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)

Ischemia/reperfusion of organs and cells induces apoptosis through a complicated series of changes in mitochondria, mainly the generation of oxygen free radicals, permeability transitions, calcium translocations, and release of apoptogenic factors such as cytochrome c and Bcl-2 family members. The liberation of these factors occurs very early after reoxygenation and it has been assumed that it takes place without any structural alteration of the mitochondrial membranes. The aim of this study was to detect ultrastructural changes of mitochondria in the initial stages of reperfusion at the time when Bcl-2 and succinic dehydrogenase, located in the outer and inner membranes, respectively, were released. Ischemia/reperfusion was produced in adult rats by clamping one renal artery for 60 min and reoxygenating for 60, 120, 180, and 240 min. A model of chemical hypoxia with intra-arterial 50 mM sodium azide served as comparison, allowing free blood flow for 30, 60, 120 and 180 min. Light and electron microscopy, immunostaining for Bcl-2, and enzyme histochemistry for succinic dehydrogenase were performed. Our results showed mitochondrial swelling, rupture of inner and outer membranes, and leakage of mitochondrial matrix into the cytoplasm in ischemia after 120 min of reperfusion. Bcl-2 immunoreactivity and focal lowering of SDH reactivity were also noted and became more pronounced at the same time that the mitochondrial ultrastructure demonstrated more evident changes including rupture of the inner and outer membranes. Our studies seem to indicate that in early ischemia-reperfusion and in chemical hypoxia-induced apoptosis, the earliest ultrastructural changes take place in mitochondria and that swelling and rupture of mitochondrial membranes occur in parallel with the loss of Bcl-2 and SDH activity.
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PMID:Morphologic, biochemical and molecular mitochondrial changes during reperfusion phase following brief renal ischemia. 1119 33

The role of endogenous NO on cell survival was investigated in human melanoma cells and melanocytes. Inducible NO synthase (iNOS) was always expressed in a panel of melanoma cell lines from metastatic lesions and in normal adult melanocytes. iNOS was also detected by immunohistochemistry in melanoma cells from metastases. Release of NO by tumor cells and melanocytes was inhibited by a specific iNOS inhibitor, aminoguanidine (AMG). Inhibition of endogenous NO synthesis did not affect cell cycle progression of melanoma cells but led to cell death by apoptosis, as indicated by Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. By contrast, iNOS inhibition by AMG did not promote apoptosis in normal adult melanocytes. A mitochondrial pathway was involved in melanoma apop tosis, as indicated by altered mitochondrial membrane potential (delta psi(m)) and down-regulation of Bcl-2 protein level after iNOS inhibition. AMG treatment triggered release of caspase-1, enzymatic activation of caspase-3, and degradation of poly(ADP-ribose) polymerase, one of the main caspase-3 substrates. Melanoma cell apoptosis induced by iNOS inhibition was completely blocked by peptide inhibitors of caspase-1 and caspase-3 (Ac-DEVD-CHO and AC-YVAD-CHO) or by an exogenous NO donor, sodium nitroprusside, or by addition of serum. Finally, comparison of control and AMG-treated melanoma cells by pathway-specific gene array analysis indicated that inhibition of NO synthesis led, before induction of apoptosis, to up-regulation of mRNA levels of genes involved in the apoptosis pathway such as Bax, caspase-1, caspase-3, caspase-6, gadd45beta, mdm2, and TRAIL. Taken together, these results indicate that melanoma cell survival is regulated by endogenous NO resulting from iNOS activity.
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PMID:Antiapoptotic role of endogenous nitric oxide in human melanoma cells. 1119 80

We have reported previously that among human prostate cancer cell lines LNCaP but not PC-3 cells undergo apoptosis after treatment with the protein kinase inhibitor staurosporine (STS). We have now further investigated this model to uncover the molecular mechanism causing resistance to STS-induced apoptosis in PC-3 cells. S-100 lysates of both cell lines showed biochemical changes typical of apoptosis after the addition of cytochrome c and dATP, suggesting that the postmitochondrial phase of apoptosis was intact. Upon addition of STS, the proapoptotic molecules Bax and Bad became predominantly mitochondrial in both cell lines. This, in turn, was followed by loss of mitochondrial transmembrane potential, translocation of cytochrome c to the cytosol, activation of caspase-9, -3, and -7, and cleavage of the apoptotic targets, DNA fragmentation factor and poly(ADP-ribose) polymerase, in LNCaP but not in PC-3 cells. Components of the mitochondrial permeability transition pore, adenine nucleotide transporter and voltage-dependent anion channel, were normally expressed in the correct subcellular fraction of both cell lines. Overexpression of the proapoptotic proteins Bax and Bad, fused to a green fluorescent protein but not of green fluorescent protein alone, induced apoptosis in >80% of PC-3 cells. These experiments suggested that a factor protecting the mitochondria of PC-3 cells mediates resistance to STS-induced apoptosis. A wide search among the antiapoptotic Bcl-2 family members was performed, and Bcl-X(L) was found to be overexpressed in PC-3 cells. Experiments down-regulating Bcl-X(L) expression by using the tyrosine kinase inhibitor genistein, sodium butyrate, or an antisense Bcl-X(L) oligonucleotide restored sensitivity to apoptosis in PC-3 cells. Thus, Bcl-X(L) overexpression is one of the mediators of resistance to STS-induced apoptosis in the prostate cancer cell line PC-3.
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PMID:Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. 1124 86

Proatherogenic oxidized low-density lipoprotein (oxLDL) induces endothelial apoptosis. We investigated the anti-apoptotic effects of intracellular and extracellular nitric oxide (*NO) donors, iron chelators, cell-permeable superoxide dismutase (SOD), glutathione peroxidase mimetics, and nitrone spin traps. Peroxynitrite (ONOO-)-modified oxLDL induced endothelial apoptosis was measured by DNA fragmentation, TUNEL assay, and caspase-3 activation. Results indicated the following: (i) the lipid fraction of oxLDL was primarily responsible for endothelial apoptosis. (ii) Endothelial apoptosis was potently inhibited by *NO donors and lipophilic phenolic antioxidants. OxLDL severely depleted Bcl-2 levels in endothelial cells and *NO donors restored Bcl-2 protein in oxLDL-treated cells. (iii) The pretreatment of a lipid fraction derived from oxLDL with sodium borohydride or potassium iodide completely abrogated apoptosis in endothelial cells, suggesting that lipid hydroperoxides induce apoptosis. (iv) Metalloporphyrins dramatically inhibited oxLDL-induced apoptosis in endothelial cells. Neither S-nitrosation of caspase-3 nor induction of Hsp70 appeared to play a significant role in the antiapoptotic mechanism of *NO in oxLDL-induced endothelial apoptosis. We propose that cellular lipid peroxyl radicals or lipid hydroperoxides induce an apoptotic signaling cascade in endothelial cells exposed to oxLDL, and that *NO inhibits apoptosis by scavenging cellular lipid peroxyl radicals.
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PMID:Inhibition of oxidized low-density lipoprotein-induced apoptosis in endothelial cells by nitric oxide. Peroxyl radical scavenging as an antiapoptotic mechanism. 1127 75

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.
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PMID:Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells. 1131 91

Our results demonstrate that sodium phenylbutyrate, a compound with a low degree of toxicity, exerted a cytotoxic effect on human retinoblastoma Y79 cells in a time- and dose-dependent manner. Treatment of Y79 cells for 72 h with phenylbutyrate reduced cell viability by 63% at 2 mM and 90% at 4 mM. Cell death caused by phenylbutyrate exhibited the typical features of apoptosis, as shown by light and fluorescent microscopy. Western blot analysis demonstrated that exposure of Y79 cells to phenylbutyrate decreased the level of the antiapoptotic factor Bcl-2 and induced the activation of caspase-3, a key enzyme in the execution phase of apoptosis. Moreover, treatment with phenylbutyrate markedly increased the level of acetylated histone-H3. Combined treatment with phenylbutyrate and topotecan, a topoisomerase I-inhibitor, resulted in a clear synergistic effect. We suggest that the effects exerted by phenylbutyrate on Y79 cells essentially depend on modifications of gene expression consequent to histone hyperacetylation.
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PMID:Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: the effect of combined treatment with the topoisomerase I-inhibitor topotecan. 1135 Dec 56

The impact of dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/MDA6 has been examined in U937 human monocytic leukemia cells in relation to cell cycle arrest and differentiation following treatment with the histone deacetylase inhibitor sodium butyrate (SB). Cells stably transfected with a p21WAF1/CIP1/MDA6 antisense construct, in marked contrast to their wild-type counterparts, failed to up-regulate p21WAF1/CIP1/MDA6, undergo G1 arrest, or express the maturation marker CD11b when exposed to 1 or 3 mM SB. However, antisense-expressing cells were significantly more susceptible to SB-mediated mitochondrial injury and apoptosis, manifested by increased cytosolic translocation of cytochrome c, activation of pro-caspase 3, and degradation of PARP. Dysregulation of p21WAF1/CIP1/MDA6 did not modify the extent of SB-induced histone acetylation, but did result in cleavage of p27KIP1, Bcl-2 and pRb, as well as diminished levels of full-length underphosphorylated pRb. Finally, dysregulation of p21WAF1/CIP1/MDA6 did not modify SB-mediated down-regulation of E2F-1 or c-Myc, but was associated with enhanced down-regulation of cyclins D1 and E. Together, these findings indicate that in U937 leukemia cells, p21WAF1/CIP1/MDA6 plays a critical functional role in SB-mediated G1 arrest and maturation, and suggest that cells displaying dysregulation of this CDKI respond to SB by engaging a default apoptotic program.
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PMID:Evidence of a functional role for the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). 1140 41

Exposure of insulin-secreting RINm5F cells to the chemical nitric oxide donor sodium nitroprusside (SNP) resulted in apoptotic cell death, as detected by cytochrome c release from mitochondria and caspase 3 activation. SNP exposure also leads to phosphorylation and activation of enzymes involved in cellular response to stress such as signal-regulated kinase 2 (ERK2) and c-Jun NH(2)-terminal kinase 46 (JNK46). Both cytochrome c release and caspase 3 activation were abrogated in cells exposed to MEK and p38 inhibitors. Treatment of cells with the NO donors SNP, DETA-NO, GEA 5024, and SNAP resulted in phosphorylation of the antiapoptotic protein Bcl-2, which was resistant to blockade of MEK, p38, and JNK pathways and sensitive to phosphoinositide 3-kinase (PI3K) inhibition. In addition, transient transfection of cells with the wild-type PI3K gamma gene mimics the increased rate of Bcl-2 phosphorylation detected in NO-treated cells. The generation of phosphoinositides seems to participate in the process since Bcl-2 phosphorylation was not observed in cells overexpressing lipid-kinase-deficient PI3Kgamma. The potential of SNP toxicity directly from NO was supported by our finding that the NO scavenger carboxy-PTIO prevented cell death. We found no evidence to support the contention that oxygen radicals generated during cellular SNP metabolism mediate cell toxicity in RINm5F cells, since neither addition of catalase/superoxide dismutase nor transfection with superoxide dismutase prevented SNP-induced cell death. Thus, we propose that exposure to apoptotic concentrations of NO triggers ERK- and p38-dependent cytochrome c release, caspase 3 activation, and PI3K-dependent Bcl-2 phosphorylation.
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PMID:Sodium nitroprusside-induced mitochondrial apoptotic events in insulin-secreting RINm5F cells are associated with MAP kinases activation. 1157 Aug 14

The central nervous system is one of the main target organs in cyanide toxicity. In this study, primary cultures of chick embryonic neurons were used to characterize sodium cyanide (NaCN)-induced cell death and to investigate the mechanism of NaCN-mediated preconditioning. After treatment of the cells with 1mM NaCN for 1h followed by a NaCN-free incubation period of 23 h, we observed features of apoptosis such as a reduction in nuclear size, chromatin condensation and nuclear fragmentation as evaluated by nuclear staining with Hoechst 33258 and electron microscopy. In addition, NaCN-induced neurotoxicity was reduced by the protein synthesis inhibitor cycloheximide (CHX) suggesting an active type of cell death. Most of the neurons with condensed chromatin and a shrunken nuclei also showed membrane damage at a late stage. Mitochondrial membrane potential as well as the protein levels of Bcl-2 and Bcl-x(L) decreased 15-60 min and 1-3 h after the exposure to NaCN (1mM, 1h), respectively. Preconditioning caused by incubating chick neurons with 100 microM NaCN for 30 min followed by a NaCN-free interval of 24h significantly protected the neurons against subsequent NaCN (1mM, 1h)-induced damage. Preconditioning prevented NaCN-induced decrease in the mitochondrial membrane potential as well as in the protein levels of Bcl-2 and Bcl-x(L) suggesting that preconditioning-induced neuroprotection is mediated by preserving mitochondrial function.
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PMID:Preconditioning-induced protection against cyanide-induced neurotoxicity is mediated by preserving mitochondrial function. 1179 57

Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit tumorigenesis in colorectal cancer due to the induction of apoptosis. Disturbances of cellular pathways ultimately leading to apoptosis may contribute to the process of neoplastic transformation and immortalization. In this study we wanted to determine the influence of different NSAIDs (indomethacin, ibuprofen and sodium salicylate) and hydrocortisone on Bcl-2 expression and the apoptotic behavior of head and neck tumor cell lines and normal oral keratinocytes. Bcl-2 expression was determined by monoclonal antibody staining and fluorescence-activated cell-sorting measurement. Apoptotic cells were visualized with a epifluorescence microscope after staining with CytoDeath M30 antibody. Indomethacin (1 mM) and ibuprofen (1 mM) significantly reduced Bcl-2 expression in the cancer cell lines tested and might be thought responsible for the observed increase in apoptosis. At all concentrations tested the influence of sodium salicylate and hydrocortisone on Bcl-2 expression was not significant. In contrast, the NSAIDs tested had only a minor influence on normal oral keratinocytes. Our results demonstrate a significant reduction in growth and an increase in apoptosis, possibly due to a reduction in Bcl-2 expression. after exposure to indomethacin and ibuprofen in the head and neck cancer cell lines tested.
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PMID:Non-steroidal anti-inflammatory drugs induce apoptosis in head and neck cancer cell lines. 1181 3


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