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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is a cell-surface receptor that belongs to the tumor-necrosis factor (TNF)/nerve growth factor receptor family. Fas can transduce an apoptotic signal through the death domain in the cytoplasmic region, which has similarity with the corresponding region of the TNF type-I receptor. Here, we expressed human Fas in mouse L929 cells or its subline (C12), which express extremely low levels of cytosolic phospholipase A2 (cPLA2). L929 cells were sensitive to the cytotoxic activity of TNF, while C12 cells were resistant. Cross-linking of human Fas with anti-(human Fas antibody) Ig killed both L929 transformants and C12 transformants expressing human Fas. Various inhibitors of the arachidonate metabolism significantly inhibited the TNF-induced cytotoxicity in L929 cells, but they did not have any effect on Fas-mediated apoptosis. These results indicated that cPLA2 is required for TNF-induced apoptosis, whereas it is dispensable for Fas-mediated apoptosis, and suggested that the TNF receptor and Fas use different signaling pathways for apoptosis.
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PMID:Different apoptotic pathways mediated by Fas and the tumor-necrosis-factor receptor. Cytosolic phospholipase A2 is not involved in Fas-mediated apoptosis. 861 26

The cell surface receptor Fas is a major trigger of apoptosis. However, expression of the Fas receptor in many tumor cell types does not correlate with sensitivity to Fas-mediated cell death. Because a prooxidant state is a common feature of tumor cells, we examined the role of intracellular reactive oxygen intermediates in the regulation of Fas-mediated cytotoxicity. Our results show that an oxidative stress induced by increasing the intracellular superoxide anion (O2-) concentration can abrogate Fas-mediated apoptosis in cells which are constitutively sensitive to Fas. Conversely, an O2- concentration decrease is observed to sensitize cells which are naturally resistant to Fas signals. These observations suggest that intracellular O2- may play a key role in regulating cell sensitivity to a potentially lethal signal and provide tumor cells with a natural, inducible mechanism of resistance to Fas-mediated apoptosis.
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PMID:Superoxide anion is a natural inhibitor of FAS-mediated cell death. 861 97

Escape of tumor cells from apoptotic-mediated stimuli results in tumor cell survival and resistance to cytotoxic mechanisms. Kaposi's sarcoma (KS) is the most common malignancy associated with AIDS, although its pathogenesis is not known. It is clinically important to determine whether AIDS-KS cells are resistant to apoptosis via the Fas system. Three isolates of AIDS-KS cells were studied. Although all KS cells express Fas on the cell surface, these cells were resistant to cytotoxic anti-Fas antibody (IgM, CH-11). Treatment of AIDS-KS cells with actinomycin D sensitized the tumor cells to anti-Fas cytotoxicity and apoptosis. Apoptosis was assessed by morphological changes and DNA fragmentation analysis. Three possible mechanisms related to AIDS-KS cells, resistance to anti-Fas cytotoxicity were examined. First, synthesis and secretion of soluble Fas by the tumor cells can neutralize antibody-induced cytotoxicity. However, none of the three types of KS cells expressed soluble Fas mRNA as determined by reverse transcription (RT)-PCR. Second, the expression of the proto-oncogene bcl-2 can protect cells from apoptotic signals. Analysis of bcl-2 mRNA by RT-PCR revealed that all three AIDS-KS cells express very low levels of bcl-2 mRNA. Third, the Fas-associated phosphatase-1 (FAP-1) is an antiapoptotic molecule reported to interact with Fas and can block transduction of the apoptotic signal. RT-PCR analysis revealed that all three types of AIDS-KS cells express high levels of FAP-1 mRNA, and treatment of KS cells with actinomycin D reduced the levels of FAP-1 mRNA significantly. These findings demonstrate that AIDS-KS cells are resistant to Fas-mediated apoptosis and suggest that FAP-1 may be involved in the acquisition of resistance of AIDS-KS to anti-Fas antibody-mediated apoptosis.
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PMID:Resistance of AIDS-associated Kaposi's sarcoma cells to Fas-mediated apoptosis. 862 May 7

Engagement of the CD95 (APO-1/Fas) receptor induces apoptosis in a variety of cell types. However, the nature of the cytotoxic signal and the intermediate messenger molecules remain to be elucidated. In an effort to understand CD95-mediated signaling, we assessed possible changes in the DNA binding activity of NF-kappaB as a result of CD95 engagement in various tumor cells. By performing electrophoresis mobility shift assays, we show that CD95 can stimulate the DNA binding activity of NF-kappaB in a variety of cells, irrespective of their sensitivity or resistance to CD95-mediated cytotoxicity. Moreover, deletion of 37 carboxyl-terminal residues from the cytoplasmic domain of CD95, which abrogates CD95-mediated apoptosis, only marginally affects NF-kappaB activation. Taken together, these observations indicate that CD95 has a function that involves activation of NF-kappaB and that appears to be unrelated to its role as an inducer of apoptotic cell death.
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PMID:The CD95 (APO-1/Fas) receptor activates NF-kappaB independently of its cytotoxic function. 862 45

Perforin- and Fas-based cytolytic pathways are two major mechanisms of cell-mediated cytotoxicity. Recently, we have shown that an inhibitor of vacuolar type H+-ATPase, concanamycin A (CMA), inhibits perforin-based cytotoxic activity, mostly due to accelerated degradation of perforin by an increase in the pH of lytic granules. Here we show that CMA failed to inhibit the cytolytic activity of CD4+ CTL clone and perforin-deficient CD8+ CTL clone, which exclusively mediate Fas-based cytotoxicity, although CMA inhibited acidification and induced drastic vacuolation of cytoplasmic granules in these clones. In a wide range of alloantigen-specific CTL, a significant amount of the lysis of Con A blasts from normal mice and of Fas-positive tumor cells remained unaffected even in excess concentrations of CMA. However, CMA almost completely inhibited the lysis of Con A blasts from lpr mice and of Fas low expressing or negative tumor cells. Cytolysis by alloantigen-specific CD8+ CTL derived from gld mice was completely prevented by CMA. Furthermore, CMA-insensitive cytolysis exerted by CD8+ CTL clone was completely inhibitable by soluble Fas molecules. Thus, these data clearly indicate not only that CMA-insensitive cytolysis mediated by alloantigen-specific CTL is Fas dependent, but also that CMA is a selective inhibitor to block only the perforin-based killing pathway. In contrast, brefeldin A blocked the Fas-based cytotoxicity, but only marginally reduced the perforin-based cytotoxicity. Moreover, CMA and brefeldin A in combination completely abrogated all cytolytic activity of alloantigen-specific CTL. Taken together, these results reveal that CTL mainly exert perforin-based cytotoxicity and complementary Fas-based cytotoxicity, and that CMA is a powerful tool to clarify the contributions of the two distinct cytolytic pathways.
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PMID:Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. 862 2

Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT-alpha and a converted form of LT-beta wherein the normally type II LT-beta membrane protein was changed to a type I secreted form. Recombinant LT-alpha 1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined with human IFN-gamma arrested tumor growth. The delineation of a biological signaling event mediated by the LT-beta-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-beta-R may have an application in tumor therapy.
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PMID:Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. 864 91

Fas/Apo-1 molecule, also designated as CD95, is a member of the TNF receptor family. Fas cross-linking by its natural ligand or by agonistic mAbs results in rapid induction of apoptosis in susceptible cells. in addition to the Fas full-length mRNA, human activated PBMC and tumor cell lines express several mRNA Fas variants that derive from alternative splicing of the primary transcript. All five variants identified, two of which are newly described here, code for soluble proteins that, with the exception of FasTMDel, are truncated in the extracytoplasmic region and possess short C-terminal amino acid sequences corresponding to a different reading frame. We have identified Abs that recognize all splicing variants and established a sandwich ELISA by which the soluble Fas molecules could be detected in culture supernatants of transfected cell lines and in PBMC following T cell activation. Next, we have studied in detail the functional role of these variants by apoptosis inhibition studies. We found that all soluble proteins block the apoptosis induced by either an agonistic Ab or, more importantly, by the natural Fas ligand in Fas-positive sensitive cell lines. interestingly, this functional property can be assigned to the first 49 amino acids of the mature protein that is the only region shared by the five soluble Fas molecules.
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PMID:An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. 864 5

MT-PVLT-10 transgenic mice express large T-antigen of polyomavirus under the control of the mouse metallothionein-1 promoter and mates of this transgenic line develop testicular tumors at advanced ages. The differential display technique was employed to compare mRNA expression from immortalized cell lines derived from normal or adenomatous testis from MT-PVLT-10 transgenic males. Using this technique, a complementary DNA fragment corresponding to the mouse Fas antigen receptor was recovered from normal testicular cells but not from tumor cells. RNAse protection assays with the Fas antigen specific fragment confirmed its differential expression. Normal testicular cells from the transgenic animals responded to treatment of interferon-gamma by increasing the expression of Fas antigen specific mRNA and were sensitive to the proliferative inhibitory effect of anti-Fas antibody in vitro. This proliferative inhibition was characterized by an accumulation of cells in S phase of the cell cycle. In contrast, the testicular tumor cells did not respond to either interferon-gamma or to anti-Fas antibody in vitro. These results suggest that the toss of proliferative inhibitory effect mediated by the Fas antigen pathway in tumor cells may be an important step in testicular tumor progression in the MT-PVLT-10 transgenic mice.
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PMID:Decreased Fas antigen receptor expression in testicular tumor cell lines derived from polyomavirus large T-antigen transgenic mice. 864 5

Cytokines in the tumor necrosis factor (TNF) family regulate development and function of the immune system. We have isolated a new member of this family, designated Apo-2 ligand (Apo-2L), via an expressed sequence tag. Apo-2L is a 281-amino acid protein, related most closely to Fas/Apo-1 ligand. Transfected Apo-2L is expressed at the cell surface with its C terminus exposed, indicating a type II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal extracellular region of Apo-2L (amino acids 114-281) exhibits a homotrimeric subunit structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well as non-lymphoid tumor cell lines. The effect of Apo-2L is not inhibited by soluble Fas/Apo-1 and TNF receptors; moreover, expression of human Fas/Apo-1 in mouse fibroblasts, which confers sensitivity to induction of apoptosis by agonistic anti-Fas/Apo-1 antibody, does not confer sensitivity to Apo-2L. Hence, Apo-2L acts via a receptor which is distinct from Fas/Apo-1 and TNF receptors. These results suggest that, along with other family members such as Fas/Apo-1 ligand and TNF, Apo-2L may serve as an extracellular signal that triggers programmed cell death.
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PMID:Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. 866 10

To study how MHC-associated self antigens may regulate the function of T cells in the periphery, we generated CD8+ T cell lines specific for a single residue variant of a self peptide. The self peptide (GAYEFTTL) was isolated from H-2-Kb class I MHC molecules immunopurified from tumor cells. CD8+ CTL lines from H-2b mice were generated against a variant peptide, pE4R, (arginine for glutamic acid at the TCR contact position 4). In short-term 51Cr-release assays, these CTL lysed H-2Kb targets that were pulsed with picomolar levels of pE4R but did not lyse target cells coated with the self peptide at micromolar levels. However, in overnight assays the CTL lysed Fas-positive target cells in the presence of nanomolar levels of the self peptide. This killing was shown to be entirely Fas/Fas ligand mediated by blocking with anti-Fas antibody and Fas-Fc chimeric molecules. While the self peptide was unable to induce serine esterase release from the CTL, it did induce secretion of IFN-gamma. By these criteria then, the unmodified self ligand served as a partial agonist for the CTL raised against a single-residue variant. CD8+ T cell lines raised by in vitro stimulation with the self peptide were likewise unable to kill self peptide-coated targets via the perforin pathway but did lyse targets via Fas. These and similar data from other groups show that self antigens (i.e., MHC/peptide complexes) may be recognized by mature peripheral T cells. The T cell population is tolerant of the self antigen in the sense that they do not respond to physiological levels of the MHC/peptide complex. However, when the level of self antigen is increased (by using synthetic peptide loading) CD8+ T cells may respond by proliferation, IFN-gamma secretion, Fas ligand upregulation, and Fas-mediated cytolysis but are still unable to respond by perforin-mediated cytolysis or granzyme release. The physiological significance of such partial activation in regulation of the immune system remains to be demonstrated.
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PMID:Selective activation of Fas/Fas ligand-mediated cytotoxicity by a self peptide. 867 65


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