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)

Genetic analysis of programmed cell death in C. elegans has led to the identification of two genes, ced-9, a cell death suppressor, and ced-3, a cell death inducer, that play critical roles in regulating programmed cell death. The ced-9 and ced-3 genes were found to encode proteins that share structural and functional similarities with the mammalian proto-oncogene product Bcl-2 and interleukin-1 beta converting enzyme (ICE), respectively. Multiple members of the Bcl-2 family and the ICE family have been identified in vertebrates. These results suggest that the mechanism of apoptosis in vertebrates may be evolved from a much simpler version of a similar pathway in primitive organisms.
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PMID:Genetic control of cellular suicide. 910 Mar 13

The interleukin-2 (IL-2) receptor (IL-2R) is composed of three subunits. Of these, IL-2Ra is required for high-affinity IL-2 binding, while IL-2R beta and IL-2R gamma(c) are required for the transduction of IL-2-generated signals. Signals transduced via the S region of the IL-2R beta (amino acids 267-322) in BAF/3 cells activate the phosphatidylinositol 3-kinase (PI3-kinase) and induce the expression of Bcl-2 and c-myc. Through the induction of Bcl-2, IL-2 inhibits apoptosis and through the combination of Bcl-2 and c-myc it stimulates progression through the cell cycle. Here we show that the protein kinase encoded by the Akt proto-oncogene is activated by IL-2. Akt activation by IL-2 depends on PI3-kinase signals transduced via the S region of the IL-2R beta and is linked to the translocation of Akt to the cell membrane. Expression of catalytically active Akt mutants in BAF/3 cells expressing IL-2R beta[A0]delta S promotes the expression of Bcl-2 and c-myc, inhibits apoptosis induced by IL-3 deprivation or staurosporine, and stimulates cell cycle progression. The same mutants also stimulate cell cycle progression in 2780a, an IL-2-dependent T cell line that undergoes G1 arrest rather than apoptosis after IL-2 deprivation. The activation of Akt by IL-2 via the PI3-kinase and the rescue of the PI3-kinase-mediated antiapoptotic and proliferative IL-2 signals by catalytically active Akt indicate that these signals are transduced by Akt.
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PMID:Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. 910 28

Apoptosis, or programmed cell death, is responsible for deleting cells in normal tissues to maintain homeostasis after DNA damage. Apoptosis has several physiological inhibitors, one of the most important being the proto-oncogene bcl-2. An immunohistochemical study was made of bcl-2 expression in 25 squamous cell carcinomas of the larynx, in laryngeal mucosa distant from the primary neoplasm, and in lymph node metastases. The relationship between bcl-2 expression and various clinical and pathological parameters was investigated. Bcl-2 was detected in 40% of primary tumors and in 71% of lymph node metastases; it seems to be a late event in laryngeal malignant transformation. We found no statistical association between bcl-2 expression and most of the clinical and pathological parameters examined. Only tumor differentiation was related to bcl-2 expression, bcl-2 positive tumors being moderately or poorly differentiated (p < 0.02).
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PMID:[Expression of proto-oncogene bcl-2 in squamous cell carcinoma of the larynx]. 913 20

Expression of the c-kit proto-oncogene receptor on mast cells is essential for their normal proliferation and maturation as well as for several biological responses such as chemotaxis and attachment. In the present study we report that the interleukin-3 (IL-3)-dependent mast cell line CFTL-15 lacks the extracellular domain of the c-kit receptor. This observation was made after noting that the c-kit ligand stem cell factor (SCF) could not prevent IL-3 deprivation-induced mast cell apoptosis and that CFTL-15 cells did not proliferate in response to SCF. Flow cytometric analysis employing monoclonal anti-c-kit antibodies, and immunogold labelling with analysis by electron microscopy, subsequently showed a diminished expression of c-kit on CFTL-15 cells. There was no identifiable message for the extracellular domain of c-kit in these cells, as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). These previously unrecognized properties of the CFTL-15 mast cell line allowed the examination of other biological consequences of the lack of c-kit on mast cells. Analysing the ability of these cells to adhere to surface-bound fibronectin, it was found that addition of SCF did not increase their adhesion to this substrate, in opposition to what is reported with other mast cells. Similarly, CFTL-15 mast cells did not adhere to fibroblasts, which is known to require c-kit expression. Also, there was no protein tyrosine phosphorylation in these cells in response to SCF. CFTL-15 cells underwent apoptosis on removal of IL-3 coincident with a decrease in endogenous Bcl-2 mRNA. Overexpression of Bcl-2 cDNA prolonged survival of Bcl-2-transfected CFTL-15 cells upon withdrawal of IL-3. Thus, the CFTL-15 cell line that lacks surface c-kit is not able to proliferate in response to SCF, undergoes apoptosis in the presence of SCF, and does not adhere to fibroblasts. These results confirm earlier studies on the functional consequences of c-kit and provide a novel experimental model for further investigation.
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PMID:Characterization of a mast cell line that lacks the extracellular domain of membrane c-kit. 917 4

It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. Previous studies have demonstrated a high frequency of Bcl-2 expression in tumors arising from cells derived from the neural crest and in tumor cell lines of neural origin. The present investigation was undertaken to determine whether similar molecular events occur in human pheochromocytoma. With the aim of determining the potential role of apoptosis in the pathogenesis of this tumor, we assessed proto-oncogene Bcl-2 and c-myc protein products as well as Bcl-2 messenger RNA levels in a collection of such tumors. Western blot analysis revealed that such tumors expressed the 26 kDa Bcl-2 (5 of 8 cases) and the 64 kDa c-Myc (7 of 8 cases) proteins. Northern blot analysis detected the Bcl-2 transcripts in 6 of 8 tumors. Immunoperoxidase staining, using a monoclonal anti-Bcl-2 antibody, was positive in 18 (82%), including 5 malignant tumors, of the 22 specimens examined. This Bcl-2 immunoreactivity was seen in 14 of 18 (78%) sporadic tumors, including 2 that were extra-adrenal, and all familial tumors. Of the 22 tumor samples examined for c-Myc protein, 20 (91%) tumors were positive. Our results suggest that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of human pheochromocytoma. The genetic complementation of simultaneously deregulated Bcl-2 and c-myc may be implicated in this process.
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PMID:Expression of the apoptosis-suppressing gene BCL-2 in pheochromocytoma is associated with the expression of C-MYC. 917 12

Modulation of ara-C-induced apoptosis in human leukemia cells by the macrocyclic lactone PKC activator bryostatin 1 occurs at multiple levels, and involves a variety of oncogenes and signalling pathways. Under some circumstances, bryostatin 1 may lead to enhanced conversion of ara-C to its lethal metabolite, ara-CTP. However, bryostatin 1 is able to potentiate ara-C-mediated cytotoxicity in the absence of metabolic perturbations, presumably by modulating the cell death pathway itself. For example, chronic exposure of cells to bryostatin 1 leads to PKC down-regulation, which may alter the balance between survival (e.g., ERK) versus stress (e.g., SAPK/JNK)-related pathways. The ability of bryostatin 1 to enhance ara-C-mediated apoptosis is inversely related to its capacity to induce leukemic cell maturation and may involve the failure to down-regulate expression of the cell cycle progression-related proto-oncogene, c-myc. Finally, recent evidence suggests that bryostatin 1 may act, through modification of Bcl-2 phosphorylation status, at a distal site in the cell death pathway. These studies could provide a paradigm important for understanding the mechanism(s) by which agents acting through signal transduction pathways modulate cytotoxic drug-induced cell death
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PMID:Modulation of ara-C induced apoptosis in leukemia by the PKC activator bryostatin 1. 919 93

The proto-oncogene bcl-2 and a bcl-2-related gene bcl-x prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), we find that expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia) and that the cell death does not involve ROS, suggesting that Bcl-2 or Bcl-xL exerts an anti-cell death function by a mechanism other than through regulation of ROS activity. Using electron microscopy, and confocal and non-confocal fluorescence microscopy, we show that hypoxia induces both necrosis and apoptosis. Overexpression of Bcl-2 or Bcl-xL blocks hypoxia-induced apoptosis and, although to a lesser extent, necrosis. The anti-apoptotic proteins Bcl-2 and Bcl-xL effectively inhibit KCN-induced cell death which is characterized by necrotic features including apparently intact chromatin, remarkable mitochondrial swelling with loss of crista structure and loss of plasma membrane integrity. The necrotic cell death is also inhibited by inhibitors of ICE (interleukin-1 beta converting enzyme)(-like) proteases, the common mediators of apoptosis. These results indicate that Bcl-2/Bcl-xL and ICE(-like) proteases modulate both apoptotic and at least some forms of necrotic cell death, suggesting that both cell death pathways involve some common mediators.
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PMID:Bcl-2 and Bcl-xL block apoptosis as well as necrosis: possible involvement of common mediators in apoptotic and necrotic signal transduction pathways. 920 97

We have previously demonstrated that CD4 cross-linking (CD4XL) results in apoptosis of CD4+ T cells and augmentation of Fas antigen (CD95, APO-1) expression in CD4+ and CD8+ T cells. Here we demonstrate that CD4XL mediated by both, anti-CD4 monoclonal antibody (MoAb) or human immunodeficiency virus (HIV) envelope protein gp120 reduces the expression of the proto-oncogene Bcl-2 in CD4+ T cells, but not in CD8+ T cells, concurrently with the induction of CD4+ T cell-apoptosis. Additionally, the Bcl-2dim population expressed high levels of Fas antigen. Bax, an antagonist of Bcl-2, was brightly expressed even in the Bcl-2dim population. Addition of interleukin (IL)-2 rescued CD4+ T cells from CD4XL-induced Bcl-2 downmodulation and apoptosis induction. These results support the hypothesis that CD4 ligation by HIV-1 envelope protein in vivo in HIV-infected patients selectively reduces Bcl-2 protein in CD4+ T lymphocytes, thereby facilitating Fas/Fas-ligand triggered apoptosis; furthermore the findings reported expand the rationale for use of IL-2 in HIV disease.
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PMID:Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2. 922 75

The CHST8 mouse hepatocyte cell line, conditionally immortalized with the temperature-sensitive SV40 large T antigen gene, rapidly proliferates at 33 degrees C with active expression of the c-myc proto-oncogene but, due to the heat-labile nature of the mutant T antigens, becomes growth arrested and morphologically senescent at 39 degrees C; this is accompanied by the disappearance of c-myc transcripts. In a previous study, we transfected the CHST8 cells at 33 degrees C with an activated c-H-ras or a c-myc, both of which are frequently involved in mouse hepatocarcinogenesis in vivo. When the temperature was shifted to 39 degrees C, cells with only one of the exogenous oncogenes did not escape from the senescence, but those containing both exhibited an immortal phenotype. In the present study, using this in vitro model of hepatocarcinogenesis, we demonstrated that phenobarbital, a tumor promoter of rodent hepatocarcinogenesis, triggers remarkable apoptosis specifically in the c-myc-transfected CHST8 cells at 39 degrees C, which show abundant c-myc expression despite growth arrest. Dissociation of p53 proteins from degrading T antigens followed by a phenobarbital and c-myc-dependent, 15-fold induction of Bax protein, known to activate the apoptotic pathway downstream of p53, occurred in association with this phenomenon. The effects of phenobarbital and c-myc in increasing Bax on shifting the temperature from 33 degrees C to 39 degrees C were additive, with both having similar degrees of influence on the protein level. Interestingly, subsequent introduction of an activated c-H-ras oncogene into the c-myc-transfected CHST8 cells resulted not only in escape from the growth arrest at 39 degrees C but also in complete inhibition of the phenobarbital-inducible apoptosis along with de novo induction of the Bax antagonist, Bcl-2. These findings strongly suggest that the phenobarbital-inducible apoptosis is mediated by Bax. Although it is a common notion that phenobarbital promotes liver tumor development through suppression of apoptosis, our results, together with the known fact that phenobarbital occasionally inhibits hepatocarcinogenesis in mice, indicate a problematic complexity in its biological activities.
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PMID:Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression: characterization of an unexpected effect. 923 Jan 98

The proto-oncogene product Bcl-2 regulates cell survival in both the immune and central nervous systems. We withdrew growth factors from IL-3-dependent murine myeloid progenitor cells (factor dependent cell progenitors (FDCP)) and measured a time-dependent 80% reduction in endogenous expression of Bcl-2. This decline in Bcl-2 is directly associated with a fourfold increase in the apoptotic population after 12 h and an eightfold increase after 24 h. Since IL-4 and insulin-like growth factor-I (IGF-I) regulate myeloid cell growth, we used IL-3-deprived FDCP cells to determine whether IL-4 and IGF-I maintain Bcl-2 expression and prevent apoptosis. We demonstrate that IL-4, like IGF-I and IL-3, promotes survival of FDCP cells by reducing the apoptotic population. Flow cytometric measurement of intracellular Bcl-2 established that IL-4 and IGF-I maintain 10-fold higher levels of Bcl-2 than in IL-3-deprived cells. Similarly, Western analysis of Bcl-2 in lysates of IL-3-deprived myeloid progenitors confirmed that both IL-4 and IGF-I share with IL-3 the ability to maintain intact Bcl-2 protein. However, IL-4 and IGF-I do not change expression of the apoptotic inducer, Bax, although they maintain high levels of Bcl-2 that coimmunoprecipitate with Bax. Collectively, these data demonstrate that IL-4 and IGF-I, like IL-3, inhibit apoptosis in myeloid progenitors and maintain high levels of Bcl-2/Bax heterodimers, suggesting that Bcl-2 is a critical convergence point in the signaling pathways used by IL-4 and IGF-I.
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PMID:IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors. 923 17


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