Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell surface receptor Fas (FasR, Apo-1, CD95) and its ligand (FasL) are mediators of apoptosis that have been shown to be implicated in the peripheral deletion of autoimmune cells, activation-induced T cell death, and one of the two major cytolytic pathways mediated by CD8+ cytolytic T cells. To gain further understanding of the Fas system., we have analyzed Fas and FasL expression during mouse development and in adult tissues. In developing mouse embryos, from 16.5 d onwards, Fas mRNA is detectable in distinct cell types of the developing sinus, thymus, lung, and liver, whereas FasL expression is restricted to submaxillary gland epithelial cells and the developing nervous system. Significant Fas and FasL expression were observed in several nonlymphoid cell types during embryogenesis, and generally Fas and FasL expression were not localized to characteristic sites of programmed cell death. In the adult mouse, RNase protection analysis revealed very wide expression of both Fas and FasL. Several tissues, including the thymus, lung, spleen, small intestine, large intestine, seminal vesicle, prostate, and uterus, clearly coexpress the two genes. Most tissues constitutively coexpressing Fas and FasL in the adult mouse are characterized by apoptotic cell turnover, and many of those expressing FasL are known to be immune privileged. It may be, therefore, that the Fas system is implicated in both the regulation of physiological cell turnover and the protection of particular tissues against potential lymphocyte-mediated damage.
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PMID:Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. 860 66

The cell surface receptor Fas (FasR, Apo-1, CD95) and its ligand (FasL) are mediators of apoptosis which have been shown to be implicated in peripheral deletion of autoimmune cells, activation-induced T cell death, and one of the two major cytolytic pathways mediated by CD8+ cytolytic T cells. Analysis of FasL expression during mouse embryogenesis and in adult tissues reveals that FasL, although initially thought to be restricted to lymphoid cells, is constitutively expressed in a wide array of non lymphoid tissues. FasL mRNA is detectable in mouse embryos from 16.5-d onwards in epithelial cells of the submaxillary gland, and neurons of the developing nervous system. In general, FasL mRNA was not detectable in characteristic sites of embryonic programmed cell death. In the adult mouse, by RNase protection analysis, FasL mRNA is detectable in all 20 tissues tested except for the heart and pancreas. Similar analysis performed simultaneously for Fas indicates that several tissues, including the thymus, lung, spleen, small intestine, liver, seminal vesicle, prostate and uterus co-express the two genes. Most tissues constitutively co-expressing Fas and FasL in the adult mouse are characterized by apoptotic cell turnover, and many of those expressing FasL are known to be immune-privileged. The pattern of FasL expression in mice suggests that FasL may be implicated in the regulation of physiological cell turnover, and the protection of tissues against potential lymphocyte mediated damage.
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PMID:Constitutive Fas ligand expression in several non-lymphoid mouse tissues: implications for immune-protection and cell turnover. 895 Apr 73

CD95 antigen (also known as Fas or Apo-1) and Fas ligand play key roles in apoptosis of cells of the immune system, function as effector molecules of cytotoxic T lymphocytes, and function in the elimination of activated lymphocytes during the downregulation of the immune response. The critical roles of the Fas-Fas ligand system in apoptosis suggest that its inactivation may be involved in malignant transformation. We analyzed the expression of Fas antigen on adult T-cell leukemia (ATL) cells by flow cytometry and found that Fas antigen expression was absent in a case of ATL and markedly decreased in another case among 47 cases examined. Apoptosis could not be induced in the Fas-negative ATL cells by antibody against Fas antigen. Sequencing of reverse transcription-polymerase chain reaction products of the Fas genes in the Fas negative cells showed two types of aberrant transcripts: one had a 5-bp deletion and a 1-bp insertion in exon 2, and the other transcript lacked exon 4. These mutations caused the premature termination of both alleles, resulting in the loss of expression of surface Fas antigen. These aberrant transcripts were not detected in a nonleukemic B-cell line from the same patient. An RNase protection assay of the Fas gene showed mutations in 2 additional cases with Fas-positive ATL cells of 35 cases examined: 1 case lacked exon 4 and the other was a silent mutation. In the Fas antigen-negative case, leukemic cells were resistant to anticancer drugs in vivo, indicating that the loss of expression of Fas antigen may be associated with a poor response to anticancer drugs. Indeed, Fas-negative ATL cells were resistant to adriamycin-induced apoptosis in vitro, which is consistent with the finding that ATL in this case was resistant to chemotherapy. These findings indicate that mutation of the Fas gene may be associated with the progression of ATL and with resistance to anticancer drugs.
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PMID:Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells. 957 32

Onconase (ONC) a ribonuclease from amphibian oocytes is cytostatic and cytotoxic to many human tumor lines, shows in vivo antitumor activity in mouse tumor models and is in Phase III clinical trials. The mechanism of antitumor activity of ONC is presumed to be due to its internalization, degradation of intracellular RNA and suppression of protein synthesis. Since apoptosis triggered by TNF-alpha is known to be potentiated by inhibitors of protein synthesis, we have hypothesized that it also may be potentiated by ONC. Indeed, preincubation of U-937 or HL-60 leukemic cells with 0.17 microM ONC rendered them more sensitive to induction of apoptosis by TNF-alpha or antibody to CD95 (Fas). The mechanism by which ONC amplifies the effect of TNF-alpha may involve suppression of induction of the survival genes whose expression is triggered by activation of NFkB by this factor.
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PMID:Potentiation of tumor necrosis factor induced apoptosis by onconase. 962 97

Werner's syndrome (WS) is an inherited disease with clinical symptoms which resemble premature aging. The Werner's syndrome gene (WRN), which is located on human chromosome 8p12, encodes a predicted protein of 1432 amino acids and shows significant similarity to DNA helicases. We have cloned the full-length mouse cDNA homologue of the human WRN gene encoding a predicted protein of 1320 amino acids and have obtained a full-length 70 kb genomic clone containing the moWRN gene. This gene has been mapped to chromosome 8A3 in mice. The expression of the moWRN gene was increased during apoptosis after IL-2 deprivation, and decreased in the spleen of aged mice. Lymphoid cells isolated from a patient with WS exhibited increased apoptosis after incubation with anti-Fas but not after incubation with the topoisomerase inhibitor VP16. RNase protection reviled dysregulation of the ICE family of apoptosis molecules in the WS cell line. These results indicate that the WS helicase is involved in certain pathways of apoptosis, and defective WS gene expression leads to accumulation of cells that are highly susceptibility to Fas-induced apoptosis.
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PMID:Effect of age and apoptosis on the mouse homologue of the huWRN gene. 968 77

Cytokine-driven activation of hepatic stellate cells (HSC) in tissue injury and inflammation is a key pathogenetic event in liver fibrogenesis leading to an expanded pool of matrix producing myofibroblasts (MFB) which represent the transformed counterpart of HSC. We hypothesize that expansion of the pool of MFB might also be accomplished by modulation of apoptosis, which plays an opposite and complementary role to mitosis in the cellular homeostasis. We characterized the susceptibility of HSC in primary culture and of MFB in secondary culture to apoptosis induced by the soluble Fas ligand (sFasL) and related the effects to the expression levels of Fas (APO-1/CD95) and some major proapoptotic and contra-apoptotic protooncogenes. MFB showed a dose-dependent apoptotic reaction upon exposure to sFasL as evidenced by a strong increase of nucleosomal DNA fragments, loss of cellular DNA, positive TUNEL reaction, and annexin staining. The effect was found only if protein synthesis (cycloheximide) or RNA synthesis (actinomycin D) were arrested. HSC maintained for various times in primary culture were completely resistant to sFasL in combination with cycloheximide, but in late primary cultures (day 7 onward) an increasing susceptibility to sFasL-mediated apoptosis was developed. By semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis and alkaline phosphatase-anti-alkaline phosphatase staining Fas receptor was identified both in HSC and MFB at comparable expression levels. The expression of the contra-apoptotic protooncogenes bcl-2 and bcl-xl was found to be much stronger in early HSC than in late HSC and MFB as shown by ribonuclease protection assay. The expression of bcl-2 was additionally confirmed by semiquantitative RT-PCR and immunoblotting. Proapoptotic bax was found in comparable quantities at the RNA level in HSC and MFB but at the protein level MFB showed increased bax expression. It is concluded that transformation of HSC to MFB is paralleled by an increasing sensitivity to sFasL-mediated apoptosis, which might be related to a strong decrease of bcl-2 and bcl-xl expression, leading to a preponderance of proapoptotic gene expression in MFB. Modulation of apoptotic susceptibility of transforming HSC could be an important complementary pathway in the pathogenesis of fibrosis.
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PMID:Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. 969 16

Interferon gamma (IFNgamma) induces apoptosis in purified human erythroid colony-forming cells (ECFC) and inhibits cell growth. Fas (APO-1; CD95) and Fas ligand (FasL) mediate apoptosis induced by IFNgamma, because Fas is significantly upregulated by IFNgamma, whereas Fas ligand is constitutively present in the ECFC and neutralization of FasL greatly reduces the apoptosis. Because conversion of caspases from their dormant proenzyme forms to active enzymes has a critical role in transducing a cascade leading to apoptosis, we performed further studies of the expression and activation of caspases in normal human and IFNgamma-treated day-6 ECFC to better understand the mechanism of IFNgamma action in producing this cell death. RNase protection assays showed that the caspase-1, -2, -6, -8, and -9 mRNAs were upregulated by IFNgamma, whereas the caspase-5 and -7 mRNAs were not increased. Western blots showed that FLICE/caspase-8 was upregulated and activated by 24 hours of incubation with IFNgamma. FADD was not similarly altered by incubation with IFNgamma. Western blots of ICE/caspase-1, which might be required for amplification of the initial FLICE activation signal, showed that pro-ICE expression significantly increased after treatment with IFNgamma for 24 hours and cleavage of pro-ICE also increased. CPP32/apopain/caspase-3, responsible for the proteolytic cleavage of poly (ADP) ribose polymerase (PARP), was also studied and treatment of ECFC with IFNgamma resulted in an increased concentration of caspase-3 by 24 hours and a clear induction of enzyme activation by 48 hours, which was identified by the appearance of its p17-kD peptide fragment. The cleavage of PARP was demonstrated by an obvious increase of the 89-kD PARP cleavage product, which was observed at almost the same time as caspase-3 activation in the IFNgamma-treated cells, whereas untreated ECFC showed little change. Peptide inhibitors of the caspase proteins, DEVD-fmk, DEVD-cho, YVAD-cho, and IETD-fmk, were incubated with the ECFC to obtain further evidence for the involvement of caspases in IFNgamma-induced apoptosis. The activation of FLICE/caspase-8 and CPP32/caspase-3 and cleavage of PARP clearly were inhibited, but the reduction of cell growth due to apoptosis, induced by IFNgamma, was only partially blocked by the presence of the inhibitors. These results indicate that IFNgamma acts on ECFC not only to upregulate Fas, but also to selectively upregulate caspases-1, -3, and -8, which are activated and produce apoptosis, whereas the concentrations of FasL and FADD are not demonstrably changed.
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PMID:Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. 1023 83

To develop an animal model of hepatitis C virus (HCV) infection, transgenic mice carrying part of the HCV cDNA (C980) encoding HCV-core and envelope proteins under control of the mouse class I major histocompatibility complex gene (H-2K) regulatory region were produced. HCV-C980 RNA and HCV-core protein were present in livers from line H36 as determined by RNase protection assay and immunostaining, respectively. More than 40 animals from line H36 were examined histologically. Most of these H36 mice after 10 months of age developed spontaneous focal infiltration of lymphocytes, hepatocyte necrosis, degeneration, and altered foci with mitotic hepatocytes. These pathological lesions were absent in livers from the age-matched control littermates. Liver cells from these H36 mice were sensitive to damage induced by intravenous administration of an anti-Fas antibody. It is suggested that HCV-C980 proteins by themselves may be one causative agent of liver cell injury in subjects with HCV infection.
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PMID:Hepatitis C virus structural proteins induce liver cell injury in transgenic mice. 1050 57

Human thyrocytes are resistant to Fas-mediated programmed cell death (PCD). It has been reported that a labile protein inhibitor is involved in the protection of thyrocytes from PCD, and its action can be reversed by incubation of thyrocytes with cycloheximide (CHX) during treatment with agonist anti-Fas Ab. Fas-associated phosphatase-1 (FAP-1) is a protein that has been shown to interact with the negative regulatory domain of Fas and block Fas-mediated apoptosis in FAP-1 transfected Jurkat cells. We investigated the possibility that FAP-1 might be involved in protection against Fas-mediated PCD in human thyrocytes. FAP-1 mRNA was detected in primary thyrocytes using a ribonuclease protection assay. The presence of FAP-1 protein was confirmed by immunohistochemical staining and flow cytometry using a polyclonal anti-FAP-1 Ab. FAP-1 protein also disappeared from thyroid cells in response to CHX. To determine whether FAP-1 is a functional inhibitor of PCD in thyrocytes, we incubated thyrocytes with synthetic SLV (Ac-SLV) tripeptide to compete with Fas for interaction with FAP-1. Thyrocytes treated with Ac-SLV tripeptide showed significantly increased cell death as compared to cells treated with control tripeptide. In addition, in the presence of a suboptimal concentration of CHX, the Ac-SLV tripeptide yielded a strong, synergistic increase in Fas-mediated PCD as compared to thyrocytes treated with control tripeptide. These results implicate FAP-1 as a regulator of Fas-induced PCD in thyrocytes.
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PMID:Characterization of FAP-1 expression and function in thyroid follicular cells. 1053 75

The Fas/FasL system mediates apoptosis in several different cell types, including T lymphocytes. Fas ligand (FasL), a 40-kD type II membrane protein also expressed in activated T cells, belongs to the tumor necrosis factor ligand family. We describe a new alternative splicing of mouse FasL, named FasL short (FasLs), cloned by reverse transcriptase-polymerase chain reaction. FasLs is encoded by part of exon 1 and part of exon 4 of FasL gene. The protein encoded by FasLs mRNA has a putative initiation code at position 756 and preserves the same reading frame as FasL, resulting in a short molecule lacking the intracellular, the transmembrane, and part of the extracellular domains. RNase protection and immunoprecipitation analysis showed that FasLs is expressed in nonactivated normal spleen cells and in hybridoma T cells and that it is upregulated upon activation by anti-CD3 monoclonal antibody (MoAb). Moreover, FasLs-transfected cells expressed soluble FasLs in the supernatant and became resistant to apoptosis induced by agonist anti-Fas MoAb. Thus, FasLs, a new alternative splicing of FasL, is involved in the regulation of Fas/FasL-mediated cell death.
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PMID:Cloning and expression of a short Fas ligand: A new alternatively spliced product of the mouse Fas ligand gene. 1055 56


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