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)

Ara-C has been shown to induce apoptosis of human acute myelogenous leukemia HL-60 cells. The DNA repair enzyme poly(ADP-ribose) polymerase (PARP) is known to be degraded during apoptosis. PARP as a substrate is cleaved by the Yama protease, encoded by the CPP32beta/Yama gene. Yama belongs to the interleukin 1beta converting enzyme/ced-3 family of cysteine proteases that are activated as a cascade, producing proteolytic cleavage of specific substrates that results in the morphological and biochemical features of apoptosis. In the present studies, we determined the effect of high intracellular levels of the antiapoptosis Bcl-2 or Bcl-xL protein on Yama protease activation and PARP degradation during Ara-C-induced apoptosis. For this, we utilized HL-60/Bcl-2, HL-60/Bcl-xL, or control HL-60/neo cells, which were created by transfection of the cDNA of the bcl-2, bcl-xL, or the neomycin-resistant genes, respectively. As compared to HL-60/neo, HL-60/Bcl-2 and HL-60/Bcl-xL cells have 5-fold greater expression of Bcl-2 and Bcl-xL, respectively. However, these cell lines have similar levels of p32Yama and PARP. Treatment with 10 or 100 microM Ara-C for 4 h produced DNA fragmentation and morphological features of apoptosis in HL-60/neo cells. This was associated with the cleavage and activation of p32Yama and PARP degradation but not with the induction of Yama mRNA. In contrast, in HL-60/Bcl-2 and HL-60/ Bcl-xL cells, Ara-C-induced p32Yama activation by its cleavage, PARP degradation and apoptosis were significantly inhibited. High Bcl-2 and Bcl-xL levels in these cells also inhibited Yama protease activity, PARP degradation, and apoptosis due to clinically relevant concentrations of etoposide and mitoxantrone. These results suggest that the activation of the Yama protease and PARP degradation are involved in Ara-C-, etoposide-, or mitoxantrone-induced apoptosis. In addition, they suggest that Bcl-2 and Bcl-xL antagonize drug-induced apoptosis by a mechanism that interferes in the activity of a key cysteine protease that is involved in the execution of apoptosis.
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PMID:Overexpression of Bcl-2 or Bcl-xL inhibits Ara-C-induced CPP32/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells. 884 Sep 93

Permanent occlusion of the middle cerebral artery in rats was used to assess the effects of focal ischemia on the expression of members of the bcl-2 family which have been implicated in the regulation of programmed cell death. Intraluminal occlusion of one middle cerebral artery for 6 h resulted in histologically detectable brain damage within the ipsilateral caudate putamen, basolateral cortex and parts of the thalamus. In the infarcted basolateral cortex and thalamus fragmentation of DNA was detected in many nuclei using in-situ end-labeling of DNA breaks by terminal transferase, whereas only scattered labeled nuclei were visible in the infarcted caudate putamen. Immunohistochemical analysis revealed activation of c-Fos in the infarcted cortex and thalamus and in the non-infarcted cingulate cortex as has been shown by others. A decrease in immunoreactivity for Bcl-2, and Bcl-X and an increase in immunostaining for Bax was observed exclusively in neurons within the ischemic cortex and thalamus. Within the infarcted caudate putamen, however, protein levels of all bcl-2 family members declined and c-Fos remained absent. By reverse transcription and polymerase chain reaction it was demonstrated that levels of bcl-2 mRNA markedly decreased in the ipsilateral hemisphere, whereas the amount of bax mRNA was elevated. These findings suggest that a shift in the ratio of cell death repressor Bcl-2 to cell death effector Bax and a concomitant activation of c-Fos may contribute to neuronal apoptosis in the infarcted thalamus and cortex.
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PMID:Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. 887 9

The apoptosis-regulating proteins Bcl-2, Bax, Bcl-X, Bak, and Mcl-1 were examined by immunohistochemical methods in 48 archival specimens of adenocarcinoma of the stomach, and the results were correlated with tumor histology (intestinal versus diffuse pattern) and clinical stage (early- versus late-stage disease, ie, stages I and II versus stage III). Tumor cells containing immunostaining for the anti-apoptotic proteins Bcl-2, Bcl-X, and Mcl-1 were present in 26 (54%), 41 (85%), and 36 (75%) of the 48 cases evaluated, respectively, whereas immunopositivity for the pro-apoptotic proteins Bax and Bak was found in 44 (92%) and 42 (88%) specimens Comparisons of these immunostaining results with tumor histology revealed statistically significant differences for Bax (P = 0.03), Bcl-X (P = 0.003), and Mcl-1 (P = 0.005), which were all more frequently immunopositive for tumors with an intestinal than a diffuse histological pattern (chi 2 analysis). In addition, the percentage of immunopositive tumor cells was significantly higher for Bcl-X (62 +/- 6% versus 45 +/- 6%, mean +/- SE, P = 0.01) and for Mcl-1 (48 +/- 6% versus 30 +/- 6%; P = 0.04) in tumors with intestinal versus diffuse histology (unpaired t-test). In contrast, the percentage of Bcl-2-immunopositive tumor cells was higher in tumors with diffuse histology compared with intestinal (32 +/- 5% versus 12 +/- 5%; P = 0.01), whereas the percentages of Bax- and Bak-immunopositive tumor cells were not significantly different between these two histological types. In 34 specimens, residual normal gastric epithelial cells (foveolar cells) were present for direct comparisons of immunointensity with tumor cells. The immunointensity for the Bcl-2, Bcl-X, and Mcl-1 proteins was stronger in tumor cells compared with normal foveolar cells in 7 (21%), 15 (44%), and 8 (2.1%) of 34 cases, respectively, whereas the immunointensity of the proapoptotic proteins Bax and Bak was reduced compared with normal cells in 8 (24%) and 24 (71%) cases. Immunointensity, however, did not correlate with histology. clinical stage was not significantly associated with the presence or absence of immunopositive tumor cells, the percentage of immunopositive cells, or immunointensity. Taken together, these results establish for the first time that several Bcl-2 family proteins are expressed in gastric adenocarcinomas and suggest that the repertoire of these proteins may differ depending on the histological type. The findings therefore support the notion that the intestinal and diffuse types of gastric cancer arise at least in part through different mechanisms.
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PMID:Immunohistochemical analysis of Bcl-2 family proteins in adenocarcinomas of the stomach. 890 34

Using in situ hybridization, Northern blotting and RT-PCR we studied the post-ischemic expression of bcl-2, bcl-x, bax and ICE. One day following 5 min or 10 min of global ischemia bcl-2 and bcl-x mRNAs were induced in CA1 hippocampal pyramidal neurons while bax was unchanged. By 72 h after ischemia the expression of bcl-2, bcl-x and bax mRNAs decreased in CA1. The large isoform of bcl-x (bcl-xL), detected using RT-PCR, decreased in whole hippocampus by 24-72 h after ischemia relative to the putative short (bcl-xS) and transmembrane deleted (bcl-x delta TM) forms. Oligonucleotides to interleukin-1 beta convertase (ICE), which detected the expected 2-kb transcript and two lesser 1.5- and 3-kb hybridizing species, demonstrated slight mRNA induction in the CA1 region at 72 h following ischemia. DNA nick end-labeling at 3 days following ischemia showed DNA fragmentation in neurons limited to the CA1 region of hippocampus following 5 min ischemia, while DNA fragmentation was detected in CA1, CA3, dentate gyrus and cortical neurons following 10 min ischemia. The data support the view that hippocampal neurons might undergo an apoptosis-like death after global ischemia. Since global ischemia decreases total protein synthesis especially in the CA1 region, the increases in bcl-2 mRNA levels may not necessarily lead to increased Bcl-2 protein levels. This may explain why the CA1 neurons die despite the prominent induction of the protective bcl-2 gene. The observed decrease by 24 h in the bcl-xL/bcl-xS ratio which preceded DNA fragmentation may participate in the cell death produced by ischemia. However, because of the ischemia-induced decrease in total protein synthesis, the decreased bcl-xL/bcl-xS ratio does not necessarily lead to a changed ratio in the amount of the appropriate proteins. Since ICE-like mRNA was induced at 72 h when the CA1 neurons were dead, the significance of this ICE-like mRNA induction remains unclear.
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PMID:Global ischemia induces apoptosis-associated genes in hippocampus. 891 83

Bcl-2 was first identified as a novel transcript associated with the t(14;18) chromosomal breakpoint which occurs in most follicular lymphomas. The deregulated expression of bcl-2 was found to contribute to multistep neoplasia through the suppression of cell death, or apoptosis, in transgenic mouse models. Bcl-2 was subsequently shown to be normally expressed in a variety of tissues and to significantly inhibit the induction of apoptosis in many experimental systems. Bcl-2 is now known to be structurally similar to other proteins, in particular within the domains referred to as BH1 and BH2. This multigene family of cell death regulators includes members which enhance rates of apoptosis, including bcl-xs and bax, and those which inhibit apoptosis, including MCL-1 and bcl-xL. Members of the bcl-2 family physically interact with other proteins, including other family members and these interactions appear to modulate their function. The mechanism(s) by which bcl-2 family members regulate cell death remain in large part unknown, although recent evidence suggests that bcl-2 may interfere with cellular signalling events involved in apoptosis induction.
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PMID:Importance of the Bcl-2 family in cell death regulation. 891 32

One of the principal mechanisms thought to maintain B cell tolerance to self Ags is deletion of cells bearing functional IgM receptors for self Ag via apoptosis in the bone marrow. Because of its characteristic growth arrest and apoptosis in response to surface IgM cross-linking, the B cell line WEHI-231 has been a useful model system for studies of Ag receptor-mediated apoptosis. Unmethylated CpG dinucleotides in oligonucleotides (CpG DNA) can be strong B cell mitogens. In the present study we evaluated whether CpG DNA can rescue WEHI-231 cells from anti-IgM-induced cell cycle arrest and apoptosis. The addition of CpG DNA protected WEHI-231 cells from anti-IgM-mediated apoptosis as well as growth arrest. The protective effect of CpG DNA was dependent on the presence of unmethylated CpG dinucleotides. Kinetic analyses showed that the addition of CpG DNA can be delayed for up to 3 h after anti-IgM treatment with no decrease in the protection. CpG DNA reversed anti-IgM-induced down-regulation of c-myc expression in WEHI-231 and up-regulated myn, bcl2, and bcl-xL mRNA expression. Our results suggest that CpG DNA protection of WEHI-231 cells from anti-IgM-induced apoptosis may be mediated by specific and/or cooperative interactions of multiple genes and that CpG DNA could be a useful tool for studies of B cell tolerance.
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PMID:CpG DNA rescue of murine B lymphoma cells from anti-IgM-induced growth arrest and programmed cell death is associated with increased expression of c-myc and bcl-xL. 894 96

Numerous studies have demonstrated a prolonged expression of c-Jun transcription factor in neurons following axotomy, and it has been hypothesized that c-Jun may be causally involved in neuroregeneration in vivo. By contrast, there is growing evidence from in vitro studies that induction of c-Jun may be necessary for neuronal cell death induced by growth factor starvation. It has been demonstrated that protein levels of cell death repressor Bcl-2 and cell death promotor Bax determine the threshold for neuronal cell death and that their expression is dynamically modulated at the onset of neurodegeneration. In the present study, we investigated by double-immunolabeling methods activation of c-Jun transcription factor and expression of members of the Bcl-2 family of cell death effector proteins in axotomized neurons. Six days after transection of the sciatic nerve in young rats, when axotomized neurons start to degenerate, strong nuclear Jun immunostaining in spinal cord motoneurons was associated with intense cytoplasmic Bax labeling and signs of neuronal atrophy. Bcl-2 and Bcl-X proteins were present only at moderate to low levels. In situ end-labeling by terminal transferase revealed nuclear DNA fragmentation in scattered motoneurons of the ipsilateral ventral horn (1 or 2 labeled nuclei per section). In the L5 dorsal root ganglia (DRG) levels of Bax, Bcl-2, and Bcl-X proteins were highly variable. High levels of Bax immunoreactivity together with intense Jun immunofluorescence were frequently observed in small-diameter sensory neurons. RT-PCR analysis revealed expression of exclusively the anti-apoptotic bcl-xL mRNA isoform in rat DRG which decreased significantly following sciatic nerve transection. These findings indicate that the high susceptibility of central neurons and small-sized DRG neurons to axotomy-induced cell death might be related to their low ratio of cell death repressor Bcl-2 and Bcl-XL to cell death promotor Bax expression. It should be noted, however, that numerous strongly Jun-positive DRG neurons contained low levels of Bax or high levels of Bcl-2 and Bcl-X immunoreactivity. Thus, high levels of c-Jun protein in axotomized neurons do not necessarily suggest a destination to die, and other factors may determine the outcome of axotomy.
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PMID:Expression pattern of candidate cell death effector proteins Bax, Bcl-2, Bcl-X, and c-Jun in sensory and motor neurons following sciatic nerve transection in the rat. 895 44

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.
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PMID:Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. 895 29

bcl-x is a member of the bcl-2 family of genes and by alternative splicing gives rise to two distinct mRNAs: bcl-xL and bcl-xS. We have previously investigated the expression of Bcl-x in neuroblastoma (NB) cell lines and have shown that Bcl-xL is expressed and functions to inhibit chemotherapy-induced apoptosis. However, none of the NB cell lines expressed Bcl-xS. The aim of the present study was to determine the effects of Bcl-xS expression on the viability of NB cells. A panel of NB cell lines (CHP-382, GOTO, SHEP-1, SHSY-5Y, and GI-CA-N) were infected with either a bcl-xS adenovirus (pAdRSV-bcl-xS) or a control virus (pAdRSV-lac-z). NB cells showed loss of viability with both viruses, although the bcl-xS virus was most toxic. Importantly, infection with the bcl-xS adenovirus resulted in rapid loss of cell viability, DNA fragmentation, and morphological features of apoptosis even in NB cells transfected to overexpress Bcl-2 and Bcl-xL. These findings suggest that deregulated expression of Bcl-xS using an adenovirus may provide a novel mechanism for initiating cell death in tumors that express Bcl-2 or Bcl-xL.
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PMID:Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. 897 Nov 84

Bax alpha can heterodimerize with Bcl-2 and Bcl-X(L), countering their effects, as well as promoting apoptosis on overexpression. We show that bax alpha transgenic mice have greatly reduced numbers of mature T cells, which results from an impaired positive selection in the thymus. This perturbation in positive selection is accompanied by an increase in the number of cycling thymocytes. Further to this, mature T cells overexpressing Bax alpha have lower levels of p27Kip1 and enter S phase more rapidly in response to interleukin-2 stimulation than do control T cells, while the converse is true of bcl-2 transgenic T cells. These data indicate that apoptotic regulatory proteins can modulate the level of cell cycle-controlling proteins and thereby directly impact on the cell cycle.
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PMID:Bax alpha perturbs T cell development and affects cell cycle entry of T cells. 900 75


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