Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is a cell-surface protein mediating apoptosis. Fas ligand is a type II membrane protein and induces apoptosis by binding to Fas. Fas ligand is expressed in activated T cells, and works as an effector of cytotoxic lymphocytes. Molecular and genetic analysis of Fas and Fas ligand indicated that mouse lymphoproliferation mutation (lpr) and generalized lymphoproliferative disease (gld) are mutations of Fas and Fas ligand respectively. The lpr of gld mice develop lymphadenopathy, and suffer from autoimmune disease. Based on these phenotypes and other studies, it was concluded that the Fas system is involved in the apoptotic process during T-cell development, specifically peripheral clonal deletion or activation-induced suicide of mature T cells. In addition to the activated lymphocytes, Fas is expressed in the liver, heart and lung. Administration of agonistic anti-Fas antibody into mice induced apoptosis in the liver and quickly killed the mice, causing liver damage. These findings suggest that the Fas system plays a role not only in the physiological process of lymphocyte development, but also in the cytotoxic T-lymphocyte-mediated disease such as fulminant hepatitis.
Prog Mol Subcell Biol 1996
PMID:Apoptosis mediated by the Fas system. 882 94

Active T cell suicide (apoptosis) is supposed to be involved in the CD4+ T cell depletion in the course of HIV infection. We investigated the expression of the apoptosis-related antigen Fas on CD4+ T cells from 25 HIV-positive individuals (CDC I-III) and 8 HIV-negative controls by two-colour flowcytometry. In addition, we evaluated: total CD4 count, HIV p24 antigen concentration in serum after immune complex dissociation, and clinical course of infection in HIV-positive individuals. We found a significant increase in mean Fas expression on CD4+ T cells from HIV-positive individuals compared to HIV-negative individuals (85.84 +/- 14.92% vs. 64.28 +/- 7.59%, P < 0.001). Within the HIV-positive group the increase in Fas expression was correlated with the decline in CD4 count (r = -0.76, P < 0.001), p24 antigen concentration in serum, after immune complex dissociation (r = 0.67, P < 0.001), and CDC stage (r = 0.73, P < 0.001). The upregulation of Fas antigen on CD4 cells is associated with CD4 depletion and other virological and clinical marker of disease progression in HIV infection.
J Mol Med (Berl) 1995 Dec
PMID:Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression. 882 55

The Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the mitogen-responsive kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require ICE (interleukin-1 beta-converting enzyme) family proteases to induce apoptosis from studies utilizing the cowpox ICE inhibitor protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK, and the tripeptide pan-ICE inhibitor Z-VAD-FMK. In this study, crmA antagonized, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation of p38 kinase activity, demonstrating that Fas-dependent activation of p38 requires ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the ICE/CED-3 family proteases. Intriguingly, p38 activation by sorbitol and etoposide was resistant to YVAD-CMK and Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, the apoptotic cysteine proteases also function to regulate stress kinase signalling cascades.
Mol Cell Biol 1997 Jan
PMID:Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. 897 82

Cross-linking of Fas (CD95) induces apoptosis, a response that has been reported to depend upon the Ras activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activating enzyme Jun kinase (JNK), downstream effectors of Ras or Ras-like small GTP-binding proteins, we evaluated the role of these molecules in Fas-mediated apoptosis. Although cross-linking of Fas on Jurkat T cells did result in JNK activation, increased activity was observed relatively late, being detectable only after 60 min of stimulation. Expression of a dominant negative form of SEK1 that blocked Fas-mediated induction of JNK activity had no effect on Fas-mediated apoptosis. Furthermore, maximally effective concentrations of anti-Fas did not cause JNK activation if apoptosis was blocked by a cysteine protease inhibitor, suggesting that under these conditions, activation of JNK may be secondary to the stress of apoptosis rather than a direct result of Fas engagement. Despite the activation of JNK, there was no induction of AP-1 activity as determined by gel shift assay or induction of an AP-1-responsive reporter. The lack of a requirement for AP-1 induction in Fas-mediated death was further substantiated with Jurkat cells that were stably transfected with a dominant negative cJun, TAM-67. While TAM-67 effectively prevented AP-1-dependent transcription of both the interleukin-2 and cJun genes, it had no effect on Fas-induced cell death, even at limiting levels of Fas signaling. Thus, induction of JNK activity in Jurkat cells by ligation of Fas at levels sufficient to cause cell death is likely a result, rather than a cause, of the apoptotic response, and AP-1 function is not required for Fas-induced apoptosis.
Mol Cell Biol 1997 Jan
PMID:Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis. 897 97

MRL/Mp-lpr/lpr mice develop a spontaneous lupus syndrome, including hypergammaglobulinemia, autoantibodies, glomerulonephritis, and lymphadenopathy. To investigate the role of lymphocytes subsets in the pathogenesis of disease, lupus-prone MRL mice deficient in alpha beta T cells, gamma delta T cells, or both were generated. Mice deficient in alpha beta T cells developed a partially penetrant lupus syndrome, characterized by lymphadenopathy, elevated levels of class-switched immunoglobulins, an increased incidence of antinuclear antibodies, and immune deposits in kidneys which progressed to renal insufficiency over time. In comparison to wild type animals, gamma delta T cell-deficient animals developed an accelerated and exacerbated disease phenotype, characterized by accelerated hypergammaglobulinemia and enhanced autoantibody production and mortality. Repertoire analysis of these latter animals identified polyclonal expansion (V beta) of alpha beta CD4+ B220-cells. Mice lacking both alpha beta and gamma delta T cells failed to generate class-switched autoantibodies and immune complex renal disease. First, these findings demonstrate that murine lupus in the setting of Fas-deficiency does not absolutely require the presence of alpha beta T cells, and they also suggest that a significant basis for MRL/lpr disease, including renal disease, involves alpha beta T cell-independent, gamma delta T cell dependent, polyreactive B cell autoimmunity, upon which alpha beta T cell-dependent mechanisms aggravate specific autoimmune responses. Second, these data indicate that gamma delta T cells partake in the regulation of systemic autoimmunity, presumably via their effects on alpha beta CD4+ B220-T cells that provide B cell help. Finally, these results demonstrate that MRL/lpr B cells, despite their intrinsic abnormalities, cannot per se cause tissue injury without T cell help.
Mol Biol Rep 1996
PMID:T cells in murine lupus: propagation and regulation of disease. 911 36

CD40 is one of the key molecules involved in the survival, growth and differentiation of B lymphocytes. In contrast, Fas (Apo-1, CD95) mediates apoptosis of a variety of cell types, including lymphocytes. Recent studies have found that Fas expression on mouse B cells could be strongly induced by CD40 ligation, a helper T cell-derived signal. Here, evidence is provided that CD40 ligation induced two distinct signals: one leading to the upregulation of Fas and the other leading to the enhanced Fas susceptibility. B lymphoma cell lines, CH31 and WEHI279, expressed Fas on cell surfaces, but were resistant to anti-Fas antibody (Ab) induced apoptosis. Treatment with CD40 ligand (CD40L), however, greatly enhanced Fas susceptibility of these cells. Similarly, normal splenic B cells became highly susceptible to Fas-mediated apoptosis following prolonged signaling through CD40. While CD40 ligation enhanced Fas-mediated apoptosis, stimulation with anti-IgM and IL-4 partially protected CD40L-activated B cells from Fas-mediated apoptosis. It was found that bcl-xL gene expression in normal splenic B cells was induced drastically by treatment with anti-IgM and IL-4, but not CD40L. By contrast, the expression of bcl-2 or bax was not significantly affected by these treatments. Moreover, in three of the four B lymphoma cell lines tested, Fas susceptibility correlated with the status of bcl-xL expression. The data suggest that an increase in bcl-xL expression may protect B cells from Fas-mediated apoptosis.
Mol Immunol 1996 Nov
PMID:Regulation of bcl-xL expression and Fas susceptibility in mouse B cells by CD40 ligation, surface IgM crosslinking and IL-4. 912 61

The Fas antigen, a cell surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, triggers programmed cell death (apoptosis) in the immune system. The three-dimensional structure of Fas and molecular details of the interaction between Fas and its ligand are currently unknown. A three-dimensional model of the Fas extracellular region was generated by comparative modeling. Inverse folding analysis suggested good sequence-structure compatibility of the model and thus reasonable accuracy. The model was analyzed in the light of information provided by studies on TNFR and CD40, another member of the TNFR family, and the Fas ligand binding site was predicted.
J Comput Aided Mol Des 1997 Jan
PMID:Prediction of the three-dimensional structure of the human Fas receptor by comparative molecular modeling. 913 10

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.
Mol Cell Biol 1997 Jun
PMID:T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. 915 98

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol-17beta and the oral contraceptive agent 17-ethylestradiol. 2-ME was recently reported to inhibit endothelial cell proliferation. The current study was undertaken to explore the mechanism of 2-ME effects on endothelial cells, especially whether 2-ME induces apoptosis, a prime mechanism in tissue remodeling and angiogenesis. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to 2-ME showed morphological (including ultrastructural) features characteristic of apoptosis: cell shrinkage, cytoplasmic and nuclear condensation, and cell blebbing. 2-ME-induced apoptosis in BPAEC was a time- and concentration-dependent process (EC50 = 0.45 +/- 0.09 microM, n = 8). Nucleosomal DNA fragmentation in BPAEC treated with 2-ME was identified by agarose gel electrophoresis (DNA ladder) as well as in situ nick end labeling. Under the same experimental conditions, estradiol-17beta and two of its other metabolites, estriol and 2-methoxyestriol (< or =10 microM), did not have an apoptotic effect on BPAEC. 2-ME activated stress-activated protein kinase (SAPK)/c-Jun amino-terminal protein kinase in BPAEC in a concentration-dependent manner. The activity of SAPK was increased by 170 +/- 27% and 314 +/- 22% over the basal level in the presence of 0.4 and 2 microM 2-ME (n = 3-6), respectively. The activation of SAPK was detected at 10 min, peaked at 20 min, and returned to basal levels at 60 min after exposure to 2-ME. Inhibition of SAPK/c-Jun amino-terminal protein kinase activation by basic fibroblast growth factor, insulin-like growth factor, or forskolin reduced 2-ME-induced apoptosis. Immunohistochemical analysis of BPAEC indicated that 2-ME up-regulated expression of both Fas and Bcl-2. In addition, 2-ME inhibited BPAEC migration (IC50 = 0.71 +/- 0.11 microM, n = 4) and basic fibroblast growth factor-induced angiogenesis in the chick chorioallantoic membrane model. Taken together, these results suggest that promotion of endothelial cell apoptosis, thereby inhibiting endothelial cell proliferation and migration, may be a major mechanism by which 2-ME inhibits angiogenesis.
Mol Pharmacol 1997 Jun
PMID:2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas expression. 918 61

To clarify whether apoptosis is involved in endometriosis, we obtained eutopic endometrial tissues along with endometriotic tissues from the uterus (adenomyosis) (n = 12) and from the ovary (n = 12) from patients undergoing gynaecological surgery. Apoptosis-induced DNA fragmentation was detected by the TdT-mediated dUTP-biotin nick-end labelling method, and immunostaining with a monoclonal antibody against the Fas, Le(y) or B-cell leukaemia/lymphoma-2 (bcl-2) was also performed using the same tissue section. Analysis showed that apoptosis was occurring in all the samples of ovarian endometriotic tissue but in only two of the 12 adenomyotic and in five of the 24 eutopic endometrial tissue samples. In none of these cases was apoptosis correlated with phases of the menstrual cycle. The expression of bcl-2 in the eutopic endometrial and adenomyotic tissues was limited to the proliferative phase, and was observed in only one of the 12 cases of ovarian endometriosis. Fas and Ley were expressed randomly across a wide range in both the eutopic and ectopic endometrial tissues. These results suggest that the features of ovarian endometriosis are different from those of adenomyosis and eutopic endometrium in terms of the involvement of apoptosis. In addition, the regulatory mechanism involved in ovarian endometriosis may differ from that in other endometrial cells.
Mol Hum Reprod 1996 May
PMID:Detection of apoptosis in human endometriotic tissues. 923 97


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