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)

Bcl-2 is an oncogene associated with prevention of apoptosis in a variety of cell types. Bcl-2 expression in B lymphoid cells prolongs antibody production, in vitro and in vivo. A line of transgenic mice (B6) has been developed that expresses human Bcl-2 in the B cells of SWR/SJL mice. B6 transgenic, nontransgenic littermates, and BALB/c mice were immunized with beta-galactosidase (B-gal) or sheep red blood cells (SRBC). The number of spleen cells recovered from immunized B6 mice was 3-4 times greater than syngeneic, nontransgenic littermates or BALB/c mice. Spleen cells from B-gal or SRBC immune B6, SWR/SJL, and BALB/c mice were fused with P3 myeloma cells to produce hybridomas. Forty-eight percent of the wells plated with fused B6 spleen cells produced B-gal-specific antibodies compared to 14% from BALB/c and 12% from SWR/SJL. Antibody-specific wells were subcloned, resulting in enhanced recovery of antigen-specific subclones with B6-derived fusions compared to controls. In the SRBC fusions, 17% of the wells plated with fused B6 spleen cells produced SRBC-specific antibodies compared to 6% for BALB/c and SWR/SJL spleens. After subcloning, B6-derived clones produced 8% positive subclones compared to 9.5% from SWR/SJL and 3.5% from BALB/c. Comparison of the isotype distribution of subclones showed a higher ratio of IgG antibodies compared to IgM from B6 mice in the B-gal fusions. IgA antibodies were recovered only from B6 mice. These data indicate that B6 transgenic mice that overexpress Bcl-2 in their B cells may be superior to other mouse strains for production of antigen-specific hybridomas.
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PMID:Evaluation of Bcl-2/B cell transgenic mice (B6) for hybridoma production. 891 86

The apoptosis of human cytokine-deprived activated T cells can be prevented by a soluble mediator secreted by fibroblasts, epithelial and endothelial cells, and this rescue occurs with fibroblasts from different species. Fractionation of W138 fibroblast-conditioned medium indicated that the survival-promoting agent(s) were > 30,000 MW. The continuous presence of the survival factor was required for prevention of apoptosis, which did not involve the induction of proliferation. Nevertheless, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bax and CD95 (Fas/Apo-1) was either unchanged or slightly increased in fibroblast-rescued T cells, suggesting that constraints on survival still existed after co-culture. A fundamental observation in the present study was that although Bcl-2 was reduced, the levels of Bcl-XL was maintained in cytokine-deprived T cells by fibroblast co-culture. This suggests that fibroblasts and/or other stromal cells may promote activated T-cell survival by a selective effect on Bcl-XL expression, which is consistent with histological examination of activated T cells within lymphoid tissue in vivo. The rescued T cell could be re-activated by CD3 antibody, but only in the presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-XL expression and also proliferation. Thus, survival signals from stromal cells in tissue microenvironments may enable activated T-cell persistence in a primed but quiescent state, and our data suggest that the regulation of Bcl-XL expression may be central in this process. The further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chronicity of immune responses in different tissues in vivo.
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PMID:Fibroblasts prevent apoptosis of IL-2-deprived T cells without inducing proliferation: a selective effect on Bcl-XL expression. 895 53

A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, 1-beta-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (delta psi m) that precedes nuclear DNA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin in vitro. Circulating tumor cells from patients receiving chemotherapy in vivo also demonstrate a delta psi m disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-XL protects against chemotherapy-induced apoptosis, at both the level of the mitochondrial dysfunction preceding nuclear apoptosis and the level of late nuclear apoptotic events. Bcl-2-mediated inhibition of ceramide-induced delta psi m disruption is observed in normal as well as anucleate cells, indicating that bcl-2 acts on an extranuclear pathway of apoptosis. In contrast to Bcl-2 and Bcl-XL, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced delta psi m disruption and apoptosis, although cytokine response modifier A does prevent the delta psi m collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, delta psi m disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and delta psi m is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.
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PMID:Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. 898 42

B lymphocytes undergo affinity maturation of their antigen receptors within germinal centers. These anatomical structures develop in secondary lymphoid organs from the clonal expansion of a few antigen-specific founder B cells, whose isolation and characterization are reported here. Human germinal center founder cells express the naive B cell markers surface IgM and IgD as well as the germinal center B cell markers CD10 and CD38. They express low levels of Bcl-2, high levels of Fas, and undergo rapid apoptosis in culture. The smaller nonproliferating sIgM+IgD+CD38+ B cells displayed a lower level of somatic mutation in their immunoglobulin variable region genes compared with the large proliferating ones. Unmutated sIgM+IgD-CD38+ tonsillar B cells may thus represent germinal center founder cells in which the program for apoptotic cell death is triggered before the onset of somatic mutation, allowing the selection of the germline antibody repertoire at an early stage.
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PMID:Germinal center founder cells display propensity for apoptosis before onset of somatic mutation. 905 56

Clinicopathological evidence has accumulated that colorectal adenocarcinoma with minimal or no glandular differentiation constitutes two entities with different prognosis. In a series of 20 predominantly nonglandular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatellite instability were analyzed and correlated to the biology of the tumors. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated by nested polymerase chain reaction. Histologically, 13 tumors showed small uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly an expansive growth pattern (69.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltrate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpart, solid or medullary carcinoma. These tumors showed less frequent lymph node as well as hematogeneous metastases than pleomorphic carcinomas. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.05) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0.05). No significant difference between the medullary and the pleomorphic tumor type was found with respect to bcl2 expression and the occurrence of Ki-ras mutations at codon 12. In contrast, microsatellite instability was almost totally restricted to poorly differentiated adenocarcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finally, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, which was, however, restricted to the peritumor lymphoid infiltrate as shown by in situ hybridization. Correlation with the biology of the tumors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months), which was the case in five of the seven patients with the pleomorphic-type carcinoma (P < 0.025). Our results clearly indicate that the poorly differentiated colonic carcinoma with minimal or no glandular structures constitute two different entities, a medullary and a pleomorphic variant, which markedly differ in their phenotype, genotype, and prognosis.
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PMID:Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. 913 4

We have previously demonstrated that daunorubicin (DNR) induces apoptosis in some leukemic myeloid cell lines. We investigated a potential protective role for Bcl-2 in apoptosis induced by DNR in two leukemic cell lines, one myeloid and one lymphoid, overexpressing the anti-apoptotic gene Bcl-2. Parental cells treated with DNR exhibited classical features of apoptosis 6 h after drug exposure, all the cells being dead after 30-48 h. In contrast, overexpression of Bcl-2 significantly delayed, but did not prevent the occurrence of DNR-induced apoptosis, with no surviving cells 96 h after drug exposure. To elucidate the mechanism of the protection mediated by Bcl-2, we explored the signaling pathway which initiates DNR-induced apoptosis. In this report, we show that, in both the myeloid and lymphoid parental cell lines, DNR triggered a sphingomyelin (SM) hydrolysis after 10-15 min with a concomitant ceramide generation. Moreover, exogenous ceramide induced DNA fragmentation in these cells, with levels similar to those observed with DNR treatment. In contrast, Bcl-2 overexpression protected the cells against apoptosis induced by ceramide treatment, without preventing the early SM hydrolysis nor the ceramide generation in these cells. Our results strongly suggest that Bcl-2-mediated protection of DNR-induced apoptosis is effected downstream of the SM-ceramide signaling pathway.
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PMID:Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells. 915 Mar 90

The chicken anemia virus protein apoptin induces a p53-independent, Bcl-2-insensitive type of apoptosis in various human tumor cells. Here, we show that, in vitro, apoptin fails to induce programmed cell death in normal lymphoid, dermal, epidermal, endothelial, and smooth-muscle cells. However, when normal cells are transformed they become susceptible to apoptosis by apoptin. Long-term expression of apoptin in normal human fibroblasts revealed that apoptin has no toxic or transforming activity in these cells. In normal cells, apoptin was found predominantly in the cytoplasm, whereas in transformed and malignant cells it was located in the nucleus, suggesting that the localization of apoptin is related to its activity. These properties make apoptin a potential agent for the treatment of a large number of tumors, also those lacking p53 and/or overexpressing Bcl-2.
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PMID:Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells. 915 62

Ligation of CD40 inhibits apoptosis and stimulates proliferation of normal B cells, whereas ligation of CD95 (APO-1/Fas) induces apoptosis of activated lymphocytes. Aberrant signalling through the CD40 and CD95 antigens could thus participate in the pathogenesis of lymphoid malignancies. The expression and function of CD40 and CD95 on neoplastic B cells from patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) were examined. CD40 was expressed by all 30 B-cell tumours, whereas CD95 was detected on neoplastic B cells in only one of 10 cases of ALL, two of 10 cases of CLL, and three of 10 cases of NHL. Incubation with an agonistic CD95 monoclonal antibody (MoAb) did not augment apoptosis in any of the unstimulated B-cell neoplasms. CD40 triggering did not consistently inhibit spontaneous apoptosis, but ultimately stimulated the growth of neoplastic B cells in most cases. Furthermore, CD40 activation led to up-regulation of the CD95 antigen in all 30 B-cell neoplasms. Ligation of CD95 on CD40-activated tumour cells augmented apoptosis in five of 10 ALL, three of 10 CLL, and nine of 10 NHL cases. The degree of apoptosis induced by CD95 triggering was greater for NHL cells than for ALL cells or CLL cells. Bcl-2 expression by ALL and NHL cells was substantially decreased after in vitro culture, whereas Bcl-2 expression by CLL cells was not significantly changed. However, there was no correlation between the level of Bcl-2 expression and sensitivity to CD95-mediated apoptosis. Thus, factors other than levels of CD95 and Bcl-2 determine susceptibility of malignant B cells to apoptosis after CD95 triggering. CD40-activated lymphoma cells appear to be very sensitive to CD95-mediated apoptosis, suggesting potential strategies for treatment of NHL. Elucidation of the mechanisms underlying resistance of ALL and CLL cells to CD95 triggering may facilitate the development of novel therapeutic approaches to these diseases as well.
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PMID:Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies. 916 8

Hypothesizing that loss of basal cells in oral lichen planus is due to apoptosis, we evaluated LP specimens for apoptosis-regulating proteins [positive regulators Bcl-xS, Bax, Fas/Fas-ligand, p53, and negative regulators (anti-apoptotic) Bcl-2, Bcl-xL and compared results with reactions in normal mucosa and chronically inflamed gingiva. Also, sections were evaluated with an in situ TUNEL assay that identifies apoptotic DNA fragments. Basal keratinocytes in normal buccal mucosa, nonspecific gingivitis, and LP were negative for Bcl-2 protein, but melanocytes and lymphoid cells were positive. Keratinocyte staining for Bcl-x was negative to weak in normal buccal mucosa and gingivitis, and moderate in LP. Keratinocytes (especially upper prickle cells) in all tissues stained similarly for Bax at weak to moderate levels. Also, no differences in Fas and Fas-ligand staining were evident. Prominent p53-positive staining was seen in all LP biopsies (10-100% of basal keratinocytes) but not in normal buccal mucosa and gingivitis. Few basal keratinocytes in 5/10 LP cases exhibited a positive in situ signal for DNA fragment-associated apoptosis. That the Bcl-2 family of proteins and Fas/Fas-ligand were detected in normal and diseased tissues, and were occasionally expressed differently in oral LP, supports the notion that apoptosis is a potential mechanism of keratinocyte loss, especially in LP. The pattern of p53 staining in oral LP suggests over-expression of wild-type protein; a phenomenon that would arrest the cell cycle to allow repair of damaged DNA, or trigger apoptosis. While immunohistochemical evidence for apoptosis-associated basal keratinocyte death in LP was slight, it appeared that it may be p53 protein, and possibly Bcl-x associated.
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PMID:Apoptosis-associated markers in oral lichen planus. 989 Apr 58

An EBV(-) BL (Burkitt lymphoma) line (Black93), established from a patient exhibiting glucocorticoid-induced ATLS (acute tumor lysis syndrome), was highly sensitive to dexamethazone (DX) in vitro in the studies including 18 lymphoid cell lines (10 BL lines). In the BL lines, the highly sensitive ones always lacked Bcl-2(bcl-2 protein), while the DX resistant ones expressed Bcl-2. Black93 is the first BL cell-line derived from a ATLS patient, proving that cell lines can be established in vitro from ATLS patients. Since some pre-B ALL lines expressing Bcl-2 were DX-sensitive, the relationship between Bcl-2 and DX-sensitivity is not straight-forward. In the BL cells, however, the absence of Bcl-2 appears to be responsible for the DX-sensitivity. The DX-sensitivity and the absence of Bcl-2 is a major characteristic carried by t(8;14) neoplasms. In addition, there may be a stage of B-lineage differentiation without Bcl-2. While rare BL cases have been reported to express TdT (terminal desoxynucleotidyl transferase), Tree92 is the first such line, expressing S-Ig(mu, lambda), TdT and RAG (recombination activating gene)-1. When surface mu is ligated with antibody, RAG-1 was suppressed in expression, indicating that the signal through S-Ig can modulate the expression of RAG-1 in the Tree92 cells. Chromosome translocation is known to be associated with a specific stage of differentiation. Such specific stage for t(8;14), however, is broad enough to cover S-Ig(+), TdT(+) and RAG-1(+) stage, too. The phenotypic classification of leukemia/lymphoma and the delineation of differentiation scheme of normal hematopoietic cells, are dependent on each other. The documentation of the properties such as DX-sensitivity, the absence of Bcl-2, the expression of RAG-1 and its modulation by the signal through S-Ig is an example in which the diverse properties of human t(8;14) neoplasms can contribute for delineating the differentiation scheme of normal hematopoietic cells more precisely.
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PMID:Diverse properties of human t(8;14) neoplasms: [1] ATLS and absence of BCL-2 [2] modulation of RAG-1 expression with S-Ig ligation. 918 67


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