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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Myc transcription factor is involved in the regulation of cellular proliferation and differentiation and is one of the most frequently deregulated genes in human cancers. While c-Myc is known to enhance the proliferative potential of cells, its activation in immortalized fibroblasts has been found to result in apoptosis following gamma-irradiation or under adverse growth conditions, including serum deprivation and hypoxia. When plating Rat-1 fibroblasts at low cell densities (100 cells/100 mm plate), we observed a substantial reduction in the clonogenicity of cells with deregulated c-Myc activity compared to cells with normal c-Myc activity. This difference in clonogenicity was apparent despite the fact that cells were plated in media containing sufficient serum and oxygen concentrations known to suppress apoptosis of exponentially growing Rat-1 fibroblasts with activated c-Myc. Therefore, we hypothesized that the observed reduction in plating efficiency in cells with activated c-Myc occurred via an apoptotic mechanism and that a fibroblast-derived factor was required for suppression of apoptosis. Overexpression of the anti-apoptotic oncogene, Bcl-2, in cells with activated c-Myc restored the plating efficiency to normal levels in cells plated at low cell densities. This strongly suggested that the decreased clonogenicity of fibroblasts with altered c-Myc activity resulted from enhanced apoptosis of the cells under these conditions. Furthermore, plating cells on a feeder layer of lethally-irradiated fibroblasts or in Rat-1 conditioned media increased the plating efficiencies of sparsely plated cells in a dose-dependent fashion. These results suggest that in addition to previously reported requirements for serum-derived growth factors and normal oxygen conditions, a paracrine factor liberated by Rat-1 fibroblasts is required to suppress c-Myc-induced apoptosis in these cells.
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PMID:Myc activation reduces fibroblast clonogenicity via an apoptotic mechanism that can be suppressed by a soluble paracrine factor. 961 79

Viruses have evolved different strategies to interfere with host cell apoptosis. Herpesvirus saimiri (HVS) and other lymphotropic herpesviruses code for proteins that are homologous to the cellular antiapoptotic Bcl-2. In this study HVS-Bcl-2 was stably expressed in the human leukemia cell line Jurkat and in the murine T-cell hybridoma DO to assess its antiapoptotic spectrum and to gain further insight into its mode of action. HVS- Bcl-2 prevented apoptosis that occurs as a result of a disturbance of intracellular homeostasis by, for example, DNA damage or menadione, which gives rise to oxygen radicals. In Jurkat cells, HVS-Bcl-2 also inhibited apoptosis mediated by the death receptor CD95. In DO cells, HVS-Bcl-2 did not interfere with CD95-mediated apoptosis but blocked dexamethasone-induced cell death. Mitochondrial damage is a central coordinating event in apoptosis induced by different stimuli. To assess the integrity of mitochondria, we used rhodamine 123, which is released upon disturbance of the mitochondrial membrane potential, and determined the release of cytochrome c into the cytosol. Both signs of mitochondrial damage were prevented by HVS-Bcl-2. This viral protein also inhibited the generation of caspase-3-like DEVDase activity and blocked the cleavage of poly(ADP-ribose) polymerase, a natural substrate of caspase-3-like proteases. In conclusion, HVS-Bcl-2 protects against a great variety of apoptotic stimuli, stabilizes mitochondria, and acts upstream of the generation of caspase-3-like activity.
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PMID:Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: stabilization of mitochondria and inhibition of caspase-3-like activity. 962 Oct 51

Bcl-2 has a role in suppressing the production of reactive oxygen species and lipid peroxidation. To explore the in situ localization of 4-hydroxy-2-nonenal (HNE)-modified proteins and the Bcl-2 oncoprotein, we used double immunofluorescence labeling and confocal imaging in the rat brain after 3 h of middle cerebral artery (MCA) occlusion followed by reperfusion. Immunoreactivity for HNE or Bcl-2 was not detected at 1 h, but appeared in some intact neurons in the boundary between the infarcted and non-infarcted zones at 12 h. At 48 h, HNE-positive microglia were colocalized with Bcl-2 in the infarcted area and the boundary zone. Bcl-2 may play an important role in the antioxidant system promoting survival of the neurons and activated microglia following reperfusion injury.
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PMID:Colocalization of Bcl-2 and 4-hydroxynonenal modified proteins in microglial cells and neurons of rat brain following transient focal ischemia. 965 17

Transforming growth factor-beta (TGF-beta) has been shown to induce apoptosis on normal hepatocytes and hepatoma cells both in vitro and in vivo. However, how the TGF-beta induces apoptosis is still not clear. We examined the expression of anti-apoptosis proteins and sensitivity to TGF-beta in three well differentiated human hepatoma cell lines. Two TGF-beta sensitive cell lines Hep3B and HuH7 totally lacked Bcl-2. In contrast, the TGF-beta resistant HepG2 cells expressed a substantial amount of Bcl-2. All three cell lines expressed equal amounts of Bcl-X(L), Bcl-X(S) and Bax. Overexpression of Bcl-2 in Hep3B and HuH7 cells protected them from TGF-beta-induced apoptosis. TGF-beta treatment increased intracellular peroxide production and suppressed the expression of glutathione-S-transferase in the Hep3B cells, and these effects were partially suppressed by the overexpression of Bcl-2. These results suggest that Bcl-2 may protect cell from TGF-beta-F-induced apoptosis by interfering TGF-beta generated signals leading to induce reactive oxygen species production.
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PMID:Bcl-2 blocks apoptotic signal of transforming growth factor-beta in human hepatoma cells. 967 89

Bcl-2 is an antiapoptotic protein located in the outer mitochondrial membrane. Cellular perturbations associated with programmed cell death may be the consequence of disrupted mitochondrial function as well as excessive production of reactive oxygen species (ROS). Numerous studies indicate that Bcl-2 is involved in opposing cell death induced by oxidative stimuli, but its mode of action is uncertain. We reexamined the role of Bcl-2 by using a loss-of-function model, Bcl-2 knockout mice. Brains from Bcl-2-deficient mice had a 43% higher content of oxidized proteins and 27% lower number of cells in the cerebellum relative to wild-type mice. Incubation of cerebellar neurons from Bcl-2 +/+ brains with 0.5 mM dopamine caused 25% cell death, whereas in Bcl-2-deficient cells, it resulted in 52% death; glial cells provided protection in both cultures. Splenocytes from Bcl-2-deficient mice were also killed more effectively by dopamine as well as paraquat. Bcl-2-deficient mice did not survive intraperitoneal injection of MPTP, which caused a decrease in dopamine level in the striatum of Bcl-2 +/- brains, which was more significant than in wild-type mice. When compared with Bcl-2 +/+ brains, brains of 8-day-old Bcl-2-deficient mice had higher activities of the antioxidant enzymes GSH reductase (192%) and GSH transferase (142%), whereas at the age of 30 days, GSH peroxidase was significantly lower (66%). Activities of GSH transferase and GSH reductase increased significantly (158 and 262%, respectively) from day 8 to day 30 in Bcl-2 +/+ mice, whereas GSH peroxidase decreased (31%) significantly in Bcl-2 -/- animals. In summary, our results demonstrated enhanced oxidative stress and susceptibility to oxidants as well as altered levels of antioxidant enzymes in brains of Bcl-2-deficient mice. It is concluded that Bcl-2 affects cellular levels of ROS, which may be due to an effect either on their production or on antioxidant pathways.
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PMID:Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. 968 65

As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
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PMID:Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. 969 72

Polymorphonuclear leukocytes (PMN) isolated from the oral cavity of healthy human volunteers, spontaneously generated superoxide, nitric oxide (NO) and other reactive oxygen species (ROS) which exhibited strong luminol chemiluminescence (LCL). To understand the physiological roles of oral PMN (OPMN), biochemical properties of the cells were analyzed. Biochemical analysis revealed that OPMN were already primed under physiological conditions. Western blot analysis revealed that they strongly expressed the inducible type of NO synthase (NOS II) and exhibited the activity to catalyze tyrosine phosphorylation of various proteins including a 115 kDa protein (cbl product). OPMN also generated H2O2 and .OH by some superoxide dismutase (SOD)-sensitive mechanism and released myeloperoxidase (MPO). Kinetic analysis using specific inhibitors revealed that OCl- generated by OPMN was predominantly responsible for the enhanced LCL. During the incubation under standard culture conditions, OPMN underwent apoptosis which proceeded more rapidly than that of the circulating PMN (CPMN). Immunochemical analysis revealed that expression of apoptosis-related gene products, such as Bcl-2, Bcl-xL and Bax, was below detectable levels with both cell types. However, caspase-3 but not caspase-1 was markedly activated in OPMN. These results indicate that the primed OPMN spontaneously generate ROS and play an important role in the defense mechanism in the oral cavity and that the generated ROS activate caspase-3 thereby inducing apoptosis of the cells.
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PMID:Biochemical properties of human oral polymorphonuclear leukocytes. 970 29

Recent reports have implicated a possible role of reactive oxygen species (ROS) in the induction and mediation of apoptosis and DNA damage. Oxidative DNA base modification induced by cupric nitrilotriacetate (Cu-NTA) and the following apoptosis were observed in human promyelocytic leukemia HL-60 cells. We measured the level of ROS in the cells by using a fluorescence probe, 2',7'-dichlorofluorescein diacetate (DCFH-DA), and the amount of a modified DNA base, 8-hydroxydeoxyguanosine (8-OHdG) by HPLC-ECD. It was found that Cu-NTA exposure significantly enhanced ROS and 8-OHdG formation in the cells. Meanwhile, we observed both DNA fragmentation and morphological changes characteristic of apoptosis, which was also determined quantitatively by flow cytometry and showed dose- and time-dependent manners. Furthermore, several antioxidants such as dimethyl sulfoxide (DMSO), superoxide dismutase (SOD), and catalase were used to detect whether the apoptosis could be blocked. Only DMSO protected against this form of cell death. To elucidate molecular events in the apoptosis, expressions of Bcl-2 protein family members, such as Bcl-2, Bcl-X and Bax, and heat shock protein 70 (HSP-70) were measured by western blotting using specific antibodies. The levels of Bax and Bcl-Xs remained largely unchanged, but the Bcl-2 and Bcl-XL expression showed down-regulation. After 24 h incubation in the presence of copper, the levels of Bcl-2 and Bcl-XL reduced about 33.8% and 51.1% compared with untreated cells, respectively. Furthermore, after 16 h incubation, the level of HSP-70 expression was about 3.4-fold greater than that in untreated cells, suggesting that HSP-70 is important in increasing resistance to oxidative stress induced by Cu-NTA. But overexpression of HSP-70 failed to protect HL-60 cells from apoptosis induced by Cu-NTA. We inferred that Cu-NTA may induce oxidative DNA damage through free radical injuries, which may turn on the apoptosis in HL-60 cells.
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PMID:Cupric nitrilotriacetate induces oxidative DNA damage and apoptosis in human leukemia HL-60 cells. 974 94

Overexpression of the proto-oncogene bcl-2 has been shown to protect a variety of cell types from oxidative and non-oxidative injury, blocking apoptotic and necrotic types of cell death. Retroviral vectors were used to stably overexpress bcl-2 in primary murine astrocyte cultures with more than 95% efficiency. Compared to beta-galactosidase-expressing and uninfected control cells, bcl-2 overexpressing astrocytes suffered < 40% injury after 24 h glucose deprivation, while controls were essentially completely injured. After exposure to 0.2 mM hydrogen peroxide, the bcl-2 overexpressing astrocytes suffered < 40% the injury seen in controls. In contrast, when the cultures were injured by combined oxygen-glucose deprivation, no difference in the extent or time course of injury was found between cells overexpressing bcl-2 and those expressing beta-galactosidase. To investigate one possible mechanism of bcl-2 protection, we measured the levels of glutathione and three antioxidant enzymes. Astrocytes overexpressing bcl-2 had elevated glutathione levels (130-200%), increased superoxide dismutase (170%) and glutathione peroxidase (140%) activities compared with beta-galactosidase-expressing controls. Bcl-2 overexpressing astrocytes suffered less lipid peroxidation after glucose deprivation, as assessed by cis-parinaric acid fluorescence, and demonstrated more rapid removal of hydrogen peroxide from the medium. When glutathione levels were decreased 80% by pretreatment with buthionine sulfoximine, the extent of protection from glucose deprivation of bcl-2 overexpressing cells was decreased by about half. Increased antioxidant defence contributes to protection from glucose deprivation in bcl-2 overexpressing astrocytes.
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PMID:Potentiation of murine astrocyte antioxidant defence by bcl-2: protection in part reflects elevated glutathione levels. 974 79

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Du145) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.
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PMID:BMD188, A novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases. 976 36


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