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

Apoptosis has been hypothesized to be mediated through the induction of free radicals via oxidative pathways. Furthermore, it has been proposed that Bcl-2 acts to inhibit apoptosis induced by a wide variety of stimuli by preventing the production of oxygen-derived free radicals. Since the generation of oxygen free radicals is dependent upon oxygen concentration, this hypothesis would lead to the prediction that the concentration of oxygen should affect the induction of apoptosis. In order to test this prediction, we have examined the induction of apoptosis in T-lymphoma cell lines S49.1 and WEHI 7.1 by dexamethasone and by withdrawal of serum from myc-immortalized fibroblasts in 95% oxygen, atmospheric oxygen (20%), and hypoxic conditions of up to 125-fold less oxygen. Culture in 95% oxygen induced apoptosis in all cells tested, confirming that oxidative damage can lead to apoptosis. However, for one cell line, WEHI 7.1, hypoxia also induced apoptosis. Furthermore, for the other cell lines tested, induction of apoptosis by either dexamethasone or by serum withdrawal was not affected by hypoxia. These results are not consistent with the hypothesis that apoptosis is mediated via oxygen-generated free radical formation.
Cancer Res 1995 Mar 01
PMID:Induction of apoptosis at different oxygen tensions: evidence that oxygen radicals do not mediate apoptotic signaling. 786 11

The in vivo patterns of bcl-X gene expression were assessed in human and mouse tissues using an immunohistochemical approach. Polyclonal antisera were raised against synthetic peptides corresponding to amino acids 46-66 and 61-79 of the human Bcl-X protein and were shown to be specific for detection of human and mouse Bcl-X-L and Bcl-X-S proteins by immunoblotting. Bcl-X immunoreactivity was detected in a wide variety of cell types and was typically present in the cytosol in a punctate pattern suggestive of association with intracellular organelles. Among the cell types with prominent Bcl-X immunostaining were: (a) a variety of neuronal populations in the brain as well as sensory neurons in dorsal root ganglia; (b) cortical (but not medullary) thymocytes and activated lymphocytes and plasma cells in lymph nodes; (c) several types of cells in the bone marrow, including megakaryocytes, red cell precursors, and some types of differentiating myeloid cells; (d) reproductive tissues, including the spermatocytes and spermatids in the testes and germinal epithelium of the ovary; and (e) a variety of epithelial cells including mammary epithelium, the secretory epithelial and basal cells of the prostate, uterine endometrium, gastric and intestinal epithelial cells, renal tubule epithelium, and differentiated keratinocytes in the upper layers of the epidermis but not in the basal cells. In many cases, these patterns of Bcl-X expression were strikingly different from those reported previously for Bcl-2, suggesting that Bcl-X and Bcl-2 regulate cell life and death at different stages of cell differentiation through tissue-specific control of their expression.
Cancer Res 1994 Nov 01
PMID:Immunohistochemical analysis of in vivo patterns of Bcl-X expression. 792 84

The bcl-2 gene is expressed in many types of human tumours and becomes transcriptionally deregulated in the majority of non-Hodgkin's lymphomas as the result of t(14;18) chromosomal translocations. The 26-kDa Bcl-2 protein has been shown to block programmed cell death (apoptosis) induced by many types of stimuli, including a wide variety of chemotherapeutic drugs and radiation. The presence of bcl-2 in tumor cells has been correlated with poor responses to therapy in patients with some types of cancer. To explore further the relevance of bcl-2 to drug resistance, we used antisense (As) approaches to achieve reductions in the levels of steady state Bcl-2 protein levels in t(14;18)-containing human lymphoma cell lines. Both synthetic bcl-2-As oligonucleotides and inducible expression plasmids that produce bcl-2-As transcripts induced reductions in bcl-2 expression, resulting in a marked enhancement in the sensitivity of neoplastic cells to conventional chemotherapeutic drugs such as cytosine arabinoside (ara-C) and methotrexate (MTX). These results suggest that novel therapeutics targeted against bcl-2 could provide the means for improved treatment of cancer by affecting physiological pathways distal to the targets of cytotoxic drugs.
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PMID:Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. 795 Mar 2

The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53-/- mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mitogenically activated T lymphocytes from these animals underwent apoptosis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53-/- lymphoblasts expressing Bcl-2 were subject to growth arrest but resisted apoptosis. Their accumulation in G1 as well as G2 is suggestive of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of survival genes may pose a greater impediment to genotoxic cancer therapy than loss of p53.
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PMID:DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. 795 87

Bcl-2 gene product functions to prevent apoptosis in a variety of in vitro and in vivo experiments. The prognostic significance of Bcl-2 protein expression was investigated by immunocytochemistry from paraffin-embedded tissue in a series of 174 women with breast cancer, treated with radical surgery with or without regional radiotherapy, and who had been followed up for the median of 31 years or until death. A minority (25%) of cancers were entirely negative for Bcl-2 protein. Moderate to strong Bcl-2 protein expression (present in 46%) was strongly associated with several favorable prognostic features, such as a low mitotic count, high histological grade of differentiation, and lack of p53 protein expression (P < 0.0001 for each). It was also significantly associated with lack of tumor necrosis, a low S-phase fraction size, low cathepsin D expression, DNA diploidy, and the lobular histological type, but not with the primary tumor size or the axillary nodal status. Women with cancer with moderate to strong Bcl-2 protein expression had more favorable short-term (69% versus 46% alive at 5 years) but similar long-term (29% versus 33% alive at 30 years) disease-specific survival as those with cancer with weak or lacking expression. Bcl-2 protein expression did not have independent prognostic value in a multivariate survival analysis. We conclude that Bcl-2 protein is frequently expressed in breast cancer, and its expression is associated with favorable clinicopathological features.
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PMID:Bcl-2 protein expression and long-term survival in breast cancer. 797 49

Mcl-1, a protein increased early in the differentiation of human myeloblastic ML-1 cells, has sequence similarity to Bcl-2. In the present study, we determined whether Mcl-1 has functional similarity to Bcl-2 by testing its ability to inhibit apoptosis induced by c-Myc overexpression. This was carried out using Chinese hamster ovary 5AHSmyc cells which contain the human c-myc proto-oncogene under the control of a heat shock promoter. Heat treatment induces c-Myc overexpression and thus apoptosis as determined by internucleosomal DNA fragmentation. We transfected 5AHSmyc cells with mcl-1 and found that clones expressing the introduced Mcl-1 protein exhibited reduced DNA fragmentation. Mcl-1 was also capable of delaying the onset of cell death as judged by loss of membrane integrity, although it could not provide complete protection from c-Myc overexpression. Thus, Mcl-1 has functional homology to Bcl-2 in that Mcl-1 can enhance cell viability under conditions that otherwise cause apoptosis.
Cancer Res 1994 Dec 15
PMID:Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. 798 27

The bcl-2 gene is a unique proto-oncogene that blocks apoptosis; its product is localized on the inner mitochondrial membrane. In non neoplastic human lymphoid tissues, bcl-2 protein is strongly expressed in the small recirculating lymphocytes of the follicular mantle zone; it is expressed less intensely in T-cell areas, and is almost absent from germinal center cells. Bcl-2 mRNA, in contrast to bcl-2 protein, is strongly expressed on most of the latter cells, a similar phenomenon also being observed in peripheral blood lymphocytes (PBL). Resting PBL express both bcl-2 mRNA and protein, while most lymphoblasts in mitogen-stimulated PBL cultures lose bcl-2 protein and become apoptotic, despite expressing higher levels of mRNA. Posttranscriptional regulation of the bcl-2 gene may cause this paradoxical down-regulation of bcl-2 protein and may play an important role in the clonal selection of lymphocytes. Bcl-2 protein is frequently expressed in follicular lymphomas bearing the t(14;18) chromosomal translocation, but it is also widely expressed in many other B- and T-cell lymphomas without bcl-2 rearrangement, showing that mechanisms other than t(14;18) translocation may deregulate bcl-2 expression. Many lymphoid and myeloid cell lines also express bcl-2 protein with no correlation being shown with differentiation stage. Thus, it is conceivable that bcl-2 protein may play a role in the oncogenesis of many hematolymphoid malignancies by interfering with programmed cell death, in concert with other oncogenes or tumor suppressor genes.
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PMID:Expression of Bcl-2 protein and Bcl-2 mRNA in normal and neoplastic lymphoid tissues. 802 26

The BCL2 gene product has been demonstrated to prevent apoptosis and provide a selective growth advantage to many cell types. We report an unexpected effect of bcl2 expression on the in vitro growth of several solid tumor cell lines. Expression of bcl2 in these cell lines resulted in growth inhibition similar to that seen with p53. In contrast, a COOH-terminal deletion mutant of bcl2 was unable to suppress growth. Thus, the bcl2 protein may exert distinct biological effects in different cell types.
Cancer Res 1994 Jul 15
PMID:Paradoxical inhibition of solid tumor cell growth by bcl2. 803 89

Bcl-2 expression and its prognostic value were evaluated using the APAAP technique in 40 ALL patients. Because of a possible synergy between c-myc and bcl-2 proteins in cell lines, we compared 40 ALL of either T or B lineage with seven Burkitt's ALL or sporadic Burkitt's lymphomas (BL). We found the same high expression of bcl-2 in adult (Ad) and childhood (Ch) malignancies examined at presentation, regardless of the T or B phenotype. No bcl-2 expression was detectable in BL cases, except for two investigated at relapse. Bcl-2 staining intensity was also not related to the stage of blast differentiation, except in Ad T-ALL, or to the relapse rate. Ki-67, a marker of proliferation, was used to investigate the possible correlation between bcl-2 expression and the proliferative activity. An inverse correlation was found only in BL at presentation. We confirm that bcl-2 expression is the rule in ALL, regardless of the immunophenotypic characteristics at presentation, and that high expression is not correlated with a bad prognosis. Sporadic BL may represent a particular type of tumor, with bcl-2 expression in relapse, but not at presentation.
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PMID:High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with the prognosis. 806 Nov 3

The bcl-2 gene becomes dysregulated in its expression in a wide variety of human cancers and has been shown to block both spontaneous and drug-induced cell death, thus conferring a selective survival advantage on malignant cells. The biochemical mechanism by which bcl-2 promotes cell survival remains enigmatic but appears to involve a downstream event in an evolutionarily conserved cell death pathway. Here we report that gene transfer-mediated increases in Bcl-2 protein levels in the human leukemia line Jurkat render these cells more resistant to induction of DNA fragmentation and cytolysis by a cloned T-cell. The killing mechanism used by these particular T-cells was consistent with apoptosis, as opposed to necrosis, in that DNA degradation occurred as a prelysis event. The findings raise the possibility that dysregulation of bcl-2 gene expression could play a role in the avoidance of immune surveillance mechanisms by cancer cells.
Cancer Res 1994 Sep 15
PMID:Bcl-2 inhibits T-cell-mediated cytolysis of a leukemia cell line. 806 51


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