared to normoxic and NNLA-treated-hypoxic group nuclei: 211.61 +/- 25.93 versus 124.8 +/- 14.88 and 133.86 +/- 7.42 OD x mm(2), respectively (p < 0.001 vs. normoxia). Nitration of Bcl-2 was not altered significantly in either group. We conclude that there is increased nitric oxide-mediated nitration of Bax in cortical neuronal nuclei during hypoxia and that this increase correlates inversely with the decrease in tissue energy levels. We speculate that, during hypoxia, nitration of Bax and Bcl-2 proteins may regulate heterodimer formation and activation of programmed cell death mechanisms.
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PMID:Nitration of Bax and Bcl-2 proteins during hypoxia in cerebral cortex of newborn piglets and the effect of nitric oxide synthase inhibition. 1180 79

The mechanisms of cytoprotection conferred by stress preconditioning remain largely uncharacterized in endothelial cells (EC). We report that stress preconditioning of EC with serum starvation induces the release of soluble mediator(s) that confer resistance to apoptosis, increase proliferation, and enhance angiogenesis in a second set of "non-preconditioned" EC. Preconditioning was found to target specifically the mitochondrial control of apoptosis in EC with increased protein levels of Bcl-2, decreased protein levels of Bax, and decreased cytosolic release of cytochrome c. Regulators of apoptosis acting upstream and downstream of the mitochondria such as p53, cIAP-1, cIAP-2, and XIAP were not altered. Mediators classically associated with preconditioning in other cell types such as adenosine, opioids, and nitric oxide are not implicated in this cytoprotective loop. Blockade of protein kinase C-dependent signaling inhibited cytoprotection of EC. Further characterization of this paracrine pathway should provide insights into the molecular regulation of preconditioning in endothelial cells.
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PMID:Paracrine repercussions of preconditioning on angiogenesis and apoptosis of endothelial cells. 1184 99

Nitric oxide (NO) can induce apoptosis in a variety of cell types. A non-toxic concentration of nitric oxide under normal oxygen conditions triggered cell death under hypoxic conditions (1.5% O(2)) in fibroblasts. Nitric oxide administered during hypoxia induced the release of cytochrome c, caspase-9 activation, and the loss of mitochondrial membrane potential followed by DNA fragmentation and lactate dehydrogenase release (markers of cell death). Bcl-X(L) protected cells from nitric oxide-induced apoptosis during hypoxia by preventing the release of cytochrome c, caspase-9 activation, and by maintaining a mitochondrial membrane potential. Murine embryonic fibroblasts from bax(-/-) bak(-/-) mice exposed to nitric oxide during hypoxia did not die, indicating that pro-apoptotic Bcl-2 family members are required for NO-induced apoptosis during hypoxia. The nitric oxide-induced cell death during hypoxia was independent of cGMP and peroxynitrite. Cells devoid of mitochondrial DNA (rho secondary-cells) lack a functional electron transport chain and were resistant to nitric oxide-induced cell death during hypoxia, suggesting that a functional electron transport chain is required for nitric oxide-induced apoptosis during hypoxia.
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PMID:Hypoxia sensitizes cells to nitric oxide-induced apoptosis. 1186 45

Interleukin 13 receptor (IL-13R)-targeted cytotoxin, IL13-PE38QQR, composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE), is found to be highly and specifically cytotoxic to human solid cancer cell lines. However, the mechanism of tumor cell death mediated by IL-13 toxin is still not known. To elucidate the mechanism, we utilized four head and neck cancer cell lines (SCC-25, HN12, KCCT873, and YCUM911), which express high levels of IL-13R, and IL-13 toxin is highly cytotoxic to these cells. We observed chromatin condensation and DNA fragmentation, indicating apoptotic cell death, after treatment with IL-13 toxin, as determined by bis-benzimide staining and DNA ladder assays. However, IL-13 did not induce cell death. Flow cytometric analysis suggested that these cancer cell lines increased the sub-G1/G0 phase DNA population in a dose- and time-dependent manner (ranged between 10 and 30%) after treatment with IL-13 toxin. By Western blot analysis, cleavage of caspase-3 and PARP was observed after treatment with a high concentration of IL-13 toxin, also suggesting apoptotic cell death. In addition, the results of immunofluorescence and RT-PCR assays showed that the apoptosis-regulator, Bcl-2 was downregulated after treatment with IL-13 toxin, while Bax was upregulated. Moreover, significant nitrite production was detected in the HN12 cell line after treatment with IL-13 toxin for 48--96 h. Taken together, our results suggest that IL-13 toxin-induced cytotoxicity is at least partially mediated by the apoptosis and nitric oxide pathways. This information may be useful in developing specific approaches where apoptotic bodies from tumor cells may be used to pulse antigen-presenting cells for immunotherapy of cancer.
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PMID:Apoptotic pathways of cell death induced by an interleukin-13 receptor-targeted recombinant cytotoxin in head and neck cancer cells. 1186 21

The effects of nitric oxide (NO) donor sodium nitroprusside (SNP) on the proliferation and apoptosis and on Bcl-2, Bax and p53 proteins of pulmonary fibroblasts were investigated by using MTT cleavage assay, agarose gel electrophoresis and flow cytometric analysis. The results showed increases in the optical density (550 nm) of MTT cleavage assay, the number of cells and the proliferation index (PI), in comparison with the control. The number of apoptotic cells was also increased, though the percentage of apoptotic cells was too low to reveal oligonucleosomal fragmentation of characteristic ladder pattern, which is associated with apoptosis. In the meantime, the level of Bcl-2 decreased and that of Bax increased, while the p53 remained unchanged. These results suggest that exogenous NO has a dual effect on proliferation and apoptosis; and the action of NO on pulmonary fibroblasts is mainly proliferative. Down regulation of Bcl-2 and up regulation of Bax are implicated in the molecular mechanisms of this action.
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PMID:Promotion of pulmonary fibroblast proliferation and apoptosis by sodium nitroprusside. 1193 Feb 31

In an effort to better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of beta-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.
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PMID:Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. 1197 40


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