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)

Lymphoid cells and small intestinal epithelial (SIE) cells are among the most radiosensitive in the body. The factors that account for the differential sensitivity to gamma-radiation among different tissue-types remain poorly understood, but can only partly be explained by differences in rates of cell proliferation. Here we demonstrate that exposure of mice to 800 cGy of gamma-radiation results in rapid elevations in the levels of the Bax protein, a pro-apoptotic member of the Bcl-2 protein family, in lymphoid cells and SIEs. gamma-Radiation-induced increase in Bax protein were evident within 2 h and persisted for at least 24 h, as determined by immunoblotting and immunohistochemical assays. Increases in Bax were followed by massive apoptosis in lymphoid organs and in the small intestinal crypts, as determined by morphological criteria and in situ end-labeling of fragmented nuclear DNA by terminal deoxynucleotidyl transferase (TUNEL method). Radiation did not induce elevations in Bax or apoptosis in radioresistant tissues such as heart, skeletal muscle, brain, kidney, liver, lung, vascular smooth muscle and connective tissue. The findings suggest that Bax may be one of the mediators of radiation-induced apoptosis in vivo.
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PMID:Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. 855 90

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

Bcl-2 functions to repress apoptosis by regulation of genes which encode proteins required for programmed cell death and by interference with peroxidative damage. We investigated the interrelationship between expression of bcl-2 and regulation of transcription factor DNA binding activities in the 2B4 T cell hybridoma and IL-2-dependent CTLL T cell line. Over-expression of bcl-2 in 2B4 resulted in enhanced basal levels of activator protein (AP)-1, octamer binding factor (Oct)-1, lymphoid enhancer binding factor (LEF)-1, RelA-p50 and NF-kappa B p50-p50 DNA binding activities. After apoptotic signaling, down-regulation of AP-1, NF-AT and Oct-1 binding activities was observed in control 2B4 and CTLL, whereas suboptimal, but higher, levels of these transcription factors were found in bcl-2-transfected cells, potentially promoting cell survival. Furthermore, after apoptotic signaling, expression of bcl-2 led to differential changes of NF-kappa B levels, resulting in a decrease in RelA-p50 and an increase in NF-kappa B p50-p50, altering the ratio of these DNA binding activities such that now p50-p50 markedly predominated in both 2B4-Bcl-2 and CTLL-Bcl-2. Apoptotic signaling in the presence or absence of Bcl-2 resulted in induction of the RelB-p50 heterodimer in 2B4. The changes in NF-kappa B/Rel levels raise the possibility that this family of transcription factors may play an important role in the regulation of apoptosis.
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PMID:Pleiotropic effects of Bcl-2 on transcription factors in T cells: potential role of NF-kappa B p50-p50 for the anti-apoptotic function of Bcl-2. 858 69

The ability of Bcl-2 to inhibit apoptotic cell death is well established. Several homologues of the bcl-2 gene, such as bax, bcl-x or mcl-1, have recently been identified. Like Bcl-2, both Bcl-XL and Mcl-1 appear to function as repressors of apoptotic cell death, whereas Bax facilitates it, indicating possible interactions among them in the control of cellular survival. To investigate the in vivo role of expression of bcl-2 gene family products, immunoblot analysis using corresponding specific antisera was performed for peripheral blood cells and some lymphoid tissues in humans. We demonstrated that all Bcl-2 family proteins were expressed at various levels in hematolymphoid cell subpopulations isolated from peripheral blood, tonsil, spleen and thymus. Lymphoid expression of Bcl-2 family proteins tended to increase following activation, but declined with time in culture. Loss of Bcl-2 in cultured lymphoid cells was especially marked. Sole expression of Bax, but not other members of the Bcl-2 family, was observed on neutrophils, seemingly reflecting their shortest life-span among blood leukocytes. The results support the notion that a balance of expression of Bcl-2 family proteins may regulate the life and death of hematolymphoid cells at different stages of cell differentiation and activation.
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PMID:Immunoblot analysis of cellular expression of Bcl-2 family proteins, Bcl-2, Bax, Bcl-X and Mcl-1, in human peripheral blood and lymphoid tissues. 858 80

The expression of intercellular adhesion molecule 1 (ICAM-1), a molecule pivotal in many inflammatory and immune paracrine interactions, has been highly correlated with malignant melanoma (MM) progression. Because numerous parallels exist between tissues of neural crest origin and the immune system in the regulation of postmitotic cell survival, ICAM-1 expression was studied in MM and compared with that of B-cell lymphoma/leukemia 2 protein (bcl-2 oncoprotein), an important regulator in prolonging lymphoid cell survival by blocking programmed cell death. Frozen sections from 33 cases were studied by immunoperoxidase techniques: 14 primary MM (five in situ), nine metastatic MM (one epidermotropic), four melanocytic nevi, and six normal skin controls. The percentages of the cells that stained and their intensities (0-4+) were graded. Both ICAM-1 (90%, 3-4+) and bcl-2 (95%, 2-4+) were strongly expressed in all nine metastases, including the epidermotropic disease extension. Bcl-2 strongly decorated the tumor cells in all 14 cases of primary MM (80%, 2-4+); in the five in situ MM, bcl-2 stained the atypical melanocytes at the dermal-epidermal junction (DEJ) and throughout the epidermis (75%, 1-2+). In contrast, ICAM-1 was negative in the in situ MM. ICAM-1 expression became strong (85%, 2-4+) in the dermal component of early invasive disease. Both ICAM-1 and bcl-2 were expressed in melanocytic nevi, decreasing in intensity deep within the dermis as the nevus cells senesced ("matured"). Only bcl-2 was expressed in the normal melanocytes of the six skin controls. These data show that bcl-2 is constitutively expressed in normal melanocytes and melanocytic nevi and persists in the transformed cells of early and late MM. ICAM-1 is expressed only after dermal involvement occurs, both in melanocytic nevi and in invasive MM; it persists in metastatic disease. The coexpression of bcl-2 and ICAM-1 demonstrates another similarity between the immune and neural crest systems, but it does not define or necessarily imply any functional interaction between the two proteins. The intercellular relationship of these two molecules, if any, remains to be investigated.
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PMID:Intercellular adhesion molecule 1 (ICAM-1) and bcl-2 are differentially expressed in early evolving malignant melanoma. 859 46

Several putative functions have been attributed to the peripheral benzodiazepine receptor (PBR), but its precise physiologic role has not been elucidated. In the present study, we investigated PBR function by quantifying this receptor in leukocyte subsets from healthy donors and in leukemic blasts from lymphoid and myeloid lineages. Using a monoclonal antibody (MoAb) directed against the human PBR and a quantitative flow cytometric assay, we found that phagocytic cells from healthy donors displayed a higher level of PBRs than lymphocytes or natural killer (NK) cells. Among the lymphoid lineage, thymocytes and IgD-negative B cells expressed the lowest levels. However, because of the wide heterogeneity of PBR levels among 42 acute or chronic lymphoid and myeloid leukemias, it was not possible to assign PBR expression to a stage of maturation or a cell lineage. Although the PBR displayed a mitochondrial subcellular localization, its expression was not correlated with the mitochondrial content, suggesting a modulation of PBR density at the level of the mitochondria. This modulation was confirmed when we studied in detail the PBR expression during T-cell development by both flow cytometry and confocal microscopy. We found that the PBR was expressed with a bimodal profile during T-cell development, identical to the one observed with the proto-oncogene, Bcl-2. The high similarity in the expression of both the PBR and the Bcl-2 proto-oncogene in T-cell and B-cell subsets, their common mitochondrial localization, and the observation of high quantities of PBR in phagocytic cells, which are known to produce high levels of radical oxygen species, suggested that PBRs may participate in an antioxidant pathway. Indeed, a strong correlation was established between the ability of hematopoietic cell lines to resist H202 cytotoxicity and their level of PBR expression. Demonstration of the role of PBR in the protection against H202 was obtained by transfecting JURKAT cells with the human PBR cDNA. Transfected cells exhibited increased resistance to H202 compared with wild-type cells, suggesting that PBR may prevent mitochondria from radical damages and thereby modulate apoptosis in the hematopoietic system.
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PMID:Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical damage. 860 31

Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium, salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB --> methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the beta-hydroxylase enzyme system itself.
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PMID:Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells. 861 Nov 83

The lytic response of lymphoid cells to glucocorticoid hormones (GC) is prototypical of the induction of apoptosis: a special form of cellular demise for the removal of unwanted or redundant cells. Initiation and execution of a death programme are therefore major checkpoints in GC-sensitivity. Although Bcl-2 protein can prevent or delay apoptosis of lymphoma and leukemia cells, exposed to multiple cytotoxic agents, its antagonism of GC-induced apoptosis appears most critical in conferring resistance to corticosteroids. Moreover, Bcl-2 may modulate GC-signalling to apoptosis through its association with fundamental cellular processes such as energy state, Ca2+ homeostasis and transmembrane transport. However, this signalling pathway can also be interrupted by Bcl-2- independent mechanisms. This review discusses the various cellular and oncogenetic factors that control GC sensitivity of leukemia/lymphoma cells and proposes a hypothesis of how GC may induce a death programme, sensitive to blockade by Bcl-2.
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PMID:Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells. 862 57

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.
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PMID:bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice. 862 51

Mice defective in Fas (CD95 or APO-1) or its ligand (lpr or gld mice) develop age-dependent lymphadenopathy and systemic autoimmune disease. T cells accumulating in the lymph nodes of these mice express reduced levels of Bcl-2 protein and are susceptible to spontaneous and glucocorticoid-induced apoptosis. We backcrossed bcl-2 transgenic mice to lpr and gld mice to homozygosity to determine the effects of Bcl-2 overexpression. T cells in these mice were resistant to spontaneous and glucocorticoid-induced apoptosis in vitro. Moreover, the accumulation of CD4(-)CD8(-) T cells in the lymph nodes and the spleens was augmented, suggesting that a Bcl-2-dependent mechanism regulating the number of T cells residing in the peripheral lymphoid organs in addition to the Fas-mediated pathway exists.
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PMID:Inhibition of apoptosis and augmentation of lymphoproliferation in bcl-2 transgenic Fas/Fas ligand-defective mice. 864 Aug 68


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