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)

Interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) induce DNA synthesis and suppress apoptosis of hematopoietic cells. IL-3/GM-CSF exert pleiotropic functions by activating multiple signaling cascades through distinct domains of the common receptor subunit. As we previously reported, the Ras signaling pathway plays a pivotal role in suppressing apoptotic death rather than stimulating DNA synthesis in IL-3 dependent hematopoietic cells. In order to clarify the molecular basis of Ras-induced cell survival, we investigated the effect of Ras activation on the expression of Bcl-2 and its related molecules. Activation of the Ras pathway by using an inducible oncogenic Ras resulted in the rapid up-regulation of bcl-2 and bcl-xL, and the level of expression was nearly equivalent to that observed in growing cells. On the other hand, expression of bax, an antagonistic bcl-2 homologue, was not affected by oncogenic Ras or IL-3-deprivation. Thus, the Ras pathway regulates the expression of Bcl-2 and its related survival protein, and this appears to underlie the mechanism by which IL-3/GM-CSF inhibit apoptosis through activation of the Ras pathway.
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PMID:Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. 778 65

Acquired resistance to diverse chemotherapeutic agents has been associated with overexpression of the P-glycoprotein. We have selected human U-937 cells for clones resistant to the cytotoxic agents doxorubicin (U-A20) and vincristine (U-V20). The results demonstrate that P-glycoprotein-positive U-A20 and U-V20 cells exhibit resistance to inducers of internucleosomal DNA fragmentation. Although parental U-937 cells responded to ionizing radiation with the DNA laddering characteristic of physiological cell death, the drug-resistant lines were insensitive to this effect. The U-A20 and U-V20 clones were also resistant to endonucleolytic DNA cleavage associated with exposure to tumor necrosis factor or ceramide. Previous work has demonstrated that physiological cell death is inhibited by overexpression of the Bcl-2 protein. However, analysis of Bcl-2 revealed similar levels in the parental and drug-resistant cells. In contrast, we show that U-A20 and U-V20 cells overexpress the Bcl-2-related protein, Bcl-xL. Moreover, studies with a U-937 cell line transfected with a Bcl-XL expression vector confirm resistance to ionizing radiation-induced DNA fragmentation and cell killing. These findings suggest that, unlike Bcl-2, Bcl-XL may be constitutively overexpressed as a result of selection for cytotoxic drug resistance and that Bcl-XL participates in an acquired form of multimodality resistance to chemotherapeutic agents and radiation.
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PMID:Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced internucleosomal DNA fragmentation. 779 4

Human and rodent cells undergoing apoptosis were observed to express high levels of a novel 45,000 M(r) protein. The protein, which we have termed apoptosis specific protein (ASP), was found in Burkitt lymphoma (BL) cells and in adenovirus-transformed human and rat embryo cells induced into apoptosis by a variety of stimuli, including serum deprivation, exposure to the Ca2+ ionophore, ionomycin, treatment with inhibitors of macromolecular synthesis (cycloheximide and actinomycin D), and cold shock. In BL cells treated with apoptotic stimuli, expression of the oncoprotein Bcl-2 was found to both protect from apoptosis and prevent expression of ASP. ASP was not detected either in viable cells or in cells dying passively by necrosis. Laser scanning confocal microscopy showed high levels of ASP in the cytoplasm of cells displaying the chromatin condensation and fragmentation patterns typical of apoptosis. Retention of ASP was observed even when DNA was no longer detectable, and two-color immunofluorescence staining indicated that the protein primarily colocalized with, but was clearly distinct from, non-muscle actin. These findings, together with the observation that biochemical extraction of ASP was only possible under conditions which caused solubilization of the cytoskeleton, leads us to conclude that ASP forms part of, or at least strongly associates with, a modified cytoskeleton unique to cells undergoing apoptosis. While elucidation of its function will require further work, ASP constitutes a powerful marker for the diagnosis and quantitation of apoptosis in vivo and in vitro.
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PMID:A novel protein expressed in mammalian cells undergoing apoptosis. 779 80

The Bcl-2 proto-oncogene product blocks apoptosis. We retrospectively studied Bcl-2 expression in 124 primary tumors from patients diagnosed with T1 (2 cm or less) breast carcinoma with (T1N1) or without (T1N0) lymph-node metastasis. Bcl-2 protein was detected by immunohistochemistry on paraffin-embedded tissue sections. Multivariate logistic regression modeling was used to estimate prevalence odds ratios for lymph-node metastasis. Bcl-2 was widely expressed among T1 tumors showing a strong positive relationship with estrogen (ER)- and progesterone (PR)-receptor-positive tumors. However, a significant inverse correlation was seen between Bcl-2 expression and histological grade, Bcl-2 being absent in the majority of T1 undifferentiated tumors (grade-III carcinomas). Furthermore, Bcl-2 was more frequently expressed in T1N1 cases (72.2%) than in T1N0 specimens (45.7%). The odds for lymph-node metastasis in the Bcl-2-positive group was 3.6 times larger than that in the Bcl-2-negative group. The co-expression of PR significantly modified the effect of Bcl-2 on the odds for lymph-node metastasis, suggesting the existence of a synergistic interaction between the 2 parameters. We studied the percentage of dead cells in primary tumors by in situ DNA fragmentation (FDNA), and found an inverse correlation between Bcl-2 expression and FDNA. This supported the hypothesis that Bcl-2 extends cell survival. In conclusion, our study provides evidence that Bcl-2 expression is involved in breast-cancer progression, at least in a subset of well-differentiated and PR-positive tumors.
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PMID:Bcl-2 expression is associated with lymph node metastasis in human ductal breast carcinoma. 781 52

Epstein-Barr virus (EBV) is associated with tumours of both lymphoid and epithelial origin. Whilst a role for EBV latent genes in the development of these malignancies is accepted, it is also possible that viral proteins involved in EBV replication may influence the oncogenic process. BHRF1 is an immediate early protein which has homology with the Bcl-2 oncogene and can protect B cells from apoptosis. In vivo this protein is most abundantly expressed in the upper layers of oral 'hairy' leukoplakia (HL), a benign hyperparakeratotic tongue lesion which represents a focus EBV replication. We have transfected BHRF1 into the human squamous cell carcinoma line SCC12F which retains several features of normal keratinocytes behaviour in vitro. BHRF1 expression in these epithelial cells is associated with a delay in the commitment of cells to terminal differentiation, increased resistance to the DNA damaging drug, cis-platin and enhanced survival under conditions of serum deprivation. As the differentiation of epithelial cells is an apoptotic process, this data strongly suggests that BHRF1 expression delays the terminal differentiation of epithelial cells through the prevention of apoptosis. This effect of BHRF1, which may normally function to promote productive EBV infection, could contribute to the development of EBV-associated tumours.
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PMID:BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial cell differentiation. 782 80

A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (> 10-fold) to several clinically active anticancer drugs, including VP-16 and cisplatin. Previous studies showed that resistance to these drugs was not due to expression of the mdr1 gene, or modifications in topoisomerases but may have resulted from high expressions of certain proto-oncogenes (Yamazaki et al. (1994) Biochim. Biophys. Acta 1226, 89-96). Flow cytometry, DNA gel electrophoresis and northern blot analysis were used to further characterize drug responses in sensitive and resistant cells. Treatment of the sensitive PC3 cells with VP-16 and CDDP resulted in accumulation of cells in S and G2, and G1 and S phases, respectively, and caused significant degradation of the genomic DNA into internucleosomal sized DNA fragments, indicating apoptosis. In contrast, resistant PC3 cells showed little or no DNA fragmentation. Resistant PC3(R) cells expressed 2-3-fold more bcl2 protein than the parental PC3 cells, and overexpressed c-myc, c-jun and H-ras mRNA compared to sensitive cells. Treatment with VP-16 or CDDP significantly induced c-myc mRNA levels in sensitive PC3 cells. H-ras message was not affected by either VP-16 or CDDP treatment in PC3 cells. These studies, taken together, suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to altered levels of bcl2 and/or oncogene overexpression in PC3(R) cells.
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PMID:Relationships between proto-oncogene expression and apoptosis induced by anticancer drugs in human prostate tumor cells. 782 30

Oligodeoxynucleotides have been proposed as both in vitro and in vivo inhibitors of gene expression because of the specificity of Watson-Crick base pair hybridization. Phosphodiester oligodeoxynucleotides (normal DNA) cannot be used as drugs because they are nuclease sensitive. Significant efforts have been made to study phosphorothioate oligodeoxynucleotides, which have a sulfur atom substituted for one of the phosphate oxygen atoms at a nonbridging position. These oligodeoxynucleotides are nuclease resistant, and over the past year they have entered clinical trials. They have also been extensively examined in vitro and have been targeted to the bcr-abl and bcl2 messenger RNAs among others. Methods to maximize the intracellular oligodeoxynucleotide concentration have also been devised. However, significant problems remain, including the significant nonsequence specificity of phosphodiester oligodeoxynucleotides as well as questions of oligodeoxynucleotide uptake into and compartmentalization within cells. An improvement of our understanding of these phenomena is critical to the elaboration of this technology into a clinical therapeutic modality.
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PMID:Antisense oligodeoxynucleotides. 782 70

Activated c-myc gene was introduced into the cells of three normal Epstein-Barr virus (EBV)-positive lymphoblastoid B cell lines (LCL). The cells were monitored for the appearance of new phenotypic and functional features compared with the control LCL cells transfected with plasmid that did not contain the c-myc gene. The LCL-expressing c-myc constitutively did not arrest growth in low serum concentration. However, the cell number in the cultures failed to increase because of substantial cell death. Death was due to apoptosis as demonstrated by flow cytometric analysis of propidium iodide-stained cells, by typical DNA laddering in gel electrophoresis, and by the inspection of Giemsa-stained cell smears. Apoptosis was also induced by exposing the transfected cells to antibodies directed to the immunoglobulin mu chain (a-mu-ab) irrespective of the serum concentration in the culture. Exposure of the cells to CD40 ligand (CD40L) or CD40 monoclonal antibody prevented cell apoptosis. Upon transfection with c-myc, the LCL cells acquired a vacuolated morphology that was never observed in control cells. Moreover, the expression of CD10 and CD38 was upregulated, while that of CD39 and especially CD23 was downregulated. Unlike that observed in certain Burkitt lymphoma (BL) cell lines that share the same surface phenotype (CD10+CD38+CD23-CD39-), the c-myc-transfected cells expressed lymphocyte function-associated (LFA) 1, LFA-3, and intercellular adhesion molecule 1 and grew in large clumps rather than single-cell layers. Expression of CD10 and CD38 was particularly evident on the cells undergoing apoptosis, thus suggesting a correlation between the presence of these markers and the apoptotic process. Cells placed in conditions favoring in vitro apoptosis displayed downregulation of Bcl-2 protein. Bcl-2 expression was, however, upregulated when the cells were exposed to CD40L. These data indicate that the B cells expressing c-myc constitutively acquire some of the features of normal centroblasts and of BL cells, including the expression of CD10 and CD38, and the propensity to undergo apoptosis, which can be prevented by exposure to CD40L. Therefore, these cells can serve as a model system to study both BL lymphomagenesis as well as the process of B cell selection occurring in the germinal centers.
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PMID:Transfection of the c-myc oncogene into normal Epstein-Barr virus-harboring B cells results in new phenotypic and functional features resembling those of Burkitt lymphoma cells and normal centroblasts. 783 23

Polymorphonuclear leukocytes are generated by differentiation of early myeloid precursors. Once fully differentiated, blood neutrophils are programmed to die rapidly and are removed by tissue macrophages. In normal myeloid cells, the death mechanism seems to be coupled to the differentiation pathway and is accomplished by a process termed apoptosis. In the present study, we have examined the role of Bcl-2 in the differentiation pathways of the promyelocytic cell line HL-60. Treatment of HL-60 with retinoic acid or phorbol ester, which induced neutrophil or macrophage-like cell differentiation, respectively, resulted in progressive loss of cellular viability and internucleosomal DNA degradation. In HL-60, differentiation and apoptosis were coupled to down-regulation of the Bcl-2 protein. Overexpression of Bcl-2 by gene transfer inhibited apoptosis triggered by terminal differentiation of HL-60. Yet, Bcl-2 did not alter the expression of surface markers or other phenotypic changes that are induced upon myeloid differentiation. In contrast to HL-60, another immature myeloid cell line, K562, did not produce Bcl-2 but expressed a related protein, Bcl-xL, that functions as a repressor of apoptotic cell death. K562 has been shown to be relatively resistant to a variety of apoptotic stimuli. Incubation of HL-60 and K562 with inhibitors of macromolecular synthesis induced apoptosis, which appeared earlier in HL-60 than in K562. Interestingly, Bcl-2 overexpression protected K562 cells from apoptosis induced by inhibitor of macromolecular synthesis but it had little or no effect on HL-60 cells. We conclude that although differentiation and apoptosis proceed simultaneously, they can be uncoupled by expression of Bcl-2. Down-regulation of Bcl-2 appears to be part of the differentiation pathway and may serve to facilitate the apoptotic response.
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PMID:Regulation and function of Bcl-2 during differentiation-induced cell death in HL-60 promyelocytic cells. 785 57

Recent studies have proposed that tumor necrosis factor alpha (TNF-alpha) and ionizing radiation induce apoptosis by activating hydrolysis of sphingomyelin to ceramide. Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis. Herein, we report that internucleosomal DNA fragmentation, characteristic of apoptosis and induced by ionizing radiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X mRNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA fragmentation after exposure to TNF-alpha and C2-ceramide was also associated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, while Bcl-X mRNA production was unaffected. These results suggest that modulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-alpha. Changes in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF-alpha in some human and tumor cells.
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PMID:Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide. 786 10


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