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)

Previous studies by our laboratory have reported that the T cell receptor (TCR) TCR/CD3 complex could mediate activation as well as apoptosis of T lymphocytes. Two tyrosine residues in the ITAM (immuno-receptor tyrosine-based activation motifs) of CD3 epsilon were required for apoptosis signalling of Jurkat T lymphocytes. Stable cell lines TJK and T3JK produced from CD8(-) Jurkat T lymphocytes by transfection with wild-type and mutant CD8 epsilon (fusion of the extracellular and transmembrane domains of human CD8 alpha to the intracellular domain of mouse CD3 epsilon), were used with CD8(-) Jurkat T lymphocytes for studying the role of single intact CD3 epsilon. 5-Fluorouracil (5-FU), a chemotherapeutic drug can induce cell death of many tumour cell lines. In the present experiments, we examined the expression of caspase-3, p53 and Bid in the three cell lines induced by 5-FU and/or anti-CD8 antibody. We found high expression of p53 during activation-induced cell death of TJK cells mediated by anti-CD8 antibody and apoptosis of TJK and T3JK induced by 5-FU, implicating p53 involvement in apoptosis of leukemia cells induced by anti-CD8 antibody and 5-FU. We also detected the active form of caspase-3 and Bid in apoptotic leukemia cells after treatment with 5-FU and/or anti-CD8 antibody, indicating that the drug and antibody induced cell death through caspase-3 and the signal pathway may involve the Bcl-2 protein family. Our results showed that combined treatment with 5-FU and anti-CD8 antibody could enhance the rate of apoptosis induced by 5-FU or anti-CD8 antibody through increased expression of p53 and by promoting activation of caspase-3 and Bid. This suggests that the combination of 5-FU and anti-CD8 antibody may play an important role in inducing apoptosis of leukemia cells.
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PMID:5-Fluorouracil enhances apoptosis sensitivity of T lymphocytes mediated by CD3 epsilon. 1512 84

Sustained signaling from the T cell receptor (TCR) and costimulatory molecules is thought necessary for generating high numbers of effector T cells. Here, we show that Survivin is controlled in peripheral T cells by OX40 cosignaling via sustained PI3k and PKB activation. Survivin is induced by OX40 independent of mitotic progression in late G1, and blocking Survivin suppresses S-phase transition and division of T cells and leads to apoptosis. Moreover, Survivin expression alone is sufficient to restore proliferation and to antagonize apoptosis in costimulation-deficient T cells and can rescue T cell expansion in vivo. Survivin allows effector T cells to accumulate in large numbers, but Bcl-2 family proteins are required for T cell survival after the phase of active division. Thus, sustained Survivin expression from costimulatory signaling maintains T cell division over time and regulates the extent of clonal expansion.
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PMID:Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion. 1589 70

CD8(+) T cells are activated by the presentation of antigenic peptide through MHC class I molecules. Newly synthesized proteins formed as defective ribosomal products (DRiPs) can act as a major source of antigenic peptides for MHC class I presentation pathway. Majority of these peptides are generated from the intracellular degradation of self antigens. In the present study, we have shown that newly synthesized T cell receptor (TCR) beta chains formed as DRiPs in T cells are ubiquitinated and degraded by the proteasomes. These TCR-DRiPs are processed and presented by activated T cells to cognate anti-idiotypic CD8(+) T cells. Presentation of TCR idiopeptide (peptide derived from the variable region of idiotypic TCR) by activated T cells leads to Bcl-2 expression and cytokine secretion by anti-idiotypic CD8(+) T cells. Presentation of intracellular antigen by T cells may have important implications in immunoregulation, control of lymphotropic virus infection and autoimmune diseases.
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PMID:Idiotypic T cells specific for Morbillivirus nucleocapsid protein process and present their TCR to cognate anti-idiotypic CD8+ T cells. 1618 24

To investigate the effect of Bcl-2 on Ca2+ signaling in T cells, we continuously monitored Ca2+ concentration in Bcl-2-positive and -negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2-negative cells, high concentrations of anti-CD3 antibody induced a transient Ca2+ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca2+ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca2+ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca2+ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP(3)) receptor subtypes by small interfering RNA inhibited the Ca2+ elevation induced by high but not low anti-CD3, suggesting that Ca2+ responses to high and low anti-CD3 may have different requirements for the InsP(3) receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca2+ elevation induced by strong TCR activation without hindering prosurvival Ca2+ signals induced by weak TCR activation.
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PMID:Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation. 1639 Oct 1

In the developing thymus, strong T cell receptor (TCR) activation by self-antigens induces negative selection and weak TCR activation induces positive selection. Both processes are mediated by Ca(2+) signals, raising the question of how a single second messenger like Ca(2+) can mediate such diverse cell fates. Recent findings indicate that graded TCR activation signals are encoded in distinct patterns of Ca(2+) elevation. The anti-apoptotic protein Bcl-2 discriminates between these Ca(2+) signaling patterns, selectively inhibiting pro-apoptotic Ca(2+) signals induced by strong TCR activation without suppressing pro-survival Ca(2+) signals induced by weak TCR activation.
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PMID:Live free or die: an immature T cell decision encoded in distinct Bcl-2 sensitive and insensitive Ca2+ signals. 1672 Oct 59

While insufficient cell death of activated T cells can result in autoimmune disorders, elimination of too many T cells can lead to immunodeficiency. Therefore, T lymphocyte fate is highly regulated and requires that cells can switch from an apoptosis-resistant towards an apoptosis-sensitive state. This switch is tightly controlled by various effector molecules. Basically, two separate pathways control the fate of antigen-activated T cells: activation-induced cell death (AICD) and activated T cell autonomous death (ACAD). Autoreactive T lymphocytes are eliminated by restimulation via their T cell receptor (TCR) and undergo AICD involving death receptors (extrinsic pathway). In contrast, ACAD can lead to T cell deletion without TCR restimulation, and is determined by the ratio between anti- and pro-apoptotic Bcl-2 family members at the mitochondria (intrinsic pathway). While the extrinsic and the intrinsic pathway lead to caspase activation, non-caspase proteases (e.g., cathepsins) can be released by the lysosomes and might contribute to AICD as well as to ACAD. Activated T cells poses cell death escape mechanisms which are needed for survival of (memory) T cells, but are deleterious for autoimmune disorders or progression of T cell lymphomas.
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PMID:How T lymphocytes switch between life and death. 1679 83

A rare case of reactive lymphoid hyperplasia (RLH) of the liver in a 75-year-old woman admitted to hospital for surgical treatment of gastric, caecal and colon carcinomas is described here. Two nodular lesions in the left and right lobes of the liver were clinically diagnosed as metastatic tumours by computed tomography of the abdomen. A demarcating grey-white mass of size 1.4 cm was observed in a partially resected liver specimen. On examining the lesion microscopically, it was found to be composed of hyperplastic lymphoid follicles, lymphocytes, plasma cells, other inflammatory cells and interlaced hyalinised fibrous tissues. In the portal tracts around the lesion, chronic inflammatory cell infiltrates were seen, but no interface hepatitis or lymphoid follicle was observed. No evidence of monoclonality was observed by immunohistochemistry for B and T cell markers, in situ hybridisation for kappa and lambda light chains, and polymerase chain reaction analysis of immunoglobulin heavy chains or T cell receptor beta and gamma gene rearrangements. Bcl-2 immunoreactivity was not observed in the germinal centre. Epstein-Barr virus (EBV) antigen (latent membrane protein-1) and EBV-encoded small RNAs were not detected. A proliferation neither of myofibroblasts nor of cells positive for follicular dendritic cell markers was observed. RLH, formerly known as pseudolymphoma, has been reported of the liver in only 14 cases and is considered to be a differential diagnosis of small nodular lesions of the liver. That RLH has an inflammatory reactive nature, not a neoplastic disposition, and that EBV does not participate in the pathogenesis of RLH is supported by this case.
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PMID:Reactive lymphoid hyperplasia of the liver in a patient with multiple carcinomas: a case report and brief review. 1693 75

The mechanisms that allow the maintenance of immunological memory remain incompletely defined. Here we report that tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 1, a protein recruited in response to several costimulatory TNFR family members, is required for maximal CD8 T cell responses to influenza virus in mice. Decreased recovery of CD8 T cells in vivo occurred under conditions where cell division was unimpaired. In vitro, TRAF1-deficient, antigen-activated T cells accumulated higher levels of the proapoptotic BH3-only family member Bim, particularly the most toxic isoform, Bim(S). In the presence of excess IL-15, memory phenotype T cells with similar surface phenotype and comparable levels of Bcl-2 family members could be generated from WT or TRAF1-deficient T cell receptor transgenic OT-I T cells. However, when the memory CD8 T cells were allowed to compete for survival signals in the absence of antigen in vivo, the TRAF1-deficient T cells showed decreased recovery compared with TRAF1-sufficient T cells. This defect in T cell recovery in vivo was alleviated by introduction of siRNA to down-modulate Bim in TRAF1-deficient memory T cells. These studies identify the TRAF1 signaling axis and Bim down-regulation as critical for CD8 memory T cell survival in vivo.
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PMID:A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival. 1711 75

T cell apoptosis is a process necessary for central and peripheral tolerance. It ensures the proper removal of autoreactive T cells during thymic development as well as T cell homeostasis and the downregulation of immune responses against antigens in the periphery. Thus it is essential for the prevention of autoimmunity. Apoptotic pathways can be triggered by intrinsic (mitochondria-based) and extrinsic (receptor-based) stimuli. Both pathways involve a cascade of proteolytic enzymes called caspases whose activation commits the cell to death. In the periphery, autoreactive lymphocytes can be silenced by developmental arrest (anergy), or deleted by programmed cell death (apoptosis) through receptor-based activation-induced cell death (AICD). Central tolerance seems to rely more heavily on the mitochondria-based, T cell receptor (TCR)-stimulated apoptotic pathway, since thymocytes lacking the pro-apoptotic Bcl-2 family member Bim are resistant to TCR-induced apoptosis. Furthermore, defects in the intrinsic pathway of apoptosis may impair clonal deletion of autoreactive T cells. Several animal models exist in which impaired apoptosis results in autoimmunity. Here, we discuss data that suggest defects in T cell apoptosis in type 1 diabetes mellitus.
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PMID:Death pathways in T cell homeostasis and their role in autoimmune diabetes. 1748 32

The Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (Bak) are essential regulators of lymphocyte apoptosis, but whether they play a role in viable T cell function remains unclear. Here, we report that T cells lacking both Bax and Bak display defects in antigen-specific proliferation because of Ca(2+)-signaling defects. Bax(-/-), Bak(-/-) T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) mobilization because of altered endoplasmic reticulum (ER) Ca(2+) regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca(2+) signals to stimulate mitochondrial NADH production in excess of that utilized for ATP synthesis was dependent on Bax and Bak. Blunting of Ca(2+)-induced mitochondrial NADH elevation in the absence of Bax and Bak resulted in decreased reactive-oxygen-species production, which was required for T cell proliferation. Together, the data establish that Bax and Bak play an essential role in the control of T cell proliferation by modulating ER Ca(2+) release.
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PMID:The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis. 1772 8


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