UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The work reviewed in this article separates T cell development into four phases. First is an expansion phase prior to TCR rearrangement, which appears to be correlated with programming of at least some response genes for inducibility. This phase can occur to some extent outside of the thymus. However, the profound T cell deficit of nude mice indicates that the thymus is by far the most potent site for inducing the expansion per se, even if other sites can induce some response acquisition. Second is a controlled phase of TCR gene rearrangement. The details of the regulatory mechanism that selects particular loci for rearrangement are still not known. It seems that the rearrangement of the TCR gamma loci in the gamma delta lineage may not always take place at a developmental stage strictly equivalent to the rearrangement of TCR beta in the alpha beta lineage, and it is not clear just how early the two lineages diverge. In the TCR alpha beta lineage, however, the final gene rearrangement events are accompanied by rapid proliferation and an interruption in cellular response gene inducibility. The loss of conventional responsiveness is probably caused by alterations at the level of signaling, and may be a manifestation of the physiological state that is a precondition for selection. Third is the complex process of selection. Whereas peripheral T cells can undergo forms of positive selection (by antigen-driven clonal expansion) and negative selection (by abortive stimulation leading to anergy or death), neither is exactly the same phenomenon that occurs in the thymic cortex. Negative selection in the cortex appears to be a suicidal inversion of antigen responsiveness: instead of turning on IL-2 expression, the activated cell destroys its own chromatin. The genes that need to be induced for this response are not yet identified, but it is unquestionably a form of activation. It is interesting that in humans and rats, cortical thymocytes undergoing negative selection can still induce IL-2R alpha expression and even be rescued in vitro, if exogenous IL-2 is provided. Perhaps murine thymocytes are denied this form of rescue because they shut off IL-2R beta chain expression at an earlier stage or because they may be uncommonly Bcl-2 deficient (cf. Sentman et al., 1991; Strasser et al., 1991). Even so, medullary thymocytes remain at least partially susceptible to negative selection even as they continue to mature.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The development of functionally responsive T cells. 138 62

The t(14;18) of human follicular B cell lymphoma translocates the Bcl-2 gene into the Ig H chain locus and markedly deregulates Bcl-2 expression. We sought to determine if Bcl-2 could be directly implicated in a growth-factor pathway. Consequently, we introduced a retrovirus containing the murine Bcl-2 gene (N2-M-Bcl-2) or the parental retrovirus (N2) into a series of factor-dependent hemopoietic cell lines. Overexpressed Bcl-2 resulted in no long term IL-2, IL-3, or IL-6 independent clones, indicating that Bcl-2 could not spare the need for a specific ligand-receptor interaction. However, Bcl-2 did extend the short term survival of IL-3-dependent cell lines after factor deprivation. Although viable, IL-3-deprived pro B lymphocytes (FL5.12) bearing N2-M-Bcl-2 were in Go, and deregulated Bcl-2 did not obviously influence cell-cycle progression. Bcl-2 predominant effects were to delay the onset of cell death and to modestly augment viable cell growth in the first 48 h after IL-3 deprivation. This death sparing was associated with increased levels of Bcl-2 RNA and protein in factor-deprived cells possessing N2-M-Bcl-2. This result was not restricted to prolymphocytes because an IL-3-dependent mast cell line (32D) as well as a promyeloid line (FDC-P1) demonstrated the same response to Bcl-2. Moreover, the effect was not limited to the IL-3/IL-3R signal transduction pathway in that promyeloid cells maintained in granulocyte-macrophage-CSF or IL-4 displayed a similar response. Yet, Bcl-2-enhanced cell survival was not universal as an IL-2-dependent T cell line, and an IL-6-dependent myeloma line demonstrated no consistent effect upon IL withdrawal. Thus, Bcl-2 appears to interfere with cell death but in a cell type and/or factor-restricted fashion.
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PMID:Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. 218 93

The immune system provides a useful model system in which to study the signal transduction events involved in the regulation of programmed cell death. Mature lymphocytes have the capacity to survive in the body for prolonged periods of time. During an immune response, cells of the appropriate antigenic specificity must undergo clonal amplification to mount a protective response, and cells participating in inflammatory immune responses need to have the capacity to survive at sites of inflammation. However, upon completion of a successful inflammatory response, the majority of cells produced must die off in order to maintain the homeostasis of the organism. Over the last several years we have learned a great deal about how mature lymphocytes regulated their susceptibility to undergo programmed cell death. Three types of information appear to be used by the lymphocyte to control its susceptibility to undergo programmed cell death. The intrinsic susceptibility of a cell to undergo programmed cell death is determined by members of the Bcl-2 gene family. In addition, extrinsic survival factors, such as IL-2, can initiate signal transduction events that can prevent a cell from initiating apoptosis. Finally, lymphocytes appear to have specific receptors, such as Fas, that can directly induce programmed cell death upon ligand binding. The integration of these three systems is discussed.
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PMID:Receptors that regulate T-cell susceptibility to apoptotic cell death. 748 1

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

Bcl-2, bcl-x, and bax genes code for proteins that affect the susceptibility of cells to apoptosis. In general, the expression of bcl-2 or bcl-x inhibits apoptosis while bax promotes apoptosis. We examined the levels of these proteins by immunoblotting in resting and activated T cells and in thymocytes. Bcl-2 and Bax proteins vary coordinately, but Bcl-x varies independently: Bcl-2 and Bax are higher in splenic T cells than in thymocytes, and their levels increase even more after T cell activation. In contrast, Bcl-x is almost undetectable in splenic T cells but is manyfold greater in thymocytes and in activated splenic T cells. When CTLL-2 cells or activated T cells are starved of IL (IL-2), the level of Bcl-x but not Bcl-2 protein drops before the onset of apoptosis. Stable transfection of either bcl-2 or bcl-x expression plasmids promotes the survival of CTLL-2 cells in the setting of IL-2 withdrawal. Over 70 to 90% of the transfected cells remain viable at 48 h after IL-2 withdrawal when all of the control transfected cells are apoptotic. These findings suggest that a decrease in Bcl-x protein levels precedes apoptosis after IL-2 withdrawal in T cells and that transfected bcl-2 promotes survival after IL-2 withdrawal by functionally masking this drop in Bcl-x.
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PMID:Expression of Bcl-2, Bcl-x, and Bax after T cell activation and IL-2 withdrawal. 765 Mar 67

IL-2 was found to promote the rapid growth of a minority population contained within the germinal centre (GC) cell-enriched (CD39- and/or IgD- buoyant) fraction of human tonsillar B lymphocytes. The cells emerging in response to IL-2 had a high mitotic index and morphologically resembled plasmablasts. Cultures could be maintained in the absence of feeder cells for up to 3 weeks in IL-2 and were characterized by large amounts of IgM in their supernatants: approximately 40% of the cells contained readily detectable cytoplasmic IgM by day 10 of culture. Negligible quantities of IgG and IgA were found. The target population for IL-2-driven expansion and IgM secretion was smIg+/CD38+ and was subject to suppression by anti-IgM antibody. While only 8% of cells within the GC cell-enriched fraction were CD5+ (compared with 15% of high density resting B cells), their removal led to an 83% reduction in the amount of IgM produced in response to IL-2, IL2 selectively expanded this minor CD5+ subset such that by day 6 of culture they comprised 57% of all viable cells. Cultures established with IL-2 showed increasing expression of cytoplasmic Bcl-2 and withdrawal of growth factor resulted in cell death via apoptosis. We discuss these results in relation to CD5+ B cells and their potential role in antibody responses to TD antigens.
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PMID:IL-2 expands and maintains IgM plasmablasts from a CD5+ subset contained within the germinal centre cell-enriched (surface IgD-/CD39- buoyant) fraction of human tonsil. 769 41

Recent studies have disclosed variable effects of IL-10 on viabilities of human B lineage cells. Thus, IL-10 has been shown to prevent apoptosis of germinal center B cells, whereas IL-10 has been found to induce apoptosis of B-chronic lymphocytic leukemia cells, suggesting the possibility that the effects of IL-10 might be different depending on the state of activation of B cells. The current studies therefore examined in detail the regulation of the survival of human peripheral blood B cells by IL-10 and its relevance to Ig production. Highly purified B cells from healthy adult individuals were cultured with Staphylococcus aureus (SA) Cowan I in the presence or absence of IL-10. When IL-10 was present during the initial activation of B cells with SA, IL-10 facilitated the apoptosis of SA-activated B cells, as determined by staining with propidium iodide, followed by analysis with flow cytometry, thus resulting in very modest IgM production. IL-2 prevented the IL-10-mediated progression of the apoptosis of SA-activated B cells during the initial activation, and thus restored the further differentiation of these B cells into Ig secreting cells. By contrast, IL-10 rather rescued SA-activated B cells from apoptosis and thus supported the differentiation of these B cells without any influences of IL-2, when it was added after 72 h of culture. Of note, cyclosporin A prevented the IL-10-mediated promotion of the apoptosis of SA-activated B cells, thus resulting in the marked enhancement of IgM production of B cells stimulated with SA + IL-10. Finally, the promotion or prevention of the IL-10-mediated apoptosis was correlated with the expression of Bcl-2 oncoprotein in SA-activated B cells. These results indicate that the effects of IL-10 are different depending on the state of activation of B cells after ligation of Ag receptors. Thus, the data have demonstrated that IL-10 during the initial activation delivers negative signals that promote the apoptosis of B cells, whereas IL-10 supports the differentiation of B cells in the complete absence of IL-2 during the subsequent responses following activation. These results therefore emphasize unique biphasic effects of IL-10 on human B cell responsiveness in determining the outcome of humoral immune responses.
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PMID:The role of IL-10 in human B cell activation, proliferation, and differentiation. 772 92

We have shown that the ability of the human follicular lymphoma-derived cell line SU-DHL-6 to proliferate and survive in vitro depends on both Bcl-2 expression and multiple autocrine growth factors. Treatment with Bcl-2 antisense (AS Bcl-2) decreased Bcl-2 protein levels. However, a cytotoxic effect was seen only at very restricted cell densities. Below such densities cells underwent spontaneous death without any treatment, while above these cell densities no cytotoxic effect of AS Bcl-2 could be seen. The conditioned medium of SU-DHL cells supported the survival and growth of these cells cultivated at low cell densities and partially reversed the cytotoxicity associated with Bcl-2 depletion. RT/PCR analysis revealed autocrine expression of IL-1 beta, IL-2, IL-5 and TNF-beta in SU-DHL cells. Neutralizing antibodies against these cytokines inhibited SU-DHL proliferation. Thus, development of autocrine GF secretion may be the second step in the pathogenesis of follicular lymphomas.
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PMID:The role of Bcl-2 protein and autocrine growth factors in a human follicular lymphoma-derived B cell line. 779 71

Apoptosis (programmed cell death) plays a critical role in many physiological processes, but the mechanism(s) which regulate apoptosis are poorly understood. We demonstrate that in a hematopoietic cell line, which can grow in either interleukin (IL)-2 or IL-3, both of these growth factors can increase bcl-2 mRNA levels and prevent apoptosis normally seen following growth factor withdrawal. Herbimycin A, a protein tyrosine kinase inhibitor, blocks the ability of IL-2 and IL-3 to up-regulate bcl-2 mRNA levels and induces apoptosis. Transfection of a bcl-2 expression vector not only prolongs survival following growth factor withdrawal but also confers resistance to the effect of herbimycin A. We conclude that herbimycin A-sensitive protein tyrosine kinases are involved in the regulation of apoptosis and bcl-2 expression, but these protein tyrosine kinases appear not to be required for the action of Bcl-2 since Bcl-2 can exert its growth survival effect even in the presence of herbimycin A.
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PMID:Tyrosine kinase(s) regulate apoptosis and bcl-2 expression in a growth factor-dependent cell line. 822 83

Recent studies have established that interleukin (IL)-10 induces growth and most notably differentiation of normal human B lymphocytes. We studied here the effects of IL-10 on the proliferation and survival of B-chronic lymphocytic leukemia (B-CLL) cells. IL-10 was found to inhibit 54-96% of the spontaneous tritiated thymidine incorporation observed in 3 of 12 B-CLL samples. Furthermore, IL-10 decreased the viable cell recovery of all five B-CLL samples tested, irrespective of whether cells were spontaneously synthesizing DNA or not. After 1 wk, B-CLL populations cultured with IL-10 were lost while those cultured without IL-10 survived. Flow cytometric analysis, DNA gel electrophoresis, and Giemsa staining all revealed that IL-10 induced B-CLL cells to die from apoptosis. This IL-10-mediated apoptosis was dose dependent and specific as it could be inhibited by a neutralizing anti-IL-10 antibody. B-CLL cells undergoing apoptosis in response to IL-10 showed decreased Bcl-2 protein levels. Addition of IL-2, IL-4, interferon gamma, and anti-CD40 monoclonal antibody prevented the IL-10-mediated apoptosis of B-CLL cells. None of the malignant B cell populations obtained from eight non-Hodgkin's lymphomas and three hairy cell leukemias underwent apoptosis after IL-10 treatment, thus suggesting that the apoptotic effect of IL-10 is specific for B-CLL cells. Thus, IL-10 inhibits the DNA synthesis and most notably the survival of B-CLL cells, findings that call for considering IL-10 in the immunotherapy of chemoresistant B-CLL.
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PMID:Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells. 827 Aug 86

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