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 cellular localization and roles of bone morphogenetic protein (BMP)-2 and apoptosis-associating factors in human orofacial development remain unclear. In this study, BMP-2, osteocalcin, and TGF-beta, which are bone-differentiating markers, apoptosis-associating factors (i.e., Bcl-2, Bax, Fas, and Fas ligand), apoptotic cells detected by the in situ 3'-end labeling method (TUNEL), and proliferating cell nuclear antigen (PCNA) were immunohistochemically examined in the heads (in particular, the jaw bone and tooth germs) of human fetuses of 11-week pregnancy. BMP-2 was positive in osteoblasts and newly formed osteoid of the incisive and palatal bone of the maxilla and the mandible, which indicated that BMP-2 was exclusively involved in intramembranous ossification in the human fetal head. Fas was positive in the cytoplasm of osteocytes and a few osteoblasts. In contrast, Fas ligand was positive in the cytoplasm of osteoblasts and abundant in the stroma of the osteoblastic layer, periosteum, and perichondrium. The Fas ligand in the stroma was recognized as the soluble form, which was possibly produced by osteoblasts. TUNEL-positive apoptotic cells were found in a few osteocytes and a few osteoblastic cells in new bone, and in monocytes of degenerate Meckel's cartilage. The induction of apoptosis observed in monocytes seems to be caused via a Fas-Fas ligand cell death system, because some of these monocytes were Fas-positive, and most of them were Fas ligand-positive. Interestingly, the abundant soluble Fas ligand observed in the periosteum probably protects the bone-formative zone from the invasion of the activated lymphocytes by binding to Fas expressing in these lymphocytes and killing these cells. Fas and Fas ligand were focally positive in the dental lamina and inner enamel epithelium and cusps of the enamel organ, nevertheless, the presence of TUNEL-positive cells was very rare. Bcl-2 was clearly and Bax was weakly positive in the cells throughout the dental lamina and enamel organ. These findings indicated that Fas-mediated apoptosis was inhibited by the Bcl-2 family in the development of teeth.
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PMID:The immunohistochemical localization of Fas and Fas ligand in jaw bone and tooth germ of human fetuses. 1077 1

In the present study, we have aimed at clarifying the CD4-dependent molecular mechanisms that regulate human memory T cell susceptibility to both Fas (CD95)-dependent and Bcl-2-dependent apoptotic pathways following antigenic challenge. To address this issue, we used an experimental system of viral and alloantigen-specific T cell lines and clones and two ligands of CD4 molecules, Leu-3a mAb and HIV gp120. We demonstrate that CD4 engagement before TCR triggering suppresses the TCR-mediated neosynthesis of the Flice-like inhibitory protein and transforms memory T cells from a CD95-resistant to a CD95-susceptible phenotype. Moreover, evidence that the apoptotic programs were executed while Fas ligand mRNA expression was inhibited led us to analyze Bcl-2-dependent pathways. The data show that the engagement of CD4 separately from TCR influences the expression of the proapoptotic protein Bax independently of the anti-apoptotic protein Bcl-2, whereas Ag activation coordinately modulates both Bax and Bcl-2. The increased expression of Bax and the consequent dissipation of the mitochondrial transmembrane potential (DeltaPsim) suggest a novel immunoregulatory function of CD4 and demonstrate that both passive cell death and activation-induced cell death are operative in CD4+ memory T cells. Furthermore, analysis of the mechanisms by which IL-2 and IL-4 cytokines exert their protective function on CD4+ T cells in the presence of soluble CD4 ligands shows that they were able to revert susceptibility to Bax-mediated but not to CD95-dependent apoptotic pathways.
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PMID:Engagement of CD4 before TCR triggering regulates both Bax- and Fas (CD95)-mediated apoptosis. 1079 64

The mechanism of injury and death of muscle cells in the inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure. We and others have not detected apoptosis in the muscle biopsies from patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and FasL is present on degenerating muscle cells and many infiltrating mononuclear cells. The expression of both Fas and FasL in the inflamed tissue makes the absence of apoptosis more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antiapoptotic molecule FLICE (Fas-associated death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients and in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP with antisense oligonucleotides promotes significant cleavage of poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis. These studies strongly suggest that the resistance of muscle to Fas-mediated apoptosis is due to the expression of FLIP in muscle cells in the inflammatory environment in myositis.
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PMID:The inhibition of apoptosis in myositis and in normal muscle cells. 1079 13

This article reviews advances in the study of the molecular mechanisms for ultraviolet (UV)-induced keratinocyte apoptosis, with particular reference to the cytokines tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL). TNF-alpha and FasL induce their respective receptors and then activate caspase enzymes that are critically involved in the apoptotic process. This activation is further amplified by intracellular mitochondria-associated mechanisms. Using gene-targeted knockout mice lacking either the TNF-Rp55 or the TNF-Rp75, we have shown that TNF-alpha plays an important role in UV-induced keratinocyte apoptosis via TNF-Rp55. TNF-Rp55 shares homology with Fas and contains an intracellular death domain. UV seems to directly stimulate cross-linking of Fas, resulting in the engagement of the death machinery. Fas-associated death domain protein (FADD) acts as an adapter protein in both the TNF-Rp55 and Fas death-inducing cascades and is responsible for downstream signal transduction by recruiting caspases. Moreover, signaling of p53 contributes to the induction of apoptosis by regulating Bcl-2 family expression and increasing surface Fas expression. In addition to induction mechanisms of apoptosis, there are numerous inhibitory molecules that play a role in restricting the apoptotic pathway. Thus, the ultimate determination of whether or not a cell undergoes apoptosis after UV radiation is based on the balance between agonist and antagonist pathways.
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PMID:Molecular mechanism of ultraviolet-induced keratinocyte apoptosis. 1084 Oct 72

Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.
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PMID:The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia. 1086 Oct 77

It is well known that human leukemia cells, such as HL-60 and U937 are sensitive to antitumor drugs, but human normal lung fibroblasts, such as WI-38 cells are resistant to the drugs. However, the mechanisms of the different responses to apoptosis in these cell lines remain unclear. We report here that an increase of Fas and Fas ligand (FasL) expression was required for antitumor drug-induced apoptosis in WI-38 and baby hamster kidney (BHK) cells, but not in HL-60 cells. Then, we used BHK cells transfected with the bcl-2 gene to investigate the involvement of complex formation of Bcl-2 and calcineurin. Calcineurin was imported to the nucleus in response to the drug treatment. Overexpression of Bcl-2 and cyclosporin A treatment inhibited the nuclear import and FasL expression, and as a result, both inhibited apoptosis. Although a caspase inhibitor, z-Asp-CH2-DCB, suppressed the drug-induced apoptosis, it failed to inhibit the drug-induced expression of Fas and FasL. These findings suggest that initially the Fas / FasL system is activated by calcineurin-dependent transcription followed by activation of the downstream caspase cascade resulting in antitumor drug-induced apoptosis in BHK cells, but not in HL-60 cells. Furthermore, Bcl-2 inhibits the nuclear import of calcineurin and suppresses calcineurin-mediated FasL expression during antitumor drug-induced apoptosis.
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PMID:Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated baby hamster kidney cells. 1092 Feb 78

A panel of murine B lymphoma cell lines, which express different levels of Fas, was extensively studied for sensitivity to Fas-mediated death signals via an anti-Fas mAb and Fas ligand-bearing cell lines. Expression of the Fas receptor on the B lymphoma cell lines did not correlate with their capacity to undergo Fas-mediated apoptosis. Moreover, Fas-associated death domain protein recruitment to the death-inducing signaling complex (DISC) complex occurred in all cell lines expressing Fas, regardless of whether they were sensitive to Fas-mediated death. Interestingly, the protein synthesis inhibitor, cycloheximide, and protein kinase C inhibitors, such as bisindolylmaleimide, rendered one of the resistant cell lines, CH33, sensitive to signals from the Fas receptor, although the levels of Fas were unchanged. This suggests that constitutive PKC activation plays a role in Fas resistance, perhaps by up-regulating NF-kappaB or Bcl-2 family members. Interestingly, CH33 demonstrated caspase 8 activity upon engagement of the Fas receptor in the absence of pharmacological manipulation, suggesting that the block in apoptosis is downstream of the DISC complex. In contrast, the fact that Fas-associated death domain protein was recruited to the DISC complex in other resistant lines, such as WEHI-231, with no caspase 8 activation indicates that these cells may be blocked within the DISC complex. Indeed, Western blot analysis showed that WEHI-231 expressed an isoform of FLICE-like inhibitory protein (cFLIPL), an antiapoptotic protein within the DISC. These studies provide evidence that murine B lymphoma cells utilize different molecular mechanisms along the Fas-signaling cascade to block apoptosis.
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PMID:Distinct molecular mechanisms of Fas resistance in murine B lymphoma cells. 1092 64

Despite the capacity for antigen-specific activation and rapid clonal expansion, homeostatic mechanisms ensure that the mature immune system contains a relatively stable number of T cells. In recent years, it has become apparent that this stability is a consequence of apoptotic death of most of the specific T cells generated during an immune response. Clearly this process must be tightly regulated in order to retain sufficient T-cell progeny to mediate an effective response, whilst allowing the rapid deletion of these cells at the end of the response to prevent lymphadenopathy and cross-reactive autoimmunity. In this study, the factors that regulate the sensitivity of T cells to apoptosis were investigated in vitro after the induction of primary T-cell activation within a mixed lymphocyte reaction (MLR). It was found that activated T cells rapidly acquire the expression of both Fas and Fas ligand (FasL) on their surface and contain high levels of the precursor form of the pro-apoptotic enzyme, caspase 8 (FLICE). However, these T cells were resistant for up to 5 days to apoptosis following the stimulation of Fas; a maximal apoptotic response was observed after 7 days. This time point coincided with a marked reduction in expression of the FLICE inhibitory protein (FLIP) and maximal activity of caspase 8. At time points beyond day 7, the number of viable cells in the MLR decreased further despite a reduction in the expression of FasL. However, the expression of interleukin-2 (IL-2) at these late time points was low, resulting in a decrease in expression of the anti-apoptotic protein Bcl-2. This can produce apoptosis by allowing leakage of cytochrome-c from mitochondria resulting in direct activation of the caspase cascade. In this study, it is shown that T cells are resistant to apoptosis for the first 5 days after activation as a consequence of insensitivity of the Fas pathway and the presence of intracellular Bcl-2. After between 5 and 7 days, the cells become sensitive to Fas-mediated apoptosis while retaining Bcl-2 expression. At later time points, Fas ligation is reduced but the cells respond to a decreased availability of IL-2 by reducing Bcl-2 expression; this encourages further apoptosis by allowing the direct activation of caspase enzymes.
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PMID:Regulation of T-cell apoptosis: a mixed lymphocyte reaction model. 1092 50

Moloney murine leukemia virus (M-MuLV) is a replication-competent, simple retrovirus that induces T-cell lymphomas when inoculated into neonatal mice. The tumor cells are typically derived from immature T cells. During preleukemic times, a marked decrease in thymic size is apparent in M-MuLV-inoculated mice. We previously demonstrated that this thymic regression is correlated with enhanced levels of thymocyte apoptosis (C. Bonzon and H. Fan, J. Virol. 73:2434-2441, 1999). In this study, we investigated the apoptotic state of M-MuLV-induced tumors. M-MuLV-induced tumors were screened for expression of the apoptotic proteins Fas and Bcl-2 by three-color flow cytometric analysis. Single-positive (SP; CD4(+) CD8(-) and CD4(-) CD8(+)) tumor cells generally displayed lower cell surface expression of Fas than SP thymocytes from uninoculated control mice. Double-positive (DP; CD4(+) CD8(+)) M-MuLV-induced tumor cells fell into two categories: those with normal high levels of Fas and those with low levels of Fas. Additionally, the vast majority of DP tumors showed elevated Bcl-2 levels. The DP tumor cells retaining normal/high Fas expression were capable of transducing an apoptotic signal upon anti-Fas engagement. In addition, DP and CD4(+) SP tumor populations displayed higher levels of Fas ligand than normal thymocytes with the same phenotypes. In contrast, CD8(+) SP and CD4(-) CD8(-) tumors did not show elevated Fas ligand expression. There was no significant correlation between Fas and Fas ligand expression in the DP tumors, suggesting that Fas Ligand expression was not the driving force behind Fas down-regulation. These results suggest that both the Fas death receptor and mitochondrial pathways of apoptotic death are active in M-MuLV-induced tumors and that they must be modulated to permit cell survival and tumor outgrowth.
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PMID:Moloney murine leukemia virus-induced tumors show altered levels of proapoptotic and antiapoptotic proteins. 1093 26

The present study investigates the role of the HIV-suppressive beta-chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1 and RANTES in activation-induced cell death (AICD). A pool of these beta-chemokines reduced anti-CD3-induced apoptosis of T cell blasts from healthy blood donors in a dose-dependent manner. Although the pooled beta-chemokines were more effective, the inhibitory effect could also be mediated by each of the individual chemokines and was blocked by neutralizing anti-chemokine antibodies. The beta-chemokines also inhibited pokeweed mitogen/staphylococcal enterotoxin B-induced T lymphocyte apoptosis in 33/49 HIV-infected (HIV+) individuals. This anti-apoptotic effect was not correlated with the patients' CD4 T cell counts. beta-chemokines did not lead to altered secretion of IL-2, IL-4, IFN-gamma or IL-10 in response to activation stimuli in either normal T cell blasts or peripheral blood mononuclear cells from HIV+ individuals. Co-incubation with beta-chemokines did not inhibit anti-CD3-induced expression of cell surface Fas ligand, nor did it alter levels of the death receptor Fas or Bcl-2 in T cell blasts, suggesting that the beta-chemokines are blocking AICD downstream of Fas. These observations indicate that beta-chemokines may play a novel role as modulators of AICD, in addition to their known role as chemoattractants and inhibitors of HIV replication.
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PMID:Beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals. 1094 Aug 94

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