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)

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-expressing cells. A matrix metalloproteinase-like enzyme cleaves the membrane-bound FasL to produce the soluble FasL (sFasL). Since FasL has been reported to play a pivotal role in the development of hepatitis, we evaluated clinical significance of serum sFasL in acute liver injury including acute self-limited and fulminant hepatitis. Serum sFasL in 19 patients including 12 with acute self-limited hepatitis and 7 with fulminant hepatitis was measured by an enzyme-linked immunosorbent assay (ELISA). The clinical data consisted of 18 indices including age, sex, liver function tests, hepatocyte growth factor (HGF), outcome and sFasL. Serum sFasL in fulminant hepatitis is 0.06+/-0.01 ng/ml, being identical to that in acute self-limited hepatitis, Serum sFasL is positively correlated with AST and ALT (p<0.0001 and p<0.0001). The factors associated with outcome of the patients were HGF, albumin, prothrombin time, platelet count, cholinesterase and leukocyte count in this order. Serum sFasL serves as an indicator of liver injury in acute self-limited and fulminant hepatitis.
Res Commun Mol Pathol Pharmacol 1998 Jul
PMID:Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. 975 39

Fas ligand (FasL) belongs to the TNF superfamily. It is induced in activated lymphocytes and eliminates Fas-positive lymphocytes, resulting in the down-regulation of immune responses. FasL has also been detected in tissues other than lymphoid cells. We investigated the expression and function of FasL on human colon cancer cells. FasL mRNA was detected by RT-PCR in all six colon cancer cell lines tested and was not found on fibroblasts. FasL protein was detected in DLD-1, LoVo, HCT-116 and RPMI 4788 cells by immunohistochemical staining. DLD-1, LoVo and WiDr were cytotoxic against mouse T lymphoma cells which were transfected with human Fas receptor cDNA. The cytotoxicity was significantly enhanced by phorbol 12-myristate 13-acetate (PMA) and ionomycin. Our data suggest that the FasL expressed in human colon cancer cells may be regulated by endogenous factors in the microenvironment of the host and facilitates the escape from the host immune system.
Res Commun Mol Pathol Pharmacol 1998 Jul
PMID:Human colon cancer cells express the functional Fas ligand. 975 40

The cell surface molecule Fas (CD95) is a member of the tumor necrosis factor receptor family. Ligation of the Fas receptor can lead to induction of apoptosis in inflammatory cells. It has been suggested that expression of the Fas receptor and its ligand (FasL) in airway epithelium may modulate the inflammatory response commonly found in asthmatic lungs. We examined Fas and FasL expression on primary human tissues, on bronchial epithelial cells in primary culture, and on the immortalized human airway epithelial cell line, 1HAEo-. Receptor and ligand expression were demonstrated using multiple antibodies and multiple techniques, including immunohistochemistry, flow cytometry, Western blots, and reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining demonstrated that both columnar and basal cells of intact human lung tissues expressed cell surface Fas and FasL. In addition, both primary cultured and immortalized 1HAEo- cells expressed cell surface Fas and FasL, as demonstrated by flow cytometry; expression of Fas and FasL was confirmed at the transcription level using RT-PCR and, for additional confirmation of FasL, using Western blots. We demonstrate that both Fas and FasL are expressed by human airway epithelial cell subtypes. Expression of these molecules may play an important role in regulation of the inflammatory response.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Expression of Fas (CD95) and FasL (CD95L) in human airway epithelium. 976 49

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IkappaB superrepressor, tumor necrosis factor alpha (TNFalpha) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFalpha induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFalpha treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFalpha treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFalpha-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing DeltaFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFalpha, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFalpha-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.
Mol Cell Biol 1998 Nov
PMID:The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. 977 51

Cytotoxic lymphocytes (CLs) induce caspase activation and apoptosis of target cells either through Fas activation or through release of granule cytotoxins, particularly granzyme B. CLs themselves resist granule-mediated apoptosis but are eventually cleared via Fas-mediated apoptosis. Here we show that the CL cytoplasmic serpin proteinase inhibitor 9 (PI-9) can protect transfected cells against apoptosis induced by either purified granzyme B and perforin or intact CLs. A PI-9 P1 mutant (Glu to Asp) is a 100-fold-less-efficient granzyme B inhibitor that no longer protects against granzyme B-mediated apoptosis. PI-9 is highly specific for granzyme B because it does not inhibit eight of the nine caspases tested or protect transfected cells against Fas-mediated apoptosis. In contrast, the P1(Asp) mutant is an effective caspase inhibitor that protects against Fas-mediated apoptosis. We propose that PI-9 shields CLs specifically against misdirected granzyme B to prevent autolysis or fratricide, but it does not interfere with homeostatic deletion via Fas-mediated apoptosis.
Mol Cell Biol 1998 Nov
PMID:Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. 977 54

Protein kinase Cdelta (PKCdelta) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. A role for PKCdelta in apoptosis is supported by the finding that overexpression of the catalytic fragment of PKCdelta (PKCdelta CF) in cells is associated with the appearance of certain characteristics of apoptosis. However, the functional relationship between PKCdelta cleavage and induction of apoptosis is unknown. The present studies demonstrate that PKCdelta associates constitutively with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The results show that PKCdelta CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs with PKCdelta CF inhibits the function of DNA-PKcs to form complexes with DNA and to phosphorylate its downstream target, p53. The results also demonstrate that cells deficient in DNA-PK are resistant to apoptosis induced by overexpressing PKCdelta CF. These findings support the hypothesis that functional interactions between PKCdelta and DNA-PK contribute to DNA damage-induced apoptosis.
Mol Cell Biol 1998 Nov
PMID:Inactivation of DNA-dependent protein kinase by protein kinase Cdelta: implications for apoptosis. 977 85

The in situ apoptosis and the expression of molecules involved in this process, such as Bcl-2, Fas, and its ligand, Fas ligand (FasL), were examined in bronchial biopsies from healthy control subjects and from steroid-untreated or -treated asthmatics, using terminal transferase-mediated deoxyuridyltriphosphate nick-end labeling and immunohistochemical techniques, respectively. Bronchial submucosa from steroid- untreated asthmatics showed an increase in the number of eosinophils and a decrease in that of apoptotic cells compared with that of control subjects, but no significant changes in the number of T lymphocytes or in that of cells expressing Bcl-2, Fas, or FasL. Treatment with steroids reduced airway eosinophilia and augmented the proportion of apoptotic eosinophils. Compared with control subjects or untreated patients, steroid-treated asthmatics exhibited increased expression of Bcl-2, Fas, FasL, and of proliferating cell nuclear antigen (PCNA) in their bronchial epithelium, without changes in the number of apoptotic cells. Moreover, the intensity of the expression of Bcl-2, Fas, and FasL correlates well with that of PCNA. We conclude that steroids may reduce the inflammatory cell infiltrate in the bronchial submucosa in part by promoting eosinophil apoptosis and by inducing the expression of FasL on bronchial epithelial cells. Treatment with steroids may also augment survival and proliferation of epithelial cells, possibly via the expression of Bcl-2 and PCNA.
Am J Respir Cell Mol Biol 1998 Nov
PMID:Apoptosis, proliferation, and expression of Bcl-2, Fas, and Fas ligand in bronchial biopsies from asthmatics. 980 39

Biology of HIV-1 associated neoplasias is modulated by viral and host factors. In addition the development of tumors and their response to therapy may be further influenced by long-term treatment of HIV-1 patients with nucleoside analogs such as AZT (3'-azido-3'deoxythymidine), ddI (2',3'-dideoxyinosine), ddC (2',3'-dideoxycytidine), d4T (2',3'-didehydro-2'3'-dideoxythymidine), and 3TC [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] alone or in combination. As these compounds can trigger mechanisms involved in chemoresistance, we tested whether prolonged in vitro treatment of H9 cells (T-cell lymphoma) with AZT alters sensitivity of lymphoma cells to antitumor agents used for AIDS-associated malignancies. H9 cells grown for more than two years in medium containing 250 microM AZT developed resistance to the toxic effects of AZT while retaining sensitivity for other nucleoside analogs including ddC or cytosine arabinoside (ARA-C). These cells designated H9rAZT250 were 2 to 10-fold less sensitive to the toxic effects of antitumor agents, including cisplatin (CDDP), vincristine (VCR), doxorubicin (DOX) and etoposide (VP-16), when compared with parental H9 cells. The resistance of H9rAZT250 cells to antitumor agents was associated with inhibition of apoptosis as demonstrated by ultrastructural investigations and DNA-fragmentation assay (ELISA). The expression of the antiapoptotic gene bcl-2 was increased in H9rAZT250 cells while expression of other genes involved in the regulation of apoptosis such as c-myc, p53 and Fas was not changed. These results demonstrate that prolonged in vitro treatment of H9 lymphoma cells with AZT results in the development of resistance to antitumor agents in association with inhibition of apoptosis and increased expression of bcl-2. Therefore AZT long-term treatment of some HIV-1 patients with malignancies may have affected behavior of tumor cells including response to therapy.
Int J Mol Med 1998 Dec
PMID:Azidothymidine resistance of H9 human T-cell lymphoma cells is associated with decreased sensitivity to antitumor agents and inhibition of apoptosis. 985 Jul 37

Gene expression involving apoptosis in the hematopoietic system is reviewed. In normal and hematological disorders, Fas-Fas ligand and tumor necrosis factor-alpha-receptor interaction play a major role in enhancing apoptosis. On the other hand, bcl-2 or certain novel proteins (including FADD, RIP, TRADD and sentrin) prevent apoptosis. Apoptosis is involved in myelodysplastic syndrome and pathogenesis of leukemia. Expression of Fas antigen plays a role in negative regulation of hematopoiesis in the bone marrow as does interferon-gamma.
Int J Mol Med 1998 Jan
PMID:Apoptosis-gene expression in hematopoietic system: normal and pathological conditions (Review). 985 9


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