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

Group I and Epstein-Barr virus-negative Burkitt's lymphoma cell lines and the B104 lymphoma cell line which expresses a phenotype of immature B cells undergo apoptosis after cross-linking of their surface Ig receptors or after exposure to a calcium ionophore. We show here that tumor necrosis factor (TNF)-alpha protects these B cell lines against Ca(2+)-dependent apoptosis. Protection was associated with up-regulation of bcl-2 mRNA and protein expression. The increase of Bcl-2 expression induced by TNF-alpha was inhibited by chelerythrine, a specific inhibitor of protein kinase C (PKC), suggesting that Bcl-2 expression was dependent on PKC activation. Furthermore, we show that phorbol esters and cyclosporin A (CsA), which prevent Ca(2+)-dependent apoptosis, up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expression is controlled by calcineurin since we have shown that FK506 but not rapamycin had the same effect on Bcl-2 expression, whereas okadaic acid, an inhibitor of phosphatases 1, 2A and 2C, was ineffective. These data provide direct evidence that TNF-alpha prevents Ca(2+)-dependent apoptosis by a Bcl-2-dependent mechanism mediated by PKC.
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PMID:Tumor necrosis factor-alpha up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines. 754 79

Bcl-2 is a mitochondrial- and perinuclear-associated protein that prolongs the lifespan of a variety of cell types by interfering with programmed cell death (apoptosis). Bcl-2 seems to function in an antioxidant pathway, and it is believed that membrane attachment mediated by a COOH-terminal hydrophobic tail is required for its full activity. To identify critical regions in bcl-2 alpha for subcellular localization, activity, and/or interaction with other proteins, we created, by site-directed mutagenesis, various deletion, truncation, and point mutations. We show here that membrane attachment is not required for the survival activity of bcl-2 alpha. A truncation mutant of bcl-2 alpha lacking the last 33 amino acids (T3.1) including the hydrophobic COOH terminus shows full activity in blocking apoptosis of nerve growth factor-deprived sympathetic neurons or TNF-alpha-treated L929 fibroblasts. Confocal microscopy reveals that the T3 mutant departs into the extremities of neurites in neurons and filopodias in fibroblasts. Consistently, T3 is predominantly detected in the soluble fraction by Western blotting, and is not inserted into microsomes after in vitro transcription/translation. We further provide evidence for motifs (S-N and S-II) at the NH2 and COOH terminus of bcl-2, which are crucial for its activity.
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PMID:The protein bcl-2 alpha does not require membrane attachment, but two conserved domains to suppress apoptosis. 805 Dec 5

Two Epstein-Barr virus (EBV) gene products, latent infection membrane protein 1 (LMP1), expressed mainly in latent infection, and BHRF1, expressed in lytic infection, have the ability to promote cell survival. LMP1 protects human B cells from apoptosis by upregulating expression of Bcl-2 and A20. We have demonstrated that LMP1 transfectants of Jurkat T cells are resistant to apoptosis induced by serum depletion without affecting the Bcl-2/Bax system. Overexpression of LMP1 in epithelial cells inhibits apoptosis induced by TNF-alpha, but not by anti-Fas antibodies. These results indicate that the anti-apoptotic mechanism of LMP1 differs among different cell types. BHRF1 can prevent apoptosis induced by TNF-alpha and anti-Fas antibodies in epithelial cells. The implication of the anti-apoptotic function of LMP1 and BHRF1 is reviewed in relation to EBV infection.
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PMID:[Anti-apoptotic function of the Epstein-Barr virus LMP1 and BHRF1 proteins]. 874 77

Human monocytic leukemia U937 cells readily undergo apoptosis when cells are treated with various stimuli including antitumor agents, tumor necrosis factor (TNF)-alpha and anti-Fas antibody. However, the signal transduction mechanism resulting in apoptosis is unclear. To study the mechanism of apoptosis, we isolated and characterized a mutant, UK110, from U937 cells, which was resistant to TNF-alpha and anti-Fas antibody-induced apoptosis but was less resistant to etoposide-induced apoptosis. TNF-alpha induced signals are mediated by two types of TNF receptors (TNFR), p55- and p75-TNFR, and p55-TNFR is homologous to the Fas antigen. Interestingly, UK110 cells showed resistance to apoptosis by agonistic anti-p55-TNFR antibody, indicating that UK110 cells were resistant to Fas- and p55-TNFR-mediated apoptosis. Because expression of apoptosis-associated molecules, such as c-Myc, Bcl-2, and Bax, was similar between U937 and UK110 cells an undetermined pathway for apoptosis through Fas and p55-TNFR could be mutated in UK110 cells. To clarify the genetic phenotype of UK110 cells, we performed somatic cell hybridization with parental U937 and the UK110 cells. All of the hybrid clones were as sensitive as the parental U937 cells to apoptosis by both anti-Fas and anti-p55-TNFR antibodies, indicating that the apoptosis resistance in UK110 cells resulted from recessive genotype.
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PMID:A recessive mutant of the U937 cell line acquired resistance to anti-Fas and anti-p55 tumor necrosis factor receptor antibody-induced apoptosis. 884 4

We examined the effects of a cell-permeable ceramide analog, C2-ceramide, on the growth of TNF-alpha-resistant B lymphoma Raji cells lacking TNF-alpha-receptors (TNF-R). C2-ceramide inhibited the clonal growth of not only TNF-alpha-sensitive myeloid leukemia cells (HL60 and U937) but also Raji cells. Following stimulation with C2-ceramide, HL60 and U937 cells showed apoptotic cell death, whereas Raji cells did not show a detectable level of apoptosis. However, a cell-cycle arrest in G0/G1 phase was observed in Raji cells after the treatment with C2-ceramide, which was accompanied by the dephosphorylation of retinoblastoma (RB) gene products and decreased expression of p53 proteins. Failure of C2-ceramide to induce apoptosis in Raji cells might be explained by the lack or low expression of apoptosis-inducing proteins by two lines of evidence: (1) Raji cells were resistant to apoptosis induced by ceramide even in the presence of transcription/translation inhibitors; (2) Bax protein expression was not detectable in Raji cells, although Bcl-2 protein expression in Raji cells was even less than that in HL60 and U937 cells. Moreover, protein kinase C (PKC), whose activation has been described to inhibit ceramide-induced apoptosis, inhibitor H-7 did not induce apoptotic cell death in Raji cells, suggesting that an imbalance between PKC and ceramide pathways is not the reason for the resistance of Raji cells against ceramide-induced apoptosis. Finally, ceramide-induced activation of nuclear factor kappaB (NF-kappaB) was observed in Raji cells as well as HL60 cells, indicating that activation of this molecule may not be specific for apoptosis. By using the present model, one can dissect cell-cycle arrest and apoptosis induced by ceramide.
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PMID:Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-alpha-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. 894 36

CD40, a member of the tumour necrosis factor receptor family, is expressed on the surface of B lymphocytes where its ligation provides a potent survival signal. CD40 is also expressed in basal epithelial cells and in a number of different carcinomas where its function remains unknown. We observed that contrary to the studies in normal B cells, CD40 ligation in carcinoma cell lines and in normal primary epithelial cells resulted in growth inhibition and enhanced susceptibility to apoptosis induced by anti-neoplastic drugs, TNF-alpha, Fas and ceramide. This effect was also observed in CD40-transfected Rat-1 fibroblasts. The expression of Bcl-2 did not affect growth inhibition induced by CD40 ligation in epithelial cells but the Epstein - Barr Virus-encoded latent membrane protein 1 (LMP1) blocked the effect. Whilst transient expression of LMP-1 resulted in the inhibition of epithelial cell growth, this effect was not observed with a LMP1 mutant lacking the binding domain for TRAF3, a protein which may mediate signal transduction by interacting with the cytoplasmic domains of both CD40 and LMP1. Transient expression of TRAF3 also inhibited epithelial cell growth, whilst expression of a dominant-negative TRAF3 partially blocked the inhibitory effect of CD40 ligation and of transient LMP1 expression. These results suggest that CD40 regulates epithelial cell growth in a manner mimicked by LMP1 and implicate TRAF3 as a common mediator in the transduction of the growth inhibitory signals generated via the CD40 and LMP1 pathways.
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PMID:CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator. 895 Sep 92

The latent infection membrane protein 1(LMP1) of Epstein-Barr virus(EBV) protects human B cells from apoptosis by up-regulating expression of Bcl-2 and A20. We have demonstrated that LMP1 transfectants of Jurkat T cells are resistant to apoptosis induced by serum depletion without affecting Bcl-2/Bax system. Expression of LMP1 in epithelial cells have affected apoptosis induced by TNF-alpha but not apoptosis induced by anti-Fas antibodies, suggesting that LMP1 is involved in the signal pathway specific for TNF receptor. These results indicate that LMP1 regulates apoptosis by different mechanisms among each cell type. The regulation of apoptosis by LMP1 is discussed in relation to EBV infection.
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PMID:[Regulation of apoptosis by the latent infection membrane protein 1 of Epstein-Barr virus]. 904 15

Resting lymphocyte survival is dependent upon the expression of Bcl-2, yet the factors responsible for maintaining lymphocyte Bcl-2 protein expression in vivo are largely unknown. Natural killer (NK) cells are bone marrow-derived lymphocytes that constitutively express the beta and common gamma(c) subunits of the IL-2 receptor (R) as a heterodimer with intermediate affinity for IL-2. IL-15 also binds to IL-2Rbeta gamma(c) and is much more abundant in normal tissues than IL-2. Mice that lack the IL-2 gene have NK cells, whereas mice and humans that lack IL-2R gamma(c) do not have NK cells. Further, treatment of mice with an antibody directed against IL-2Rbeta results in a loss of the NK cell compartment. These data suggest that a cytokine other than IL-2, which binds to IL-2Rbeta gamma(c), is important for NK cell development and survival in vivo. In the current report, we show that the recently described IL-15R(alpha) subunit cooperates with IL-2Rbeta gamma(c) to transduce an intracellular signal at picomolar concentrations of IL-15. We demonstrate that resting human NK cells express IL-15R(alpha) mRNA and further, that picomolar amounts of IL-15 can sustain NK cell survival for up to 8 d in the absence of serum. NK cell survival was not sustained by other monocyte-derived factors (i.e., TNF-alpha, IL-1beta, IL-10, IL-12) nor by cytokines known to use gamma(c) for signaling (i.e., IL-4, IL-7, IL-9, IL- 13). One mechanism by which IL-15 promotes NK cell survival may involve the maintenance of Bcl-2 protein expression. Considering these functional properties of IL-15 and the fact that it is produced by bone marrow stromal cells and activated monocytes, we propose that IL-15 may function as an NK cell survival factor in vivo.
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PMID:A potential role for interleukin-15 in the regulation of human natural killer cell survival. 906 51

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

Transforming growth factor-beta (TGF-beta) plays a role as an immunosuppressive cytokine within the central nervous system (CNS). The CNS cells targeted by action of TGF-beta1 have not been defined. In this study, we tested the effect of TGF-beta1 on microglia, astrocytes and oligodendrocytes from newborn rats. TGF-beta1 selectively induced apoptosis of microglia, and not of astrocytes or oligodendrocytes. To study the apoptotic mechanism, bcl-2 oncoprotein expression in microglia, astrocytes and oligodendrocytes was measured. Bcl-2 was mainly expressed in microglia, indicating that microglial bcl-2 does not prevent TGF-beta1-mediated microglial apoptosis. The relative protein expression of bcl-2 in microglia was not related to frequency of microglial apoptosis. Thus, TGF-beta1-induced microglial apoptosis was regulated by a bcl-2-independent mechanism. Expression of cytokine (IL-1beta, IL-6, IL-12, IFN-gamma and TNF-alpha) mRNA on microglia was not influenced by treatment with TGF-beta1.
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PMID:Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression. 915 92


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