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)

Undifferentiated nasopharyngeal carcinomas (UNPC) are characterized by an association with Epstein-Barr virus and an abundant lymphoid stroma. The role of this lymphoid stroma is uncertain but is mostly thought to represent an immune response against viral or tumor antigens. We have analyzed the expression of immune regulatory receptor/ligand pairs in snap-frozen biopsies of 20 UNPCs. All cases were Epstein-Barr virus positive and the virus-encoded latent membrane protein, LMP1, was expressed in 6 cases. By immunohistochemistry, we have demonstrated the expression of CD70 and CD40 in the tumor cells of 16 and 18 cases, respectively. Infiltrating lymphoid cells expressing CD27, the CD70 receptor, and the CD40 ligand were present in all cases. The Bcl-2 protein was detected in 17 cases. Unexpectedly, tumor cells of 5 cases expressed at least one member of the B7 family (CD80, CD86, and B7-3) and many lymphoid cells expressing the corresponding counter-receptor, CD28, were detected in all cases. Interestingly, 5 of 6 LMP1-positive cases also expressed B7, whereas all 14 LMP1-negative cases were also B7 negative. Our results indicate that T cells and carcinoma cells communicate in the microenvironment of UNPCs and suggest that the presence of a lymphoid stroma may be a requirement for UNPC growth at least in certain stages of tumor development.
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PMID:Expression of immune regulatory molecules in Epstein-Barr virus-associated nasopharyngeal carcinomas with prominent lymphoid stroma. Evidence for a functional interaction between epithelial tumor cells and infiltrating lymphoid cells. 757 60

The presence of Epstein-Barr virus (EBV) correlates with some cases of Hodgkin's disease (HD), and its latent membrane protein (LMP) has oncogenic potential by inducing expression of bcl-2 protein. Bcl-2 confers a longer half-life to the cell, which overexpresses it. As the translocation t(14,18), which is most often found in follicular lymphomas, and leads to overexpression of bcl-2, has also been reported in HD, it is possible that there is a correlation between these events in this entity. We stained immunohistochemically 40 cases of HD for the presence of bcl-2 and EBV-LMP. Bcl-2 positivity within reactive lymphocytes was revealed in 29 cases. In five of these cases a week, positive reaction in cytoplasm of Reed-Sternberg cells was observed (one mixed cellularity and four nodular sclerosis cases). The EBV-LMP immunopositivity was observed in 16 of these 29 cases (ten MC and six NS cases). The simultaneous presence of bcl-2 protein and EBV-LMP was found in two cases, the remaining three bcl-2-positive cases did not have EBV-LMP. These results do not support the hypothesis of the correlation between the expression of bcl-2 protein and the presence of EBV-LMP in the pathogenesis of HD as the LMP-dependent stimulation of bcl-2 oncogene.
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PMID:Expression of bcl-2 protein and Epstein-Barr virus latent membrane protein in Hodgkin's disease. 769 30

LMP-1, an Epstein-Barr virus membrane protein expressed during latent infection, has oncogenic properties, as judged from its ability to transform B lymphocytes and rodent fibroblasts. LMP-1 induces the expression of bcl2, an oncogene which protects cells from apoptosis, as well as of genes encoding other proteins involved in cell regulation and growth control. The mechanisms by which LMP-1 upregulates these proteins is unknown, but it is plausible that LMP-1 modifies signal transduction pathways that result in the activation of one or more transcription factors that ultimately regulate transcription of oncogenic genes. NF-kappa B, a transcription factor controlling the expression of genes involved in cell activation and growth control, has been shown to be activated by LMP-1. The mechanism(s) regulating this activation remains unknown. Our data indicate that increased NF-kappa B DNA binding and functional activity are present in B-lymphoid cells stably or transiently expressing LMP-1. I kappa B alpha is selectively modified in LMP-1-expressing B cells. A phosphorylated form of I kappa B alpha and increased protein turnover-degradation correlate with increased NF-kappa B nuclear translocation. This results in increased transcription of NF-kappa B-dependent-genes, including those encoding p105 and I kappa B alpha (MAD3). These results indicate that LMP-1 activates NF-kappa B in B-cell lines by targeting I kappa B alpha. Identification of the pathways activated by LMP-1 to result in posttranslational modifications of I kappa B alpha will aid in determining the role of this virus-host cell protein interaction in Epstein-Barr virus-mediated oncogenesis.
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PMID:LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha. 788 65

The role of Epstein-Barr virus (EBV) in the pathogenesis of Hodgkin's disease (HD) has not yet been clarified. Using RNA in situ hybridization (ISH) and immunohistochemistry (IHC), the occurrence of small Epstein-Barr virus encoded RNA (EBER) and latent membrane protein-1 (LMP-1) was studied in 22 tissue samples from 21 patients between 4 and 17 years of age with Hodgkin's disease. EBER was detected in eight of 21 patients (38%) in Hodgkin and Reed-Sternberg cells and reactive lymphocytes irrespective of initial clinical stage and histological subtype, whereas LMP-1, positive in ten of 21 patients (48%), was restricted to neoplastic cells. All cases positive for EBER expressed LMP-1 as well. Additionally, oncoprotein Bcl-2 was identified in nine of 21 patients (43%), indicating, besides immortalization of HD cells by EBV, a further growth advantage due to apoptosis prevention by overexpression of this protein. Proliferation-associated antigens Ki-S1 and Ki-S5 were highly expressed in Hodgkin and Reed-Sternberg cells. CD 30 antigen was found in most cases, using two different antibodies (90% and 80%). The presence of this protein, which belongs to the family of nerve growth factor receptor (NGFR), is related to high expression of Ki-67 protein, detected by Ki-S5. CD 20 antigen was detectable in only three of 21 patients (14%). If we compare results of ISH and IHC with clinical data, the occurrence of EBV genome in children with HD seems to have no adverse effect on the final outcome of these patients.
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PMID:The impact of EBV, proliferation rate, and Bcl-2 expression in Hodgkin's disease in childhood. 814 17

Bcl-2 is an inner mitochondrial membrane protein which blocks apoptosis. Although present in many B cells, the vast majority of follicular center cells do not have detectable bcl-2 protein. The bcl-2 gene is translocated in most conventional small cleaved follicular center cell (SCFCC) lymphomas (centroblastic/centrocytic) but not in centrocytic lymphomas (CC). The translocated gene in the SCFCC lymphomas leads to 'aberrant' bcl-2 expression by the neoplastic follicular center cells. The frequency with which the normal non-translocated gene is expressed in CC lymphomas is, however, not well documented. Paraffin sections from 22 cases of centrocytic lymphoma were therefore stained with an anti-bcl-2 antibody. Genotypic studies in 14 cases demonstrated bcl-1/PRAD1 (cyclin D1; CCND1) rearrangements in ten and bcl-2 rearrangements in none. All centrocytic lymphomas demonstrated bcl-2 protein expression in the majority of neoplastic cells. Negative staining residual follicular centers were identified in four cases emphasizing the mantle zone growth pattern of a subset of CC lymphomas. Expression of bcl-2 protein in the absence of bcl-2 gene rearrangement is a feature shared by centrocytic lymphomas and mantle zone cells. However, because this type of bcl-2 expression is not specific for B-cells of the mantle zone, it does not further elucidate the true cell of origin for the centrocytic lymphomas.
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PMID:Bcl-2 protein in centrocytic lymphoma; a paraffin section study. 837 94

The stable expression of the Epstein-Barr virus (EBV) latent membrane protein (LMP) in certain EBV-negative Burkitt's lymphoma cell lines correlates with an increased expression of the oncogene Bcl-2 (S. Henderson, M. Rowe, C. Gregory, D. Croom-Carter, F. Wang, R. Longnecker, E. Kieff, and A. Rickinson, Cell 65:1107-1115, 1991). This finding is consistent with a model in which Bcl-2 contributes to the immortalization of B cells mediated by EBV. We therefore asked whether the expression of Bcl-2 protein correlates with the induction of three cellular phenotypes induced by or associated with LMP. The expression of Bcl-2 in primary B cells infected with the B95-8 strain of EBV varied between 1 and 1.8 times that in uninfected cells when 50% of the cells were infected, expressed LMP, and incorporated 20-fold more [3H]thymidine than did uninfected cells. This finding indicates that induced proliferation of these primary cells is not sufficient to induce Bcl-2. We found that BALB/c 3T3 cells and their derivatives transformed by LMP do not express Bcl-2 detectably. The expression of LMP at high levels in lymphoid cells is cytotoxic and correlates with an increased expression of Bcl-2 following stable selection for the introduced LMP gene; 2 days after transfection, control vector- and LMP-transfected populations, however, express equal levels of Bcl-2 protein. We also analyzed transient expression of LMP in an EBV-negative Burkitt's lymphoma cell line. Infection of BJAB cells with the B95-8 strain of EBV results in an increase in Bcl-2 expression with a time course similar to that of LMP expression, and LMP alone transiently induces an increase in Bcl-2 expression in these cells. We interpret these observations to indicate that increased expression of Bcl-2 is unlikely to contribute to the ability of EBV to immortalize primary B cells and that both the transformation of rodent cells and the cytotoxicity mediated by LMP are independent of Bcl-2.
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PMID:Latent membrane protein of Epstein-Barr virus induces cellular phenotypes independently of expression of Bcl-2. 839 49

The bcl-2 gene can potentially encode 26- and 22-kDa proteins that differ only in their carboxyl tails because of an alternative splicing mechanism. The larger of these proteins contains a hydrophobic transmembrane domain within its carboxyl terminus, resides (at least in part) in mitochondrial membranes and has been shown to prolong cell survival by blocking programmed cell death (also termed "apoptosis"). To explore the function of the shorter 22-kDa Bcl-2 protein that lacks a transmembrane domain, DNAs encoding p26-Bcl-2-alpha or p22-Bcl-2-beta were expressed in an interleukin-3 (IL-3)-dependent hematopoietic cell line 32D. In contrast to p26-Bcl-2 alpha that markedly prolonged cell survival, p22-Bcl-2-beta did not extend the survival of 32D cells when cultured in the absence of IL-3. Expression in 32D cells of a chimeric DNA that fused portions of the open reading frame common to Bcl-2-alpha and Bcl-2-beta (amino-acids 1-195) with sequences encoding the transmembrane and cytosolic domains of the IL-2 receptor-alpha protein resulted in production of a Bcl-2/IL-2R fusion protein that was capable of prolonging 32D cell survival in the setting of IL-3 withdrawal. Based on fractionation of cells to produce crude heavy membrane, light membrane, nuclei, and cytosolic preparations, much of the p22-Bcl-2-beta protein appeared to reside in the cytosol, whereas Bcl-2-alpha and the Bcl-2/IL-2R chimeric proteins were found exclusively in fractions that also contained the inner mitochondrial membrane protein F1-beta-ATPase. Taken together, these findings demonstrate the importance of membrane association for the function and intracellular targeting of the apoptosis-blocking Bcl-2 protein. Furthermore, despite the strong evolutionary conservation of the carboxyl regions of Bcl-2-alpha proteins observed previously for mammalian and avian species, these data suggest that a heterologous transmembrane domain can be substituted without loss of function.
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PMID:Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival. 849 57

Activation of the cell surface receptor Fas/APO-1 (CD95) induces apoptosis in lymphocytes and regulates immune responses. The cytoplasmic membrane protein Bcl-2 inhibits lymphocyte killing by diverse cytotoxic agents, but we found it provided little protection against Fas/APO-1-transduced apoptosis in B lymphoid cell lines, thymocytes and activated T cells. In contrast, the cowpox virus protease inhibitor CrmA blocked Fas/APO-1-transduced apoptosis, but did not affect cell death induced by gamma-radiation or serum deprivation. Signalling through Fas/APO-1 did not down-regulate Bcl-2 or induce its antagonists Bax and Bcl-xS. In Fas/APO-1-deficient lpr mice, Bcl-2 transgenes markedly augmented the survival of antigen-activated T cells and the abnormal accumulation of lymphocytes (although they did not interfere with deletion of auto-reactive cells in the thymus). These data raise the possibility that Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis.
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PMID:Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. 855 33

Two Epstein-Barr virus (EBV) gene products, latent infection membrane protein 1 (LMP1), expressed mainly in latent infection, and BHRF1, expressed in lytic infection, have the ability to promote cell survival. LMP1 protects human B cells from apoptosis by upregulating expression of Bcl-2 and A20. We have demonstrated that LMP1 transfectants of Jurkat T cells are resistant to apoptosis induced by serum depletion without affecting the Bcl-2/Bax system. Overexpression of LMP1 in epithelial cells inhibits apoptosis induced by TNF-alpha, but not by anti-Fas antibodies. These results indicate that the anti-apoptotic mechanism of LMP1 differs among different cell types. BHRF1 can prevent apoptosis induced by TNF-alpha and anti-Fas antibodies in epithelial cells. The implication of the anti-apoptotic function of LMP1 and BHRF1 is reviewed in relation to EBV infection.
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PMID:[Anti-apoptotic function of the Epstein-Barr virus LMP1 and BHRF1 proteins]. 874 77

The EBV-encoded latent membrane protein 1 (LMP1) suppresses apoptosis in B lymphocytes through up-regulation of Bcl-2. However, the maximum induction of Bcl-2 by LMP1 takes about 48-72 h. We show in this report that up-regulation of the Bcl-2 homologue Mcl-1 by LMP1 preceded the induction of Bcl-2 and that the up-regulation was transient; therefore, Mcl-1 levels decreased when Bcl-2 levels started to increase. This finding supports the hypothesis that Mcl-1 functions as a rapidly inducible, short-term effector of cell viability. LMP1 also blocked the decline in the Mcl-1 levels in response to apoptotic stimulation triggered by elevated cyclic AMP. This effect of LMP1 was associated with a delayed cell death in the EBV-negative Burkitt lymphoma cell line BL41. The maintenance of Mcl-1 expression by LMP1 is likely to be a crucial immediate-early response that enables cells to survive until Bcl-2 can be up-regulated.
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PMID:Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. 884 Sep 72


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