LARD: A new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing
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Fas and TNF-R1 are cysteine-rich cell surface receptors related to the low-affinity nerve growth factor receptor family. Engagement of these receptors by their respective ligands, FasL and tumor necrosis factor, leads to apoptosis that is signaled through a conserved intracellular portion of the receptor termed the "death domain." We have cloned a new member of this family, lymphocyte-associated receptor of death (LARD), which leads to spontaneous apoptosis when expressed in 293T cells. The expression of LARD is more tightly regulated than that of either Fas or TNF-R1 as it is found predominantly on lymphocytes (T and B cells) but not on macrophages or a number of transformed lymphocyte cell lines. Alternative pre-mRNA splicing generates at least 11 distinct isoforms of LARD. The full-length isoform, LARD-1, extends to include the transmembrane and death domains, whereas the other isoforms encode potentially secreted molecules. Naive B and T cells express very little LARD-1 but express combinations of the other isoforms. Upon T cell activation, a programmed change in alternative splicing occurs so that the full-length, membrane-bound LARD-1 predominates. This may have implications for the control of lymphocyte proliferation following activation.Keywords:
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Apoptosis has been implicated in tumor development and progression. Fas (CD95) and Fas ligand (FasL) are an interacting receptor ligand pair that elicits apoptosis in many cell types. Although originally described as proteins regulating peripheral immune tolerance, accumulating evidence suggests that Fas/FasL may play an important role in carcinogenesis, tumor outgrowth, and metastasis. This review summarizes our current knowledge about the regulation of Fas and FasL expression, Fas signaling, soluble Fas production, the role(s) of Fas and FasL in hematopoietic and non-hematopoietic tumorigenesis and progression, and the potential application of Fas-induced apoptosis in cancer therapy.
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Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.
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Fas-mediated apoptosis is a form of cell death that operates through a Fas-Fas ligand (FasL) interaction. In this study we investigated the role of the Fas system during development of normal and Fas-mutated lymphocytes. Irradiated RAG2–/– recipients were reconstituted with bone marrow cells from B6 and lpr mice (Fas defective) or from B6 and gld mice (FasL defective), and analyzed for long-term development. The results showed a primary role of the Fas system in peripheral cell death and thymic colonization. In the periphery, the interaction in vivo between Fas+ and Fas– T cell populations indicated that cellular homeostasis was defective. Indeed, we observed a FasL-mediated cytotoxic effect on normal-derived T cells, explaining the dominance of lpr T cells in the mixed chimeras. The Fas mutation affected neither cell activation nor cell proliferation, as the effector (Fas–) and target (Fas+) cells behaved similarly with regard to activation marker expression and cell cycle status. However, Fas– T cells failed to seed the periphery and the thymus in the long term. We suggest that this could be due to the fact that FasL is involved in the structural organization of the lymphoid compartment.
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The relationship between apoptosis,atresia folliculi and missed abortion mediated by Fas/FasL system
Fas/FasL were two kinds of transmembrane protein on the cell surface.The current study showed that FasL was the death factor and Fas was its receptor.When the FasL of a cell combined with the Fas of another,they could lead that the cell which expressed Fas died.Fas was named Apo-1,meaning CD95.Fas gene was located on human q23 of the chromosome 10 and the gene length was about 25 Kb.FasL gene was located on human q23 of the chromosome 1 and the gene length was about 8Kb.The Fas/FasL system was closely related to Physiological process of follicular atresia,autoimmune diseases,tumors and graft tolerance.Recently the incidence of missed abortion related to apoptosis has been attended by people and the Fas/FasL system is important in promoting apoptosis.
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Fas ligand (FasL) and its receptor (Fas, CD95, Apo-1) are a set of regulatory components in immune system. The aim of this study was to investigate the expression of Fas and FasL in the breast cancer. We were able to demonstrate that 90% of the invasive breast cancers expressed CD95L, with potential detrimental effects on the host organism. CD95 expression was lost (35%) in breast cancer, a mechanism probably involved in CD95L-mediated apoptosis resistance. INTRODUCTION Fas ligand (FasL) and its receptor (Fas, CD95, Apo-1) are a set of regulatory components of the immune system (Suda et al., 1993). Fas is a 45-kDa cell-surface receptor of the TNF/ nerve growth factor receptor family and is one of the most important death-domain receptors (Suda et al., 1993). Interaction of Fas with its ligand, FasL, induces receptor trimerization, which in turn results in the recruitment of the adapter protein FADD (Fas-associated death domain) and activation of caspases, which lead to irreversible cell damage and death (Nagata, 1995). FasL expression results in neoplastic cells becoming able to modify the immune response directed against them by affecting the tumor microenvironment in a way that favors the successful escape of the tumor from immune surveillance (Gutierrez et al., 1999). AIMS OF THE STUDY The aim of this study was to investigate the expression of apoptotic markers Fas and FasL in breast carcinomas. We were also interested in establishing a potential correlation between the expression of these two molecules and the clinical and biological parameters of the tumors. MATERIALS AND METHODS A number of 20 patients, diagnosed with mammary carcinoma and surgically treated in the III-rd Surgical Clinic of the “Sf. Spiridon” Hospital were taken into consideration. For each patient were investigated the following parameters: menopausal status, the histological type/gradding tumoral of the primary tumor and the lymph node status. The neoplastic samples were harvested in sterile medium and incubated with 0.4% collagenase, at 37C, over night. The isolated cells were centrifuged on glass slides (cytospin) and fixed in ethanol absolut for 15 min. at room temperature. The slides were incubated with a primary antibody (anti-Fas and anti-FasL respectively) followed by a secondary biotinylated antibody and the streptavidin-peroxidase complex. The reaction was developed with diaminobenzidine (DAB) and the cells were counterstained with hematoxylin. We have considered as positive those samples that expressed more than 5% Fas or FasL positive cells. In order to identify possible correlations between the Fas and FasL expression and the other parameters we have considered, the 2 test was employed and the statistical significance threshold was established at <0.05. RESULTS AND DISCUSSION Our investigation has revealed the following features: -FasL expression has been detected in 90% of the invasive breast carcinomas. -Fas and FasL co-expression has been evidenced in 65% of the cases. -Fas expression was partial lost in 35% of the cases. -We were not able to demonstrate a statistically significant association between the Fas and FasL molecules expression and the clinical and biological parameters taken into consideration (tables I and II). Table I. The expression of Fas associated with the clinical and biological parameters considered. Parameter Number of cases(n=20) Fas +Cells n% Fas –Cells n% Premenopause 4 4 (100%) 0 (0%) menopausal status Postmenopause 16 9(56,25%) 7(43,75%) CDI-G2 13 9(69,24%) 4(30,76%) CDI-G3 5 3(60%) 2(40%) histological type/gradding tumoral
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The regulation of neutrophil apoptosis in chronic renal failure (CRF) has not been clearly defined. The Fas/FasL system is an important apoptotic regulatory pathway in a wide variety of cells. Fas is a widely expressed cell surface protein that transduces an apoptotic signal after interaction with its natural ligand FasL. In contrast to the extensive tissue distribution of Fas, constitutive expression of FasL is relatively limited. We examined Fas and FasL expression by neutrophils in healthy subjects, patients with CRF, and patients on hemodialysis (HD) and peritoneal dialysis (PD). Fas expression was significantly higher among patients with CRF compared with control subjects, HD patients, and PD patients. FasL expression was significantly higher among patients with CRF compared with control subjects. At 24 h, neutrophil apoptosis was higher among patients with CRF compared with control subjects. Furthermore, high-neutrophil Fas expression was paralleled by a higher sensitivity to Fas-mediated apoptosis. There was a strong correlation between Fas-stimulated apoptosis and creatinine clearance as well as Fas expression. Finally, we found that uremic serum increased the expression of neutrophil-associated Fas and FasL proteins, when compared with normal serum. Further studies are under way to examine the regulation of this pathway in the uremic environment.
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Fas-mediated apoptosis is a form of cell death that operates through a Fas-Fas ligand (FasL) interaction. In this study we investigated the role of the Fas system during development of normal and Fas-mutated lymphocytes. Irradiated RAG2–/– recipients were reconstituted with bone marrow cells from B6 and lpr mice (Fas defective) or from B6 and gld mice (FasL defective), and analyzed for long-term development. The results showed a primary role of the Fas system in peripheral cell death and thymic colonization. In the periphery, the interaction in vivo between Fas+ and Fas– T cell populations indicated that cellular homeostasis was defective. Indeed, we observed a FasL-mediated cytotoxic effect on normal-derived T cells, explaining the dominance of lpr T cells in the mixed chimeras. The Fas mutation affected neither cell activation nor cell proliferation, as the effector (Fas–) and target (Fas+) cells behaved similarly with regard to activation marker expression and cell cycle status. However, Fas– T cells failed to seed the periphery and the thymus in the long term. We suggest that this could be due to the fact that FasL is involved in the structural organization of the lymphoid compartment.
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Fas and its ligand (FasL) are members of the tumor necrosis factor receptor (TNFR) and tumor necrosis factor (TNF) superfamilies, respectively. Fas−FasL interactions trigger controlled cell death (apoptosis) in the immune system and thus play a key role in the regulation of immune responses. Structural details of the Fas−Fas ligand interaction are currently unknown. Previously, six Fas residues were identified by mutagenesis as important for ligand binding. We have now extended our mutagenesis analysis and identified additional residues which contribute to the Fas−FasL interaction. Candidate and control residues were selected based on a molecular model of the Fas extracellular region. Although residues in all three extracellular domains were identified to contribute to binding, the Fas−FasL interaction is centered on the second TNFR-like domain. Important residues were compared to critical positions in TNFR and CD40, another member of the TNFR family.
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