UNIPROT:P10415 - FACTA Search

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

Several Epstein-Barr virus (EBV)-negative Burkitt lymphoma-derived cell lines (for example, BL41 and Ramos) are extremely sensitive to genotoxic drugs despite being functionally null for the tumor suppressor p53. They rapidly undergo apoptosis, largely from G(2)/M of the cell cycle. 5-bromo-2'-deoxyuridine labeling experiments showed that although the treated cells can pass through S phase, they are unable to complete cell division, suggesting that a G(2)/M checkpoint is activated. Surprisingly, latent infection of these genotoxin-sensitive cells with EBV protects them from both apoptosis and cell cycle arrest, allowing them to complete the division cycle. However, a comparison with EBV-immortalized B-lymphoblastoid cell lines (which have functional p53) showed that EBV does not block apoptosis per se but rather abrogates the activation of, or signalling from, the checkpoint in G(2)/M. Furthermore, analyses of BL41 and Ramos cells latently infected with P3HR1 mutant virus, which expresses only a subset of the latent viral genes, showed that LMP-1, the main antiapoptotic latent protein encoded by EBV, is not involved in the protection afforded here by viral infection. This conclusion was confirmed by analysis of clones of BL41 stably expressing LMP-1 from a transfected plasmid, which respond like the parental cell line. Although steady-state levels of Bcl-2 and related proteins varied between BL41 lines and clones, they did not change significantly during apoptosis, nor was the level of any of these anti- or proapoptotic proteins predictive of the outcome of treatment. We have demonstrated that a subset of EBV latent gene products can inactivate a cell cycle checkpoint for monitoring the fidelity and timing of cell division and therefore genomic integrity. This is likely to be important in EBV-associated growth transformation of B cells and perhaps tumorigenesis. Furthermore, this study suggests that EBV will be a unique tool for investigating the intimate relationship between cell cycle regulation and apoptosis.
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PMID:Epstein-Barr virus suppresses a G(2)/M checkpoint activated by genotoxins. 1064 20

We have investigated apoptosis related gene expression in tumour cells, phenotype and function of blood mononuclear cells at diagnosis in relation to clinical response in three patients with nasopharyngeal carcinoma (NPC). We have focused our study on the Epstein Barr virus latent membrane protein-1 (LMP-1) and Bcl-2 expression in the tumour cells, the essential signal-transducing zeta molecule of T cell receptor (TcR zeta) and cellular mediated cytolysis of the blood mononuclear cells. The carcinoma cells of the patients were Bcl-2 negative. They were heterogeneous with regard to the expression of LMP-1 and the number of proliferating or apoptotic cells. Decrease in the expression of mature T cells (CD3, CD4, and CD8), TcR zeta and cellular mediated cytotoxicity was detected in blood mononuclear cells of the patients. IL-2 up-regulated these phenotypes and the cytolytic capacity of the blood mononuclear cells. The patient with LMP-1 negative carcinoma cells, down-regulated TcR zeta expression and impaired IL-2 mediated cytolysis, had the worst clinical outcome. Another patient with low apoptotic, highly proliferating and LMP-1 positive carcinoma cells had recurrent disease only in the irradiated area. Interestingly, NPC with high apoptotic and few LMP-1 expressing cells was detected in the patient with a normal level of TcR zeta expression and cytolytic functions in blood mononuclear cells at the time of diagnosis. After combination treatment with chemotherapy followed by radiotherapy, this patient is still alive with complete remission and disease-free at 36 months. Suppression of the immunological functions may occur in NPC patients. Our study suggests that the immunological functions and apoptosis related gene expression in the carcinoma cells may be used as prognostic factors and help in the decision of therapy of patients with nasopharyngeal cancer.
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PMID:Alteration of cellular mediated cytotoxicity, T cell receptor zeta (TcR zeta) and apoptosis related gene expression in nasopharyngeal carcinoma (NPC) patients: possible clinical relevance. 1081 Apr 2

The recently identified bfl-1 gene (also known as A1 or GRS), a homologue of bcl-2, encodes an antiapoptotic protein that suppresses apoptosis induced by the p53 tumor suppressor protein and exhibits proliferative and potent cooperative transforming activities. We show that elevated levels of bfl-1 mRNA are a feature of Epstein-Barr virus (EBV)-immortalized B-cell lines and Burkitt's lymphoma cell lines expressing the full spectrum of EBV latent proteins. Using an EBV-negative Burkitt's lymphoma cell line in which the expression of EBV latent membrane protein 1 (LMP1) is inducibly regulated by tetracycline, we demonstrate that LMP1 expression coincides with a dramatic increase in the level of bfl-1 mRNA. Also in this system, an increase in the level of Bcl-2 protein was seen to occur earlier than that of bcl-2 mRNA, suggesting that both transcriptional and translational mechanisms are involved in the control of Bcl-2 expression by LMP-1. We show that elevated bfl-1 mRNA stability can contribute to this effect of LMP-1, thus providing evidence of a novel mechanism of gene regulation by this EBV protein. Upregulation of bfl-1 by LMP1 was not observed in the T-cell line Jurkat or the epithelial cell line C33A. Ectopic expression of Bfl-1 in an EBV-positive cell line exhibiting a latency type I infection protects against apoptosis induced by growth factor deprivation, thereby providing a functional role for Bfl-1 in this cellular context and adding Bfl-1 to the list of antiapoptotic proteins whose expression is modulated by EBV. This is the first report of the regulation of bfl-1 expression by a viral protein, and this novel finding may thus represent an important link between the EBV oncoprotein LMP1 and its cellular growth-transforming properties.
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PMID:The bfl-1 gene is transcriptionally upregulated by the Epstein-Barr virus LMP1, and its expression promotes the survival of a Burkitt's lymphoma cell line. 1086 81

The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) is absolutely required for EBV transformation of B cells. LMP-1 mimics a constitutively activated receptor of the tumor necrosis factor receptor family, mediating diverse oncogenic functions that influence growth, differentiation and susceptibility to apoptosis. Given the critical functions of LMP-1 in EBV-associated transformation, it represents a rational therapeutic target for modulation. We used antisense oligodeoxynucleotides targeted to LMP-1 as a strategy to suppress LMP-1 expression and thereby inhibit its functions. In previous studies, we have shown that short-term treatment of EBV-positive lymphoblastoid cell lines (LCLs) with LMP-1 antisense oligodeoxynucleotides can dramatically reduce levels of LMP-1 protein in association with inhibition of proliferation, stimulation of apoptosis, down-regulation of Bcl-2 and Mcl-1 and enhanced sensitivity to the chemotherapeutic agent, etoposide. Here, we provide further evidence of the profound effects of reducing LMP-1 levels using antisense oligodeoxynucleotides in EBV-transformed B cells. We have shown that LMP-1 antisense treatment of LCLs partially restores sensitivity to the anti-proliferative and apoptotic effects of transforming growth factor-beta, a potent negative regulator of normal human B-cell growth, in association with a reduction in cyclin D2 levels. In addition, LMP-1 antisense sensitizes LCLs to chemotherapeutic drugs from diverse classes, including etoposide, vincristine and dexamethasone, by enhancing apoptotic cell death. Finally, the anti-proliferative and apoptotic effects of LMP-1 antisense treatment were observed not only in laboratory-derived LCLs, but also in an EBV-positive cell line derived from an AIDS-related lymphoma. These studies demonstrate that antisense targeting of LMP-1 represents a rational therapeutic strategy for EBV-positive lymphoproliferative disorders.
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PMID:Antisense to the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) sensitizes EBV-immortalized B cells to transforming growth factor-beta and chemotherapeutic agents. 1114 26

The effect of molecular factors in the outcome of Hodgkin's Disease (HD) is being currently studied. In a previous series of HD, including patients treated only with radiotherapy and patients treated with chemotherapy (with or without radiotherapy), we found that a high proliferation index had an adverse influence in overall survival (OS) and in the achievement of a complete remission (CR). Loss of Rb expression also had an adverse prognostic influence in achievement of CR. On the other hand LMP1-EBV expression had a favorable influence for OS. The expression of other molecular factors, p53, bcl2 and CD15 did not show prognostic influence. In the present paper we have studied the effect of these molecular variables in 110 patients, of the previous series who had been treated with chemotherapy. A retrospective study was performed in these 110 patients with HD treated with chemotherapy (ABVD or variants, 62%, or regimes not containing adriamycin, 38%) with or without adjutant radiotherapy, collected at the 11 centers belonging to the Spanish Collaborative Group for the Study of Hodgkin's Disease. The prognostic value of clinical variables and the expression of p53, bcl2, CD15, Rb, LMP 1-EBV and proliferative fraction demonstrated with sensitive immunohistochemical methods were studied. Cox's multivariate analysis was performed to assess their influence in failure-free survival (FFS) and OS. A multivariate logistic regression analysis was performed for studying the effect of the variables in the achievement of a CR. Of the clinical variables, only advanced stage (III/IV) had a significant independent adverse influence in FFS, in OS and in the achievement of CR and advanced age in OS. Of the molecular variables, LMP1-EBV had an independent and strong favorable influence in FFS, in OS and in the achievement of CR. Rb expression had a modest favorable influence in CR. The rest of the molecular variables had no independent influence on the outcome of the disease. In conclusion these results confirm the favorable prognostic value of LMP1-EBV expression in the subset of patients with HD treated with chemotherapy.
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PMID:Epstein-Barr virus-latent membrane protein 1 expression has a favorable influence in the outcome of patients with Hodgkin's Disease treated with chemotherapy. 1134 39

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) is essential for immortalization of B cells by EBV, protects the infected cells from apoptotic cell death and induces Bcl-2 expression. Suppression of LMP-1 expression by antisense oligodeoxynucleotides (AS-oligo) to LMP-1 inhibits proliferation, promotes apoptosis and suppresses Bcl-2 expression in EBV-transformed B cells. However, the function of LMP-1 expression in EBV-positive natural killer (NK) cell lymphoma cells has not been reported previously. We examined the function of LMP-1 in two EBV-positive NK cell lymphoma cell lines (NK-YS and YT) through suppressing LMP-1 expression by AS-oligo to LMP-1. The AS-oligo to LMP-1 suppressed LMP-1 mRNA and protein expression in two EBV-positive NK cell lymphoma cell lines, as well as in an EBV-transformed B-cell line (CMG-1). Proliferation was inhibited, apoptosis was induced and Bcl-2 expression was suppressed in CMG-1 cells, but none of these events were observed in NK-YS or YT cells. These results suggest that proliferation, inhibition of apoptosis and Bcl-2 expression in EBV-positive NK cell lymphoma cells are not directly regulated by LMP-1 as in EBV-transformed B-cell lines, but are probably mediated through other signal transducing systems.
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PMID:Antisense oligodeoxynucleotides to latent membrane protein 1 induce growth inhibition, apoptosis and Bcl-2 suppression in Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cells, but not in EBV-positive natural killer cell lymphoma cells. 1147 49

The purpose of this study was to determine the histologic class and immunologic phenotype of lymphomas presenting initially in the oral cavity and whether this correlated to a high incidence of Epstein-Barr virus (EBV) infection as has been reported with lymphomas in the nasal cavity. Seventy-one cases of oral lymphomas from the oral pathology referral service were analyzed retrospectively. They were classified according to the Revised European American Lymphoma (REAL) classification system using routine immunohistochemistry. EBV infection was determined by detection of early viral RNA sequences (EBER) and latent membrane protein (LMP-1) expression. Only non-Hodgkin's lymphomas were observed, with a female predominance of 2:1. They were primarily of B-cell origin and histologically classified mainly as large B-cell type (68%); T-cell lymphomas were rare (8%). EBV infection was observed in 14% of the B-cell lymphomas, an incidence rate higher than that reported in studies of B-cell lymphomas not located in the oral cavity but not as high as that observed in pleomorphic T-cell lymphomas (all sites, 36%) or nasal cavity T-cell lymphomas (nearly 100%). Interestingly, EBV proliferation did not correlate with expression of either Bcl-2 or p53.
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PMID:Lymphomas of the oral cavity: histology, immunologic type, and incidence of Epstein-Barr virus infection. 1195 36

This study was undertaken to evaluate the clinical significance of the expression of Bcl-2, p53 and LMP-1 in Hodgkin and Reed - Sternberg cells of patients with Hodgkin's lymphoma. The expression of these proteins in pre-treatment tissue biopsy specimens was correlated with presenting clinical features, failure-free survival (FFS) and overall survival (OS) in 83 patients with a confirmed Hodgkin's lymphoma treated in a single institution. HIV-positive patients were excluded. Patients were classified according to the International Prognostic Score (IPS) in low-risk (0 - 2 factors) and high-risk groups. The median age was 41 years (15 - 84), 41% were women, and 93% had advanced-stage disease (IIB - IVB). The expression of Bcl-2, p53 and LMP-1 was not associated with the complete remission rate, FFS or OS. The IPS risk group was the only factor significantly associated with OS. Patients with a high IPS had a lower 5 year OS (43% vs. 79%, P = 0.003). The expression of Bcl-2, p53 and LMP-1 did not add prognostic information to the IPS.
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PMID:The prognostic value of the expression of Bcl-2, p53 and LMP-1 in patients with Hodgkin's lymphoma. 1610 7

Plasmablastic lymphoma (PBL) is an uncommon, recently described B-cell-derived lymphoma that displays distinctive affinity for extranodal presentation in the oral cavity. Plasmablastic lymphoma is strongly associated with human immunodeficiency virus (HIV) infection, but has been reported in HIV-negative individuals. Plasmablastic lymphoma may be poorly recognized by pathologists, which is partly attributable to its relatively rare occurrence and unusual immunophenotype. Five cases of oral cavity lymphomas conforming to the current World Health Organization morphological criteria for PBL were retrieved from the consultation files at the Armed Forces Institute of Pathology. An immunohistochemical panel consisting of CD3, CD20, CD30, CD38, CD45RB, CD79a, CD138, Bcl-2, Bcl-6, Alk-1, Ki-67, EBV-LMP-1, and HHV8 was performed. All 5 cases were immunoreactive for CD38 and/or CD138, confirming plasma cell differentiation of the tumor cells. CD20 was immunoreactive in 1 case, and CD79a was positive in 2 cases. HHV8 and EBV-LMP-1 were nonreactive in all cases. Follow-up revealed only 1 patient alive with no evidence of disease. Our cases show that PBL is an aggressive type of B-cell lymphoma predominantly found in the oral cavity. Plasmablastic lymphoma is often associated with HIV infection.
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PMID:Plasmablastic lymphoma: a clinicopathologic correlation. 1641 38

We compared Etk/Bmx expression in nasopharyngeal carcinoma (NPC) and non-neoplastic nasopharyngeal lesions in order to learn whether the expression of this non-receptor protein tyrosine kinase is associated with the development of NPC. We also related Etk/Bmx expression to factors resulting from Epstein-Barr virus (EBV) infection. We used immunohistochemistry (IHC) and in situ hybridization to examine 20 non-neoplastic nasopharyngeal lesions and 49 cases of NPC to assess Etk/Bmx, EB virus latent membrane protein-1 (LMP-1), Bcl-2 and EBV-encoded small RNA-1 expression in these samples. Etk/Bmx expression was present in the basal cell nuclei of the nasopharyngeal epithelium in 1/9 (11.1%) cases of chronic nasopharyngitis and 2/11 cases (18.2%) of dysplasia. While 13/49 (26.5%) NPC cases expressed Etk/Bmx, the difference in frequency between the expression of Etk/Bmx in the non-neoplastic and NPC cases was not significant. Etk/Bmx expression was correlated with the presence of EBER-1 immunopositivity in dysplasia and in NPC but not in chronic nasopharyngitis. The presence of Etk/Bmx immunopositivity was independent of the expression of either LMP-1 or Bcl-2 in either the nasopharyngeal carcinoma or the non-neoplastic lesions. This suggests that in some cases of non-neoplastic and neoplastic nasopharyngeal lesions, Etk/Bmx may participate in regulating epithelial differentiation. While EBV-related small RNA-1 may participate in this regulation, neither LMP-1 or Bcl-2 expression appears to be related to Etk/Bmx expression.
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PMID:Expression of Etk/Bmx tyrosine kinase in the tumorigenicity of nasopharyngeal epithelium and its relation with EB virus infection and the apoptosis-related protein Bcl-2. 1645 22

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