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)

The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy-chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25-fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B-CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B-cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)
Blood 1993 Sep 15
PMID:bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. 810 32

The expression of B lineage associated genes during early B cell differentiation stages is not firmly established. Using cell surface markers and multiparameter flow cytometry, bone marrow (BM) cells can be resolved into six fractions, representing sequential stages of development; i.e., pre-Pro-B, early Pro-B, late Pro-B/large Pre-B, small Pre-B, immature B, and mature B cells. Here we quantitate the levels of several B lineage associated genes in each of these fractions by RT-PCR, demonstrating different patterns of expression. We find that expression of terminal deoxynucleotidyl transferase (TdT), lambda 5, and VpreB is predominantly restricted to the Pro-B stages. Rag-1 and Rag-2 expression is also tightly regulated, and is found largely in the Pro-B through small Pre-B stages. Mb-1 is present from Pro-B throughout the pathway at high levels. Finally, Bcl-2 is expressed at high levels only at the pre-Pro-B and mature B stages, whereas it is low during all the intermediate stages. We also correlate this expression data with an analysis of the onset of Ig gene rearrangement as assessed by amplifying D-JH, VH-DJH, and VK-JK. Finally, we report differences in gene expression during B lymphopoiesis at two distinct ontogenic timings, in fetal liver and adult BM: both TdT and the precursor lymphocyte regulated myosin-like light chain are expressed at high levels in the Pro-B cell stage in bone marrow, but are absent from the corresponding fraction in fetal liver. In contrast, lambda 5, VpreB, Rag-1, and Rag-2 are expressed at comparable levels.
J Exp Med 1993 Sep 01
PMID:The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. 835 62

Bcl-2, a proto-oncogene that can block apoptosis, was found to be expressed throughout the thymic medulla, but in only scattered cells in the thymic cortex. In order to determine the precise distribution of Bcl-2 protein during thymocyte development, we utilized mAb specific for either mouse or human Bcl-2. Thymocyte subpopulations were assessed using three-color flow cytometry and a saponin-permeabilization method. Staining of adult mouse and human thymocytes was comparable, with 20 to 35% of cells expressing Bcl-2. Bcl-2 was expressed in nearly all CD4+ and CD8+, and CD3hi cells, but in only 5 to 10% of CD4+8+ cells. The CD4-8- population was more variable, with 25 to 40% of human cells and 65 to 80% of murine cells expressing Bcl-2. In sorted adult murine CD4-8- cells, the very immature Pgp-1+/IL-2R alpha- subset had a high percentage of Bcl-2+ cells. Bcl-2 expression was also examined during murine fetal development. At fetal day 15.5 to 16.5, 60 to 70% of total thymocytes expressed Bcl-2. By fetal day 17.5, overall Bcl-2 expression fell to adult levels of 20 to 30%. Bcl-2 was present in peripheral T cells from lymph node, spleen, and peripheral blood at uniformly high levels. In vitro stimulation with anti-CD3 or anti-TCR antibodies increased Bcl-2 expression in total thymocyte cultures, but could not induce Bcl-2 expression in CD4+8+ cells, even with the addition of a variety of cytokines. These data suggest that early double negative thymocytes express Bcl-2 but lose Bcl-2 with differentiation to the double positive stage. Thymocytes regain Bcl-2 during selection to a single positive state and retain Bcl-2 in the periphery.
J Immunol 1993 Sep 01
PMID:Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. 836 Apr 76

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.
Leukemia 1993 Sep
PMID:Bcl-2 protein in centrocytic lymphoma; a paraffin section study. 837 94

The bcl-2 proto-oncogene can prevent the death of many cell types. Mice were generated that were chimeric for the homozygous inactivation of bcl-2. Lymphocytes without Bcl-2 differentiated into phenotypically mature cells. However, in vitro, the mature T cells that lacked Bcl-2 had shorter life-spans and increased sensitivity to glucocorticoids and gamma-irradiation. In contrast, stimulation of CD3 inhibited the death of these cells. T and B cells with no Bcl-2 disappeared from the bone marrow, thymus, and periphery by 4 weeks of age. Thus, Bcl-2 was dispensable for lymphocyte maturation, but was required for a stable immune system after birth.
Science 1993 Sep 17
PMID:Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. 837 53

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.
J Virol 1993 Sep
PMID:Latent membrane protein of Epstein-Barr virus induces cellular phenotypes independently of expression of Bcl-2. 839 49

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence conservation, therefore, the two proteins appear to be functionally homologous. We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle.
Proc Natl Acad Sci U S A 1993 Sep 15
PMID:Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. 839 6

Mutation, deactivation and disregulated expression of oncogenes and tumour-suppressor genes may be involved in the pathogenesis of oral squamous cell carcinoma (SCC). Deactivation of the p53 tumour-suppressor gene allows cell proliferation and blocks apoptosis of malignant oral keratinocytes. Mutation in the ras oncogene results in persistent mitogenic signalling. Upregulatioed c-Myc expression, in the presence of growth factors, provides an additional proliferative signal. Loss of retinoblastoma tumour-suppressor gene (Rb) function may contribute to oral keratinocyte hyperproliferation and recent evidence suggests that simultaneous deactivation of both p53 and Rb is required for tumourigenesis. Enhanced Bcl-2 and reduced Fas expression inhibit tumour cell apoptosis and may convey resistance to cytotoxic drugs and T cell-mediated cytotoxicity, respectively. Exogenous mutagens such as tobacco, alcohol and viral oncogenes may cause altered expression of oncogenes and tumour-suppressor genes in some cases of oral SCC. The impact of these mechanisms on future therapies for oral SCC is highlighted.
Oral Dis 1995 Sep
PMID:Review article: The role of oncogenes, tumour suppressor genes and growth factors in oral squamous cell carcinoma: a case of apoptosis versus proliferation. 870 24

In the absence of E1B, the 289- and 243-residue E1A products of human adenovirus type 5 induce p53-dependent apoptosis. However, our group has shown recently that the 289-residue E1A protein is also able to induce apoptosis by a p53-independent mechanism (J. G. Teodoro, G. C. Shore, and P. E. Branton, Oncogene 11:467-474, 1995). Preliminary results suggested that p53-independent cell death required expression of one or more additional adenovirus early gene products. Here we show that both the E1B 19-kDa protein and cellular Bcl-2 inhibit or significantly delay p53-independent apoptosis. Neither early region E2 or E3 appeared to be necessary for such cell death. Analysis of a series of E1A mutants indicated that mutations in the transactivation domain and other regions of E1A correlated with E1A-mediated transactivation of E4 gene expression. Furthermore, p53-deficient human SAOS-2 cells infected with a mutant which expresses E1B but none of the E4 gene products remained viable for considerably longer times than those infected with wild-type adenovirus type 5. In addition, an adenovirus vector lacking both E1 and E4 was unable to induce DNA degradation and cell killing in E1A-expressing cell lines. These data showed that an E4 product is essential for E1A-induced p53-independent apoptosis.
J Virol 1996 Sep
PMID:Adenovirus type 5 early region 4 is responsible for E1A-induced p53-independent apoptosis. 870 47

Expression of the protooncogene bcl-2 inhibits both apoptotic and in some cases necrotic cell death in many cell types, including neural cells, and in response to a wide variety of inducers. The mechanism by which the Bcl-2 protein acts to prevent cell death remains elusive. One mechanism by which Bcl-2 has been proposed to act is by decreasing the net cellular generation of reactive oxygen species. To evaluate this proposal, we measured activities of antioxidant enzymes as well as levels of glutathione and pyridine nucleotides in control and bcl-2 transfectants in two different neural cell lines-rat pheochromocytoma PC12 and the hypothalamic GnRH cell line GT1-7. Both neural cell lines overexpressing bcl-2 had elevated total glutathione levels when compared with control transfectants. The ratios of oxidized glutathione to total glutathione in PC12 and GT1-7 cells overexpressing bcl-2 were significantly reduced. In addition, the NAD+/NADH ratio of bcl-2-expressing PC12 and GT1-7 cells was two- to threefold less than that of control cell lines. GT1-7 cells overexpressing bcl-2 had the same level of glutathione peroxidase, catalase, superoxide dismutase, and glutathione reductase activities as control cells. PC12 cells overexpressing bcl-2 had a twofold increase in superoxide dismutase and catalase activity when compared with matched control transfected cells. The levels of glutathione peroxidase and glutathione reductase in PC12 cells overexpressing bcl-2 were similar to those of control cells. These results indicate that the overexpression of bcl-2 shifts the cellular redox potential to a more reduced state, without consistently affecting the major cellular antioxidant enzymes.
J Neurochem 1996 Sep
PMID:Shift of the cellular oxidation-reduction potential in neural cells expressing Bcl-2. 875 34


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