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

Apoptosis is the mechanism by which cells are programmed to die under a wide range of physiological and developmental stimuli. Several mediators of programmed cell death have been identified and signals of apoptosis have been found to utilize common pathways, some of which have been elucidated. This review focuses on a number of apoptotic systems that have been widely studied and discuss recent progress and opinion in these areas. These include studies on Fas signaling, tumor suppressor genes, cell cycle interfaces, stress responses, genetic systems, and the Bcl-2 family. Understanding apoptosis from these perspectives sheds substantial light on processes of biological homeostasis. Furthermore, the ability to manipulate the apoptotic response may lead to novel therapeutic interventions in cancer and other diseases.
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PMID:Mechanisms of apoptotic cell death. 909 84

Actinomycin D (ActD) enhances the potency of tumor necrosis factor-alpha (TNF-alpha) in killing cancer cells. However, it is determined in this study that murine L929 fibrosarcoma cells, when pretreated with bovine testicular hyaluronidase for 12-24 h, became resistant to the cytotoxic effect of TNF-alpha in the presence of DNA intercalators, such as ActD, doxorubicin, and daunorubicin. Monoclonal anti-Fas antibody-mediated apoptosis in the presence of ActD was also blocked in hyaluronidase-pretreated L929 cells. Hyaluronidase failed to up- or downregulate the expression of apoptosis regulatory proteins, including Bcl-2, Bcl-xL, ICH-1, and TIAR, suggesting that these proteins were not involved in the hyaluronidase-induced resistance to TNF/ActD. A semisynthetic polysulfated hyaluronic acid (HA) inhibited the increased TNF/ActD resistance, whereas unmodified HA, dextran sulfate, and naturally polysulfated glycosaminoglycans had no effect. Evidence is provided here that the induced resistance is related to serum fetuin and a novel intracellular 35-kDa TNF-binding protein (intra TBP). Under serum-free conditions, L929 became refractory to TNF/ActD cytotoxicity and hyaluronidase reversed the resistance. Exogenous fetuin increased L929 cell spreading and proliferation, and restored hyaluronidase-induction of TNF/ActD resistance in these serum-starved cells. Hyaluronidase failed to reduce the expression of TNF-receptors and their binding of TNF-alpha. However, binding and Western-blotting analyses revealed that hyaluronidase downregulated the intra-TBP. Overall, these observations suggest that serum fetuin and intraTBP are involved in the hyaluronidase induction of TNF/ ActD resistance.
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PMID:Hyaluronidase induces murine L929 fibrosarcoma cells resistant to tumor necrosis factor and Fas cytotoxicity in the presence of actinomycin D. 910 95

Programmed cell death or apoptosis provides an irreversible mechanism for the elimination of excess or damaged cells. Several recent studies have implicated the activation of the interleukin 1beta-converting enzyme/Ced-3 (ICE/Ced-3) family of proteases as the "point of no return" in apoptotic cell death, while others have suggested that loss of mitochondrial membrane potential (delta psi(m)) is the ultimate determinant of cell death. The temporal relationship of these two events during apoptosis and the role of Bcl-2 proteins in inhibiting these steps has not been defined. To examine these issues, control and Bcl-x(L)-transfected Jurkat T cells were treated with Fas antibodies in the presence and absence of the ICE protease inhibitor zVAD-FMK. ICE/Ced-3 protease activity was monitored by following the cleavage of poly(ADP-ribose) polymerase (PARP) and delta psi(m) was followed by rhodamine 123 fluorescence. Although Bcl-x(L) expression did not block Fas-induced protease activation, it substantially inhibited the subsequent loss of delta psi(m) and cell death in Fas-treated cells. In contrast, zVAD-FMK blocked PARP cleavage as well as loss of delta psi(m) and cell death. Together these data demonstrate that Bcl-x(L) can maintain cell viability by preventing the loss of mitochondrial membrane potential that occurs as a consequence of ICE/Ced-3 protease activation.
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PMID:Bcl-x(L) can inhibit apoptosis in cells that have undergone Fas-induced protease activation. 910 51

Malignant glioma cells are susceptible to CD95(Fas/APO-)-mediated apoptosis triggered by agonistic antibody. Here we examined the proapoptotic effects of the natural CD95 ligand, a cytotoxic cytokine homologous to tumor necrosis factor, on malignant glioma cell lines LN-229, LN-308 and T98G. We assessed whether glioma cell killing is synergistically enhanced by cotreatment with CD95 ligand and chemotherapeutic agents, including doxorubicin, carmustine, vincristine, etoposide, teniposide, 5-fluorouracil and cytarabine. Synergy was examined at low concentrations of cytotoxic drugs and CD95 ligand with a defined effect level (IC15). Short-term-cytotoxicity assays showed prominent killing of the glioma cells by CD95 ligand but not by the drugs at relevant concentrations. CD95 ligand induced apoptosis in the acute toxicity paradigm was augmented by doxorubicin and vincristine. Growth-inhibition assays revealed prominent synergy between CD95 ligand and all drugs examined. The best synergy was obtained with CD95 ligand and doxorubicin, vincristine or teniposide. The strong synergistic antiproliferative effects were observed at much lower concentrations of CD95 ligand and cytotoxic drugs than the moderate synergistic acute cytotoxic effects. All cell lines examined express the Bcl-2 protein. LN-229 has partial wild-type p53 activity. T98G has mutant p53, LN-308 has a deleted p53 gene and lacks p53 protein expression. Thus, synergistic effects of CD95 ligand and cytotoxic drugs were observed in cell lines exhibiting two features thought to play a role in the chemoresistance of human malignant glioma cells: loss of wild-type p53 activity and acquisition of bcl-2 expression. Ectopic expression of murine bcl-2 conferred partial protection from CD95 ligand and drugs when administered alone but did not interfere with the mechanisms underlying the synergistic effects of CD95 ligand and chemotherapeutic drugs.
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PMID:Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. 911 85

Apoptotic cell death is induced in mature cycling T cells upon ligation of the Ag-specific TCR. This process is essential for the maintenance of homeostasis in the immune system, as it is capable of down-regulating ongoing immune responses. The analysis of the mechanism underlying TCR-induced programmed cell death has focused the attention of many scientists recently. In this regard, several recent reports have implicated Fas/Fas-ligand molecules as the final mediators of this process. Several other gene products have been implicated in the control of apoptosis (as Bcl-2, p53, and c-Myc); however, no information was available in the early signaling molecules that trigger this phenomena. The results presented in this work indicate that pp56(lck) src family kinase is actually required for the TCR to trigger cell death in mature cycling T cells. In fact, while inhibition of pp56(lck) expression with antisense oligonucleotides blocked TCR-induced apoptosis, pharmacologic inhibition of phosphatidylinositol 3-kinase activity had no effect. Accordingly, ligation of the Ag receptor in a cell line defective for pp56(lck) expression was unable to induce apoptosis, although it induced cellular stimulation, as measured by the expression of CD69. In addition, we show in this work that expression of constitutively active pp56(lck) mutants, but not pp59(fyn) mutants, in the absence of any other TCR-derived signal, is sufficient to induce apoptosis not only in transformed, but also in normal cycling T cells. Finally, evidence is presented indicating that a mechanism through which pp56(lck) regulates TCR-induced apoptosis in mature cycling T cells is by controlling Fas-ligand expression.
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PMID:Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells. 912 69

To understand the effects of ionizing radiation on thyroid cells, we investigated the role of p53 in mediating apoptosis and in DNA repair following in vivo and in vitro irradiation of thyroid cells. In vitro exposure of human thyroid cells to ionizing radiation of up to 5-8 Gy failed to induce apoptosis in primary cells. The same results were obtained when the thyroid gland was irradiated in the intact rat. To explore the mechanism of failure of the wild-type p53 in inducing apoptosis in thyroid cells, we investigated the expression of apoptosis-related genes, bax, bcl-2 and fas/APO-1 following irradiation or induction of temperature-sensitive p53. The expression of Bax, Bcl-2 and Fas/APO-1 in human primary cultured thyroid cells did not change after irradiation. To further confirm the results, we established a clonal cell line (tsFRO) in which a temperature sensitive p53 (Val138) expression vector was stably transfected to a thyroid carcinoma cell line lacking endogenous p53. Incubation of tsFRO cells at the permissive temperature for three days, however, did not induce apoptosis although G1 arrest was noted. Although enhanced expression of the bax mRNA level was observed, the expression of Bax, Bcl-2 and Fas/APO-1 protein did not change by shifting tsFRO cells to permissive temperature as well as irradiated primary cells. Furthermore, DNA end-jointing ability was examined by transfection of linearized luciferase plasmid into tsFRO cells. Increased luciferase activity occurred when the cells were cultured at the permissive temperature, indicating that the wild-type p53 enhances DNA end-jointing activity. Our results indicate that the wild-type p53 does not lead to apoptosis but facilitates DNA end-jointing in thyroid cells. These results may reflect specific responses in thyroid cells following irradiation.
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PMID:p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thyroid cells. 912 41

Of six prostatic carcinoma cell lines examined (ALVA31, DU145, JCA1, LNCaP, ND1, and PC3) by flow cytometric analysis, all were found to be positive for Fas antigen. Furthermore, of the prostate tissue specimens studied (six cases), all revealed Fas expression in benign and malignant epithelial cells. The agonistic anti-Fas monoclonal antibody (IPO-4) induced apoptosis in only two of six cell lines investigated, PC3 and ALVA31. PCR analysis indicated that all cell lines expressed normal transmembrane and death domains of Fas antigen. Using Western blot analysis, we found abundant expression of p53 in the cytoplasm of two Fas-resistant cell lines, DU145 and ND1, and did not find p53 in two Fas-sensitive cell lines, PC3 and ALVA31. Western blot and PCR analysis did not show consistent differences between cell lines examined in the expression of Bcl-2, Bcl-X(L), Bcl-X(S), and Bak. In contrast, Bax protein was not detected in two Fas-resistant cell lines, DU145 and ND1. We also showed that three Fas-resistant cell lines, DU145, ND1, and JCA1, expressed CD40, whereas the two Fas-sensitive cell lines, PC3 and ALVA31, were CD40 negative. Fas-sensitive cell lines were transfected with the cDNA encoding CD40, and the CD40-positive transfectant became more resistant to growth inhibition mediated by treatment with TNF-alpha and anti-Fas monoclonal antibody. Treatment with cycloheximide converted the phenotype of resistant cell lines from Fas resistant to Fas sensitive. Moreover, anti-Fas treatment of both resistant and sensitive cell lines induced rapid tyrosine phosphorylation or dephosphorylation of multiple proteins. These results suggest that the apoptotic machinery involved in DNA fragmentation is already in place in Fas-resistant cell lines, and thus, Fas-mediated apoptosis could be a target for therapeutic intervention.
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PMID:Fas-mediated apoptosis in human prostatic carcinoma cell lines. 913 20

According to current understanding, several metabolic alterations form part of the common phase of the apoptosis process. Such alterations include a disruption of the mitochondrial transmembrane potential (delta psi(m)), a depletion of nonoxidized glutathione (GSH) levels, an increase in the production of reactive oxygen species (ROS), and an elevation in cytosolic free Ca2+ levels. Using a cytofluorometric approach, we have determined each of these parameters at the single cell level in thymocytes or T cell hybridoma cells undergoing apoptosis. Regardless of the apoptosis induction protocol (glucocorticoids, DNA damage, Fas cross-linking, or CD3epsilon cross-linking), cells manifest a near-to-simultaneous delta psi(m) dissipation and GSH depletion early during the apoptotic process. None of the protocols for apoptosis inhibition (antioxidants, delta psi(m) stabilization, Bcl-2 hyperexpression, or inhibition of IL-1-converting enzyme) allowed for the dissociation of delta psi(m) disruption and GSH depletion, indicating that both parameters are closely associated with each other. At a later stage of the apoptotic process, cells manifest a near-simultaneous increase in ROS production and intracellular Ca2+ levels. Whereas the thapsigargin- or ionophore-induced elevation of calcium levels has no immediate consequence on delta psi(m') cellular redox potentials, or ROS production, pro-oxidants and menadione, an inducer of mitochondrial superoxide anion generation, cause a rapid (15 min) Ca2+ elevation. Together, these data suggest a two-step model of the common phase of apoptosis. After an initial delta psi(m) dissipation linked to GSH depletion (step 1), cells hyperproduce ROS with an associated disruption of Ca2+ homeostasis (step 2).
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PMID:Glutathione depletion is an early and calcium elevation is a late event of thymocyte apoptosis. 914 73

Although apoptosis and necrosis are morphologically distinct manifestations of cell death, apoptosis and some necroses share common features in the death signaling pathway involving functional steps of death-driving interleukin 1beta-converting enzyme family proteases and anti-cell death protein Bcl-2. One evident physiological difference in cells undergoing apoptosis versus necrosis is in intracellular levels of ATP. In this study, we specifically addressed the question of whether apoptosis depends on intracellular ATP levels, since longer incubation under ATP-depleting conditions results in necrotic cell death. Incubation of cells in glucose-free medium with an inhibitor of mitochondrial F0F1-ATPases reduces intracellular ATP levels and completely blocks Fas/Apo-1-stimulated apoptosis. ATP supplied through glycolysis or oxidative phosphorylation restores the apoptotic cell death pathway. ATP depletion also leads to a block in Fas-induced activation of CPP32/Yama(-like) proteases, and when ATP is depleted after the activation of the proteases, subsequent apoptosis is significantly blocked. Thus, ATP-dependent steps exist both upstream and downstream of CPP32/Yama(-like) protease activation in apoptotic signal transduction. Treatment with the calcium ionophore induces apoptosis under ATP-supplying conditions but induces necrotic cell death under ATP-depleting conditions, indicating that ATP levels are a determinant of manifestation of cell death.
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PMID:Intracellular ATP levels determine cell death fate by apoptosis or necrosis. 915 70

Ligation of CD40 inhibits apoptosis and stimulates proliferation of normal B cells, whereas ligation of CD95 (APO-1/Fas) induces apoptosis of activated lymphocytes. Aberrant signalling through the CD40 and CD95 antigens could thus participate in the pathogenesis of lymphoid malignancies. The expression and function of CD40 and CD95 on neoplastic B cells from patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) were examined. CD40 was expressed by all 30 B-cell tumours, whereas CD95 was detected on neoplastic B cells in only one of 10 cases of ALL, two of 10 cases of CLL, and three of 10 cases of NHL. Incubation with an agonistic CD95 monoclonal antibody (MoAb) did not augment apoptosis in any of the unstimulated B-cell neoplasms. CD40 triggering did not consistently inhibit spontaneous apoptosis, but ultimately stimulated the growth of neoplastic B cells in most cases. Furthermore, CD40 activation led to up-regulation of the CD95 antigen in all 30 B-cell neoplasms. Ligation of CD95 on CD40-activated tumour cells augmented apoptosis in five of 10 ALL, three of 10 CLL, and nine of 10 NHL cases. The degree of apoptosis induced by CD95 triggering was greater for NHL cells than for ALL cells or CLL cells. Bcl-2 expression by ALL and NHL cells was substantially decreased after in vitro culture, whereas Bcl-2 expression by CLL cells was not significantly changed. However, there was no correlation between the level of Bcl-2 expression and sensitivity to CD95-mediated apoptosis. Thus, factors other than levels of CD95 and Bcl-2 determine susceptibility of malignant B cells to apoptosis after CD95 triggering. CD40-activated lymphoma cells appear to be very sensitive to CD95-mediated apoptosis, suggesting potential strategies for treatment of NHL. Elucidation of the mechanisms underlying resistance of ALL and CLL cells to CD95 triggering may facilitate the development of novel therapeutic approaches to these diseases as well.
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PMID:Role of the CD40 and CD95 (APO-1/Fas) antigens in the apoptosis of human B-cell malignancies. 916 8


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