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)

Fas antigen and Bcl-2 protein are considered to be involved in cellular homeostasis. We precisely analyzed the expression of human Fas antigen and Bcl-2 protein on CD4+ T cells, CD8+ T cells, and monocytes. The positivities of Fas antigen on CD4+ and CD8+ T cells increased with aging. In CD4+ T cells, the Fas-/CD45RO+ subpopulation was dominant compared with the Fas+/CD45RO- subpopulation. Conversely, in CD8+ T cells, the Fas+/CD45RO- subpopulation was dominant compared with the Fas-/CD45RO+ subpopulation. Monocytes exhibited high positivity of Fas antigen and low fluorescence intensity of Bcl-2 protein compared with T cells. These results suggest that Fas antigen acts in different processes of cellular homeostasis between CD4+ and CD8+ T cells and that expression of Fas antigen and Bcl-2 protein is involved in homeostasis of monocytes as well as lymphocytes.
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PMID:Differential expression of Fas antigen and Bcl-2 protein on CD4+ T cells, CD8+ T cells, and monocytes. 754 28

During their development and after their functional activation most lymphocytes die, either because they fail to receive a survival signal or because they are actively killed. Recent experiments on Bcl-2 and Fas/Apo-1 have provided evidence that these two death processes are subject to distinct genetic control.
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PMID:Life and death during lymphocyte development and function: evidence for two distinct killing mechanisms. 754 82

To support the hypothesis that indirect mechanisms mediated by viral products like the HIV envelope glycoprotein gp120 could be responsible for T lymphocyte depletion in HIV infection, we developed a system in which the impairment of T cell functions could be investigated in vitro. In particular, we characterized the conditions that allow T lymphocytes repeatedly stimulated with an antigen to be sensitive or resistant to gp120-mediated apoptotic signals. To achieve this goal, a panel of antigen-specific CD4+ T cell clones and primary CD4+ T lymphocytes were treated for 2 and 18 h with saturating amounts of monomeric gp120 (without cross-linking with specific antibodies) and antigen-driven T cell proliferation and apoptosis were analyzed. We show that monomeric gp120 induces apoptosis only in T lymphocytes repeatedly stimulated with the antigen, that primary T lymphocytes are resistant to programmed cell death mediated by monomeric gp120, but are sensitive to anti-CD4 antibodies, and that gp120-mediated apoptosis is dependent on the period of time between the binding of gp120 to CD4 and the encounter with antigen. To investigate the different susceptibility to gp120 induced apoptosis of primary CD4+ and T cell clones further, the number of membrane CD4 molecules and their affinity for gp120, together with Bcl-2 and Fas expression, were studied. Our data suggest that a down-modulation of membrane CD4 together with high expression of the Bcl-2 gene and protein characterizes the susceptibility to apoptosis of gp120-treated cells. In conclusion, our results define the phenotypic features of T cells susceptible to HIV gp120-induced apoptosis and demonstrate that the same clonotype, depending on the activation state, may present a differential sensitivity to apoptosis induction.
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PMID:Differential susceptibility to monomeric HIV gp120-mediated apoptosis in antigen-activated CD4+ T cell populations. 758 91

Overexpression of Bcl-2 can prevent or markedly delay cell death induced by a variety of apoptotic stimuli. Although Fas and Fas ligand (FasL) interactions play a major role in the elimination of self-reactive T cells in the periphery, inhibition of Fas-mediated killing by Bcl-2 has not been consistently observed. The mouse T hybridoma 2B4.11 (2B4) has been a useful model to study glucocorticoid- and activation-induced apoptosis, which is mediated through Fas and FasL. Using both stable transfectants and transient transfections, overexpression of Bcl-2 or Bcl-xL readily blocked glucocorticoid-induced but not activation-induced apoptosis of 2B4 cells. Bcl-2 expression did not inhibit Fas-mediated cytotoxicity triggered by cells expressing FasL or by the transient transfection of human Fas. Similarly, overexpression of Bcl-2 in the mouse T hybridoma A1.1 did not block activation-induced/Fas-mediated apoptosis. In Jurkat cells, however, expression of Bcl-2 partially inhibited anti-Fas-induced cell death. A Bcl-2-related protein that can interfere with anti-Fas killing, the adenoviral E1B 19K, also did not block activation-induced/Fas-mediated apoptosis in 2B4 cells. In contrast, expression of CrmA, a cowpox virus protein that inhibits ICE-like protease activity, blocked activation-induced apoptosis in 2B4 cells but had little effect on Dex-mediated cytotoxicity. These results show that: 1) Bcl-2 can have strikingly different anti-cell death activity in the same cell depending upon the apoptotic stimulus, 2) distinct apoptosis signaling pathways may exist with differential sensitivity to Bcl-2 and ICE-like protease inhibitors.
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PMID:Bcl-2 blocks glucocorticoid- but not Fas- or activation-induced apoptosis in a T cell hybridoma. 759 63

Autoimmune-prone lpr and gld mice carry defects in the apoptosis-mediating cell surface molecule Fas and its ligand, respectively. These mice develop lymphadenopathy because of an age-related accumulation of nonmalignant CD4- CD8- T cells in the peripheral lymphoid organs, suggesting a role for Fas-mediated apoptosis in peripheral T cell homeostasis. However, these accumulating cells are more susceptible to apoptosis ex vivo than peripheral T cells from control mice. To investigate the influence of additional regulatory elements on defects in the Fas-mediated apoptosis pathway, we analyzed the expression of Bcl-2 protein, a repressor of apoptosis, in T cells of lpr and gld mice. The expression levels of Bcl-2 in peripheral T cells of aged lpr and gld mice were significantly reduced when compared with their normal counterparts. Bcl-2 expression decreased with age in peripheral T cells, but not in thymocytes, suggesting that down-regulation of Bcl-2 protein occurs in the periphery. Analysis of T cell subsets indicated that CD4+ and CD4- CD8- T cells expressed significantly reduced levels of Bcl-2, whereas CD8+ cells maintain high levels of Bcl-2 expression. However, all peripheral T cell subsets including CD8+ cells were susceptible to glucocorticoid-induced apoptosis, indicating that there is no direct correlation between the levels of Bcl-2 expression and susceptibility to glucocorticoid-induced apoptosis. These studies suggest the presence of complex regulatory mechanisms for lymphocyte apoptosis and survival.
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PMID:Age-dependent reduction of Bcl-2 expression in peripheral T cells of lpr and gld mutant mice. 760 21

This report examines the mechanisms involved in the down-regulation of the immune response in acute viral infection and documents the presence of apoptotic lymphocytes in situ in the spleens of mice during the resolution of the immune response to acute lymphocytic choriomeningitis virus infection. Apoptotic cells were detected by an in situ nucleotidyl transferase assay. Both T and B lymphocytes were shown to be dying in vivo, the latter in clusters. A biphasic occurrence of apoptosis during the course of the acute infection was observed, with elevated levels occurring at day 3 after infection and a second more pronounced peak at day 11 after infection, coincident with the decline of the cytotoxic T lymphocyte response and with the decrease in total splenic leukocyte number. Apoptosis in vivo was detected in lpr mice, suggesting that Fas expression is not imperative for lymphocyte apoptosis in the context of an acute viral infection. Apoptosis in situ and the decline of the T lymphocyte response to acute lymphocytic choriomeningitis virus infection was unaffected by the enforced lymphocyte-directed expression of Bcl-2, a protein that blocks growth factor deprivation-induced apoptosis of lymphocytes in vitro. These results argue that the silencing of the T cell response to acute infection may not be a result simply of growth factor deprivation. The susceptibility of activated T cells to apoptotic death, which has previously been associated with virus-induced immune deficiency, may therefore also explain the en masse elimination of the expanded lymphocyte pool subsequent to an acute viral infection.
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PMID:Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice. 760 87

T cell activation through the TCR can result in either cell proliferation or cell death. The role of costimulatory receptors in regulating T cell survival has not been defined. Here, we present data demonstrating that CD28 costimulation enhances the in vitro survival of activated T cells. One mechanism for this enhancement is the ability of CD28 costimulation to augment the production of IL-2, which acts as an extrinsic survival factor for T cells. In addition, CD28 costimulation augments the intrinsic ability of T cells to resist apoptosis. Although CD28 signal transduction had no effect on Bcl-2 expression, CD28 costimulation was found to augment the expression of Bcl-XL substantially. Transfection experiments demonstrated that this level of Bcl-XL could prevent T cell death in response to TCR cross-linking, Fas cross-linking, or IL-2 withdrawal. These data suggest that an important role of CD28 costimulation is to augment T cell survival during antigen activation.
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PMID:CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. 762 Oct 80

The induction of programmed cell death in lymphocytes is a common response to a wide variety of physiological and pharmacological stimuli. While there is still much to be learned about the transmembrane signals that lead to programmed cell death, progress has been made in identifying new cell surface molecules (e.g. APO-1/Fas) that may regulate the physiological induction of lymphocyte death, molecules whose expression inhibits apoptosis (e.g. Bcl-2), and the antagonism of activation-induced cell death in T-cell hybridomas and thymocytes by members of the steroid receptor superfamily.
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PMID:Signaling for death of lymphoid cells. 768 15

The Two Signal: Death/Survival Model suggests that cellular proliferation and physiological cell death should be intimately associated such that, in the absence of external influences, a normal cell departing from rest will have an equal probability of undergoing either process. The c-Myc protooncogene product has been implicated in cell cycle progression and in the control of gene expression, and more recently c-Myc has also been seen to promote apoptotic cell death. As predicted from the model, c-Myc-induced apoptosis is inhibited by growth factors or other anti-apoptotic signals including those provided by some oncogenes. Here, we discuss experiments that test the Two Signal: Death/Survival Model in the phenomenon of activation-induced apoptosis in T-cell hybridomas. Ligation of the antigen receptor on these cells leads to activation, resulting in cytokine production and apoptosis. Inhibition of c-Myc expression by addition of antisense oligodeoxynucleotides or transforming growth factor beta inhibits this form of apoptosis. Because c-Myc is known to bind to several cellular proteins, including Max, we further examined the effects of expression of a dominant negative Max on activation-induced apoptosis. We found that this Max mutant, which interferes with the function of the Myc/Max heterodimer, inhibits the induction of apoptosis by antigen receptor ligation. Thus, both Myc and Max play roles in activation-induced apoptosis, presumably via control of gene expression. Further, as predicted, signals generated from growth factor receptors or the v-Abl oncogene interfere with activation-induced apoptosis. In contrast, the anti-apoptotic effects of Bcl-2 are not active in this form of apoptosis. Finally, a role for Fas/Fas-ligand interactions in activation-induced apoptosis is considered.
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PMID:Promotion and inhibition of activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals. 769 99

Apoptosis is a required event in maintaining kinetic homeostasis within continually renewing tissues such as skin. However, no systematic study of the apoptotic process in epidermal keratinocytes of the skin has been performed. In this report, we examined the expression of proteins associated with promoting (Fas) or preventing (Bcl-2, Bcl-x, CD40) apoptosis in the normal, psoriatic, and malignant keratinocyte. Immunohistochemical staining and flow cytometry analysis revealed that normal cultured keratinocytes express low levels of Fas, CD40, and Bcl-x that was enhanced by cytokines including gamma-interferon (IFN-gamma) and a phorbol ester tumor promoter, TPA. Only faint Bcl-2 staining was detected in cultured keratinocytes exposed to IFN-gamma and TPA compared with the prominent expression of Bcl-x. Biopsies of normal skin, psoriatic plaques, and basal cell carcinomas were examined to extend the in vitro observations. Immunohistochemical staining revealed that while keratinocytes in normal epithelium express low to absent levels of Fas and Bcl-x, psoriatic keratinocytes expressed significantly higher levels of Fas and Bcl-x. In contrast, malignant keratinocytes in basal cell carcinomas expressed high levels of Bcl-2, but minimal Bcl-x, and no Fas. Immunoblot analysis revealed that the long form of Bcl-x (Bcl-xI), which prevents apoptosis in lymphocytes, is expressed by cultured keratinocytes and psoriatic plaque keratinocytes. We conclude that normal cytokine-activated keratinocytes can express an apoptotic (Fas) and an anti-apoptotic protein (Bcl-x). The overexpression of Bcl-x in psoriasis, or Bcl-2 in basal cell carcinomas, may contribute to the longevity of these cells by blocking the normal apoptotic process involved in the terminal differentiation program of epidermal keratinocytes.
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PMID:Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo. 774 3


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