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)

The germinal center forms a specialized microenvironment that is thought to play a key role in the induction of antibody synthesis, affinity maturation of B cells, isotype switching, and memory B-cell formation. Moreover, the germinal center may also be involved in the maintenance of T-cell memory. In this paper we focus on the role of adhesion receptors in cellular interactions in the germinal center, and discuss evidence indicating that these molecules play an important role in regulating B-cell activation and differentiation. Furthermore, we discuss two important diseases involving the germinal center, i.e., HIV infection and malignant lymphoma. In HIV infection, destruction of the FDC network may explain the selective loss of memory cells observed in otherwise asymptomatic patients and is likely to represent a major pathway leading to AIDS. In follicular lymphoma, escape from physiological apoptosis in the germinal center by overexpression of Bcl-2 appears be a major pathogenetic pathway.
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PMID:Cellular interactions in the germinal center: role of adhesion receptors and significance for the pathogenesis of AIDS and malignant lymphoma. 159 19

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

Expression of c-myc and macromolecular synthesis have been associated with physiological cell death. We have studied their requirement for the death of factor (interleukin-3)-dependent cells (FDC-P1) bearing an inducible bcl-2 expression construct. FDC-P1 cells expressing bcl-2 turned off expression of c-myc when deprived of interleukin-3 but remained viable as long as bcl-2 was maintained. A subsequent decline in Bcl-2 allowed the cells to undergo apoptosis directly from G0, in the absence of detectable c-myc expression. Thus c-myc expression may lead to apoptosis in some cases but is not directly involved in the mechanism of physiological cell death that can be controlled by Bcl-2. The macromolecular synthesis inhibitors actinomycin D and cycloheximide triggered rapid cell death of FDC-P1 cells in the presence of interleukin-3, but the cells could be protected by Bcl-2. Thus, the cell death machinery can exist in a quiescent state and can be activated by mechanisms that do not require synthesis of RNA or protein.
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PMID:Neither macromolecular synthesis nor myc is required for cell death via the mechanism that can be controlled by Bcl-2. 769 34

Amebic destruction of neutrophils and macrophages is contact-dependent. Adherence is mediated by a galactose-specific surface lectin on the amebic membrane. The pathway by which contact-dependent cytolysis of the target cell occurs is unknown. We hypothesized that target cell death is due to the triggering of apoptosis (programmed cell death) by the amebae. The purpose of this study was to determine whether target cell DNA is fragmented into a ladder pattern characteristic of apoptosis and to test whether overexpression of Bcl-2, a protein that confers resistance to apoptotic death from some stimuli, blocks target cell killing. The murine myeloid cell line FDC-P1 transfected with a retrovirus construct expressing the Bcl-2 protein was shown to be resistant to the apoptotic death that the parental line undergoes upon growth factor deprivation. 51Cr-labeled FDC-P1 control or bcl-2-transfected cells were incubated with Entamoeba histolytica (4:1 cell/ameba ratio) and killing of the cells was assessed by 51Cr release. Both cell lines were susceptible to contact-dependent killing. Death induced by the amebae in the bcl-2-transfected cells resulted in a DNA ladder fragmentation pattern (using [125I]iododeoxyuridine-labeled target cell DNA) identical to that seen in the control cells undergoing apoptosis upon growth factor withdrawal. Target cell DNA fragmentation was inhibited by blocking adherence with galactose. Our data suggest that target cell killing by E. histolytica can occur via Bcl-2-independent apoptotic mechanism.
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PMID:Entamoeba histolytica: target cells killed by trophozoites undergo DNA fragmentation which is not blocked by Bcl-2. 795 63

Mcl-1 is a member of the Bcl-2 family that was identified based on increased expression in myeloblastic leukemia cells undergoing differentiation. Mcl-1 was previously found to be similar to Bcl-2 in causing a delay in apoptotic cell death in Chinese hamster ovary cells. The work described here was aimed at determining whether Mcl-1 could also exert such an effect in hematopoietic cells, because endogenous Mcl-1 expression is prominent in the hematopoietic system. A further aim was to assess the effects of Mcl-1 in cells exposed to a variety of cytotoxic stimuli, because Bcl-2 is known to have a broad spectrum of activity. To approach these aims, FDC-P1 murine myeloid progenitor cells were transfected with vectors driving either constitutive or inducible expression of Mcl-1. The introduced Mcl-1 gene was found to cause a prolongation of viability under various conditions that cause apoptotic cell death, including exposure to cytotoxic agents (the chemotherapeutic drug etoposide, calcium ionophore, or UV irradiation) and the withdrawal of required growth factors. In addition, Mcl-1 was found to interact with Bax, a member of the Bcl-2 family that promotes cell death as a homodimer but that can heterodimerize with Bcl-2 to promote cell viability. Although Mcl-1 prolonged cell viability, it did not prevent eventual cell death upon continuous exposure to a cytotoxic agent. Prolongation of viability was maximal when expression of Mcl-1 was induced before the application of the apoptotic stimulus, although some increase occurred if Mcl-1 was induced shortly thereafter and before overt apoptosis. Taken as a whole, these findings provide further parallels between Mcl-1 and Bcl-2, showing that Mcl-1 can interact with Bax in hematopoietic FDC-P1 cells and can prolong cell viability under a variety of cytotoxic conditions.
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PMID:Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. 900 67

Two pathways have been implicated in the induction of apoptosis by cytotoxic T cells: the granule exocytosis pathway and a pathway using CD95 (Fas/APO-1). To test whether apoptosis induced by either of these pathways could be blocked by Bcl-2, we exposed bcl-2-transfected cells to CTL derived from normal, perforin-deficient, or CD95 ligand mutant (gld) mice. Although the levels of Bcl-2 expression achieved were able to protect FDC-P1 and Yac-1 transfectants from a variety of apoptotic stimuli, the cells were not protected from cytolysis mediated by CTL from any of these sources, by NK cells, or granules isolated from CTL. However, Bcl-2 expression significantly inhibited apoptosis induced by purified granzyme B and perforin. These results suggest that while Bcl-2 is capable of inhibiting the apoptotic pathway utilized by perforin and granzyme B, other granule components can bypass this block. We conclude that CTL harbor potent killing mechanism(s) in addition to those provided by CD95 ligand or perforin and granzyme B that cannot be overcome by Bcl-2.
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PMID:Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes. 919 Sep 29

A trace amount of the pro-apoptotic factor human Bax was sufficient to kill host Escherichia coli (Asoh, S., Nishimaki, K., Nanbu-Wakao, R., and Ohta, S., submitted). The region of Bax lethal to E. coli cells was determined by introducing truncated human bax mutant genes. A peptide corresponding to amino acid residues 115 to 144 of Bax was the smallest peptide capable of inducing cell death of E. coli. A truncated bax gene (Bax112-192) containing the region lethal to E. coli was then introduced into a murine promyeloid cell line, FDC-P1. Constitutively expressed Bax112-192 induced apoptosis as judged by decrease of transfectants surviving and DNA fragmentation. These results indicate that Bax112-192 contains the region directly responsible for mammalian apoptosis as well as bacterial death. Flow cytometric analysis by FITC-Annexin V showed that the transfectant cells expressing Bax112-192 or native Bax became apoptotic even without external stimuli. The apoptotic population in the cells expressing Bax112-192 was not decreased by co-expression of Bcl-2 or Bcl-XL, while Bcl-2 or Bcl-XL suppressed apoptosis in the cells expressing native Bax. Therefore, Bax induces apoptosis by its own activity without blocking the anti-apoptotic activity involved in Bcl-2 or Bcl-XL.
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PMID:Pore formation domain of human pro-apoptotic Bax induces mammalian apoptosis as well as bacterial death without antagonizing anti-apoptotic factors. 948 Aug 56

Cycling, splenic B cells were recultured with: (1) no stimulant to reflect poorly competitive clones; (2) soluble, whole anti-mu to reflect clones that bind soluble immune complexes; (3) soluble F(ab')2 anti-mu to reflect clones that bind soluble antigen; and (4) immobilized anti-mu to reflect clones that bind antigen presented by FDC. All four groups displayed similar levels of the death proteins Bax and Bcl-xS. In contrast, cycling B cells restimulated with either soluble F(ab')2 or immobilized anti-mu expressed heightened levels of the survival protein Bcl-xL, and only cells restimulated with immobilized anti-mu expressed the survival protein Bcl-2. Cycling B cells restimulated with either soluble F(ab')2 or immobilized anti-mu displayed a selective survival advantage over cycling B cells receiving no stimulus or soluble, whole anti-mu by both enhancing their responsiveness to CD40 ligand, a Th-cell-derived signal, and increasing the period that the cycling B cells remained responsive to this Th-cell-derived signal. The Th-cell-derived signal did not appreciably alter cycling B cell expression of Bcl-2 family members.
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PMID:Strength of signal through BCR determines the fate of cycling B cells by regulating the expression of the Bcl-2 family of survival proteins. 963 65

Cytolytic granule-mediated target cell killing is effected in part through the synergistic action of the membrane-acting protein perforin and serine proteases such as granzymes (Gr) A and B. In this study, we examine the subcellular distribution of granzymes in the presence of perforin and the induction of apoptosis in mouse FDC-P1 myeloid and YAC-1 lymphoma cells that express the proto-oncogene bcl2. Using confocal laser scanning microscopy to visualize and quantitate subcellular transport of fluoresceinated granzyme, we find that granzyme entry into the cytoplasm in the absence of perforin is not impaired in the bcl2-expressing lines. However, perforin-dependent enhancement of granzyme cellular uptake and, importantly, granzyme redistribution to the nucleus were strongly inhibited in the bcl2-expressing lines, concomitant with greatly increased resistance to granzyme/perforin-induced cell death. DNA fragmentation induced by granzyme/perforin was severely reduced in the bcl2-expressing lines, implying that prevention of granzyme nuclear translocation blocks the nuclear events of apoptosis. The kinetics of GrB nuclear uptake and induction of apoptosis were faster than for GrA, whereas YAC-1 cells showed greater resistance to granzyme nuclear uptake and apoptosis than FDC-P1 cells. In all cases, granzyme nuclear accumulation in the presence of perforin correlated precisely with ensuing apoptosis. All results supported the idea that GrA and GrB share a common, specific nuclear targeting pathway that contributes significantly to the nuclear changes of apoptosis.
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PMID:BCL-2 blocks perforin-induced nuclear translocation of granzymes concomitant with protection against the nuclear events of apoptosis. 993 85

Mcl-1, a member of the Bcl-2 family, has been identified as an inhibitor of apoptosis induced by anticancer agents and radiation in myeloblastic leukemia cells. The molecular mechanism underlying this phenomenon, however, is not yet understood. In the present study, we report that hyperpolarization of the membrane potential is required for prevention of mcl-1 mediated cell death in murine myeloblastic FDC-P1 cells. In cells transfected with mcl-1, the membrane potential, measured by the whole-cell patch clamp, was hyperpolarized more than -30 mV compared with control cells. The membrane potential was repolarized by increased extracellular K(+) concentration (56 mV per 10-fold change in K(+) concentration). Using the cell-attached patch-clamp technique, K(+) channel activity was 1.7 times higher in mcl-1 transfected cells (NP(o) = 22.7 +/- 3. 3%) than control cells (NP(o) = 13.2 +/- 1.9%). Viabilities of control and mcl-1 transfected cells after treatment with the cytotoxin etoposide (20 microgram/ml), were 37.9 +/- 3.9% and 78.2 +/- 2.0%, respectively. Suppression of K(+) channel activity by 4-aminopyridine (4-AP) before etoposide treatment significantly reduced the viability of mcl-1 transfected cells to 49.0 +/- 4.6%. These results indicate that as part of the prevention of cell death, mcl-1 causes a hyperpolarization of membrane potential through activation of K(+) channel activity.
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PMID:Protection from cell death by mcl-1 is mediated by membrane hyperpolarization induced by K(+) channel activation. 1055 59


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