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)

Bcl-2 and Bax are homologous proteins which can heterodimerize with each other. These proteins have opposing effects on cell survival when overexpressed in cells, with Bcl-2 blocking and Bax promoting apoptosis. Here we demonstrate that gene transfer-mediated elevations in Bcl-2 protein levels result in a marked increase in the steady-state levels of endogenous p21Bax protein as determined by immunoblotting in the Jurkat T-cell and 697 pre-B-cell leukemia cell lines, but not in several other cell lines including CEM T-cell leukemia, 32D.3 myeloid progenitor, PC12 pheochromocytoma, and NIH-3T3 fibroblasts. Steady-state levels of p21Bax protein were also elevated in the lymph nodes of Bcl-2 transgenic mice in which a BCL-2 transgene is expressed at high levels in B-cells. Northern blot analysis of BCL-2-transfected and control-transfected Jurkat and 697 leukemia cells revealed no Bcl-2-induced alterations in the steady-state levels of BAX mRNAs. In contrast, L-[35S]methionine pulse-chase analysis indicated a marked increase in the half-life (t1/2) of the p21Bax protein in BCL-2-transfected 697 cells compared to control-transfected cells (t1/2 > 24 h versus approximately 4 h), whereas the rate of Bax degradation was unaltered in Bcl-2-transfected CEM cells. The results demonstrate that levels of the proapoptotic p21Bax protein can be post-translationally regulated by Bcl-2, probably in a tissue-specific fashion, and suggest the existence of a feedback mechanism that may help to maintain the ratio of Bcl-2 to Bax protein in physiologically appropriate ranges.
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PMID:Overexpression of the Bcl-2 protein increases the half-life of p21Bax. 759 1

In this study, we investigated the responses of the T cell leukaemia cell line, CCRF-CEM, and a vincristine-resistant subline, CEM/VCR R, to the induction of cell death by serum withdrawal. This treatment was used to overcome any contribution of P-glycoprotein-mediated drug resistance to the responses of the CEM/VCR R cells. Following serum withdrawal both cell lines exhibited typical apoptotic responses including morphological changes and nucleosomal cleavage of the DNA. However, using several different assays for cell death the CEM/VCR R cell line was shown to undergo apoptosis at a slower rate than the parental CCRF-CEM cell line. Expression of c-Myc, Bcl-2 and p53 was found to be similar in both cell lines, discounting involvement of these proteins in the observed difference in apoptotic response. Given our previous finding that reorganisation of tubulin is involved in apoptosis, we examined the expression of alpha-, beta- and acetylated alpha-tubulin in the parental and resistant lines. The CEM/VCR R cell line had altered tubulin expression when compared to that of the CCRF/CEM line. Transnuclear microtubule networks were observed in log phase CEM/VCR R cells. In addition, increased expression of the acetylated form of the alpha-tubulin isotype suggested that a more stable microtubule network was present in the CEM/VCR R cells. These findings imply that the drug-resistance phenotype in the CEM/VCR R cells may involve the suppression of apoptosis, and that the development of an altered microtubule network may contribute to this suppression.
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PMID:Resistance to apoptotic cell death in a drug resistant T cell leukaemia cell line. 864 60

The generation of ceramides by the action of acidic and/or neutral sphingomyelinases has been implicated in many forms of apoptosis. We investigated whether exposure to ceramides is sufficient to induce apoptosis in human leukemia cells and, if so, what the characteristics of this form of apoptosis might be. Treatment of the acute lymphoblastic T-cell line CEM-C7H2 with short- and medium-chain ceramide analogs (C2-, C6-, and C8-ceramide) resulted in apoptosis, whereas the inactive C2-dihydroceramide had no effect on cell survival. Induction of apoptosis was relatively slow (approximately 40% after 24 h) and required high concentrations of ceramide analogs (40-100 microM). To investigate a possible involvement of interleukin 1-beta-converting enzyme (ICE) or ICE-related proteases, we treated CEM-C7H2 sublines constitutively expressing the vaccinia virus protease inhibitor crmA with ceramide analogs. Although such cells were completely resistant to apoptosis induced by antibodies to the Apo-1/Fas surface receptor (a form of apoptosis known to be inhibitable by CrmA), they were not protected from ceramide-induced cell death. In contrast, tetracycline-regulated overexpression of Bcl-2 protected CEM-C7H2 sublines stably transfected with corresponding constructs from ceramide-induced apoptosis. Thus, in these human leukemia cells, ceramides induce a relatively slow death response that can be prevented by Bcl-2, but is independent of CrmA-inhibitable proteases. These characteristics distinguish ceramide-induced from other forms of apoptosis, such as Apo-1/Fas-induced cell death where ceramide production has been causally implicated.
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PMID:Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA. 900 May 5

We evaluated the cytotoxic effects of various human immunodeficiency virus (HIV-1) reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, and nevirapine) on HIV-1-infected and uninfected T cell lines. Among the compounds, only stavudine (not the others) proved to be more cytotoxic to MOLT-4/IIIB cells (MOLT-4 cells chronically infected with HIV-1) than to uninfected MOLT-4 cells. Its 50% cytotoxic concentrations were 59.8 and 2.2 microM for MOLT-4 and MOLT-4/IIIB cells, respectively. Stavudine was also more cytotoxic to CEM/ROD (CEM cells chronically infected with HIV type 2) than to uninfected CEM cells. Microscopic analysis revealed that stavudine induced apoptosis in MOLT-4/IIIB cells. Apparent chromatin condensation in the nucleus was observed by electron microscopy. Furthermore, a DNA fragmentation ladder was detected by agarose gel electrophoresis. Addition of thymidine to the culture medium could rescue the cells from stavudine-induced apoptosis. The expression of anti-apoptotic protein Bcl-2 was partially downregulated in MOLT-4/IIIB cells after treatment with stavudine. This downregulation was not identified in MOLT-4 cells. These results indicate that stavudine selectively induces apoptosis in HIV-1-infected T cells and may have potential as a novel strategy for effective chemotherapy of the acquired immune deficiency syndrome (AIDS).
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PMID:Stavudine selectively induces apoptosis in HIV type 1-infected cells. 900 5

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Bax alpha to Bcl-2 accelerates apoptosis upon apoptotic stimuli. We sought to study the relevance of these apoptotic regulating gene products in leukaemia. In a panel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, L1210 and S49), the Bax alpha-to-Bcl-2 ratio as assessed by Western-blot analysis correlated with sensitivity to dexamethasone treatment. In addition, in HAbax alpha-transfected CEM C7 clones, a similar correlation was found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocytic leukaemia (ALL, n = 48; AML, n = 8), the Bcl-2 and Bax alpha levels were highly variable, but well within the range found in the Bax alpha transfectants and in the established cell lines. Bcl-2 levels were lower in T- than in B-lineage ALL, which could be ascribed to simultaneous inverse relation between Bcl-2 and WBC. By contrast, Bax alpha:Bcl-2 was independent of any presenting feature and was largely dependent on Bax alpha levels. Results suggest that Bax alpha:Bcl-2, rather than Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL.
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PMID:The Bax alpha:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. 918 97

Fas-driven apoptosis in Jurkat cells results in the inactivation of cytochrome c with cessation of oxygen consumption. Overexpression of Bcl-2 was found to protect against acidification and apoptosis mediated by Fas ligation in these cells. Bcl-2 is present in the outer mitochondrial membrane, but the molecular mechanism by which it protects cells is unknown. Because Bcl-2 projects into the mitochondrial intermembrane space and cytochrome c is located in the intermembrane space, we considered the possibility that Bcl-2 might protect cytochrome c from inactivation during Fas-mediated apoptosis. The present study shows that 1) in Jurkat cells, cytochrome c inactivation during Fas-driven apoptosis requires the permeabilization of the outer mitochondrial membrane; and 2) the post-mitochondrial fraction from CEM cells that overexpress Bcl-2 both prevents and reverses cytochrome c inactivation.
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PMID:Bcl-2 and the outer mitochondrial membrane in the inactivation of cytochrome c during Fas-mediated apoptosis. 926 20

A newly established human lymphoma cell line (OZ) has the t(14;18)(q32;q21) translocation and expresses large amounts of Bcl-2 compared to CCRF-CEM cells. VP-16 (40 micrograms/mL), a promising agent against lymphoma, caused DNA fragmentation (26.9% of total DNA) typical for apoptosis at 6 h in CCRF-CEM cells, but no significant changes in OZ cells until 24 h after the addition of VP-16. However, coincubation with calphostin C (0.2 microgram/mL), a protein kinase C (PKC) inhibitor, induced DNA fragmentation in VP-16-treated OZ cells (13.5% of total DNA) at 6 h after the treatment. Simultaneous immunoblot analysis revealed that this induction of apoptosis coincided with the downregulation of serine-phosphorylated Bcl-2 (13% of control cells). By contrast, apoptosis induced by VP-16 in CCRF-CEM cells was attenuated by the addition of 0.5 microM phorbol 12-myristate 13-acetate, a potent PKC stimulator. These observations suggest that Bcl-2 function is partly regulated by phosphorylation/ dephosphorylation mechanisms of the PKC system, and that phosphorylated Bcl-2 in lymphoma cells may play a role in the prevention of apoptosis.
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PMID:Calphostin C synergistically induces apoptosis with VP-16 in lymphoma cells which express abundant phosphorylated Bcl-2 protein. 936 70

Mitochondrial cytochrome c, which functions as an electron carrier in the respiratory chain, translocates to the cytosol in cells undergoing apoptosis, where it participates in the activation of DEVD-specific caspases. The apoptosis inhibitors Bcl-2 or Bcl-xL prevent the efflux of cytochrome c from mitochondria. The mechanism responsible for the release of cytochrome c from mitochondria during apoptosis is unknown. Here, we report that cytochrome c release from mitochondria is an early event in the apoptotic process induced by UVB irradiation or staurosporine treatment in CEM or HeLa cells, preceding or at the time of DEVD-specific caspase activation and substrate cleavage. A reduction in mitochondrial transmembrane potential (Deltapsim) occurred considerably later than cytochrome c translocation and caspase activation, and was not necessary for DNA fragmentation. Although zVAD-fmk substantially blocked caspase activity, a reduction in Deltapsim and cell death, it failed to prevent the passage of cytochrome c from mitochondria to the cytosol. Thus the translocation of cytochrome c from mitochondria to cytosol does not require a mitochondrial transmembrane depolarization.
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PMID:Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. 942 39

Due to their growth arrest- and apoptosis-inducing ability, glucocorticoids (GC) are widely used in the therapy of various lymphoid malignancies. Cell death is associated with activation of members of the interleukin-1beta-converting enzyme (ICE) protease/caspase family and, is presumably prevented by the anti-apoptotic protein Bcl-2. To further address the role of Bcl-2 in GC-mediated cytotoxicity, we generated subclones of the GC-sensitive human T-cell acute lymphoblastic leukemia line CCRF-CEM, in which transgenic Bcl-2 expression is regulated by tetracycline. Up to about 48 h, exogenous Bcl-2 almost completely protected these cells from apoptosis, digestion of poly-ADP ribose polymerase (PARP) and generation of Asp-Glu-Val-Asp cleaving (DEVDase) activity. However, when the cells were cultured for another 24 h in the continuous presence of GC, they underwent massive apoptosis that was associated with DEVDase activity and PARP cleavage. Bcl-2 did not markedly affect GC-mediated growth arrest, thereby separating the anti-proliferative from the apoptosis-inducing effect of GC. Moreover, Bcl-2 did not prevent the dramatic reduction in the levels of several mRNAs observed during GC treatment, including the transgenic Bcl-2 mRNA. Thus, Bcl-2 can be placed upstream of effector caspase activation, but downstream of other GC-regulated events, such as growth arrest and the potentially critical repression of steady state levels of multiple mRNA.
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PMID:Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis. 998 21

It has been suggested that the ratio of Bcl-2 family proapoptotic proteins to antiapoptotic proteins determines the sensitivity of leukemic cells to apoptosis. However, it is believed that Bcl-2 family proteins exert their function on apoptosis only when they target to the mitochondrial outer membrane. The vinblastine-resistant T-lymphoblastic leukemic cell line CEM/VLB100 has increased sensitivity to tumor necrosis factor-alpha (TNF-alpha)-induced cytochrome c release, mitochondrial respiratory inhibition, and consequently apoptosis, compared with parental CEM cells. However, there was no difference between the two cell lines in the expression of Bcl-2 family proteins Bcl-2, Bcl-XL, Bcl-XS, Bad, and Bax at the whole cell level, as analyzed by Western blotting. Bcl-2 mainly located to mitochondria and light membrane as a membrane-bound protein, whereas Bcl-XL was located in both mitochondria and cytosol. Similar levels of both Bcl-2 and Bcl-XL were present in the resting mitochondria of the two cell lines. Although the proapoptotic proteins Bcl-XS, Bad, and Bax were mainly located in the cytosol, CEM/VLB100 mitochondria expressed higher levels of these proapoptotic proteins. Subcellular redistribution of the Bcl-2 family proteins was detected in a cell-free system by both Western blotting and flow cytometry after exposure to TNF-alpha. The levels of Bcl-2 family proteins were not altered at the whole cell level by TNF-alpha. However, after exposure to TNF-alpha, Bax, Bad, and Bcl-XS translocated from the cytosol to the mitochondria of both cell lines. An increase in Bcl-2 levels was observed in CEM mitochondria, which showed resistance to TNF-alpha-induced cytochrome c release. By contrast, decreased mitochondrial Bcl-2 was observed in CEM/VLB100 cells, which released cytochrome c from the mitochondria and underwent apoptosis as detected by fluorescence microscopy. We conclude that mitochondrial levels of Bcl-2 family proteins may determine the sensitivity of leukemic cells to apoptosis and that, furthermore, these levels may change rapidly after exposure of cells to toxic stimuli.
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PMID:Subcellular distribution and redistribution of Bcl-2 family proteins in human leukemia cells undergoing apoptosis. 1009 Sep 46


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