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  • 1
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    Melino,G.+
    Keywords: RECEPTOR ; DEATH ; RECEPTORS ; LIFE ; DEATH RECEPTORS ; death-receptor
    Type of Publication: Book chapter
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; Germany ; DEATH ; PROTEIN ; PROTEINS ; LINES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; T-CELLS ; CELL-LINES ; VARIANTS ; UP-REGULATION ; NUMBER ; LINE ; cell lines ; REGULATOR ; SIGNALING COMPLEX DISC ; SIGNALING COMPLEX ; EFFECTOR ; CD95 APO-1/FAS ; CD95 ; HUMAN T-CELLS ; PROGRAM ; RE ; CASPASE-8 ; MEDIATED APOPTOSIS ; regulation ; CD95-MEDIATED APOPTOSIS ; SIGNALING COMPLEXES ; FLICE-INHIBITORY PROTEINS
    Abstract: c-FLIPs (c-FLICE inhibitory proteins) play an essential role in regulation of death receptor-induced apoptosis. Multiple splice variants of c-FLIP have been described on the mRNA level; so far only two of them, c-FLIPL and c-FLIPS, had been found to be expressed at the protein level. In this report, we reveal the endogenous expression of a third isoform of c-FLIP. We demonstrate its presence in a number of T and B cell lines as well as in primary human T cells. We identified this isoform as c-FLIPR, a death effector domain-only splice variant previously identified on the mRNA level. Importantly, c-FLIPR is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex upon CD95 stimulation. Several properties of c-FLIPR are similar to c-FLIPS: both isoforms have a short half-life, a similar pattern of expression during activation of primary human T cells, and are strongly induced in T cells upon CD3/CD28 costimulation. Taken together, our data demonstrate endogenous expression of c-FLIPR and similar roles of c-FLIPR and c-FLIPS isoforms in death receptor-mediated apoptosis
    Type of Publication: Journal article published
    PubMed ID: 15701649
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; Germany ; DEATH ; PROTEIN ; PROTEINS ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; INDUCTION ; INITIATION ; MOLECULAR-CLONING ; FLICE ; OLIGOMERIZATION ; SIGNALING COMPLEX ; CD95 ; COMPLEX DISC ; GEL-ELECTROPHORESIS ; signaling ; RE ; CAP3 ; MOUSE CASPASE-8
    Abstract: Formation of the CD95 (APO-1/Fas) death inducing signaling complex (DISC) plays a central role in CD95 signaling. Previously, CD95 DISC composition was analyzed by two-dimensional gel electrophoresis and four major cytotoxicity-associated proteins (CAP1-4) were found. CAP1 and CAP2 were defined to be unmodified and phosphorylated FADD, respectively. CAP4 was identified as procaspase-8a. CAP3, however, has remained elusive. In this study, we demonstrate that CAP3 is an intermediate of procaspase-8 processing. CAP3 is generated within seconds of DISC formation and subsequently processed to the prodomain of procaspase-8a that is known as p26 (CAP5). These findings lead to new insights into the mechanism of procaspase-8 processing and apoptosis initiation
    Type of Publication: Journal article published
    PubMed ID: 16179941
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; Germany ; KINASE ; PATHWAY ; DEATH ; PROTEIN ; PROTEINS ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; DENDRITIC CELLS ; T-CELLS ; BINDING ; CLEAVAGE ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; signaling ; MALIGNANT-CELLS ; RE ; FAS ; CASPASE ACTIVATION ; C-FLIP ; IKK ; death receptor ; FLICE-INHIBITORY PROTEINS ; LONG FORM ; RECEPTOR-INDUCED APOPTOSIS
    Abstract: c-FLIP proteins (isoforms: c-FLIPL, c-FLIPS, and c-FLIPR) play an essential role in the regulation of death receptor - induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor kappa B (NF-kappa B) activity by interacting with the I kappa B kinase (IKK) complex via the IKK gamma subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappa B activation and life/death decisions in lymphocytes and DCs
    Type of Publication: Journal article published
    PubMed ID: 16682493
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; Germany ; human ; PATHWAY ; PATHWAYS ; LINES ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; INDUCTION ; CELL-LINES ; CELL-DEATH ; NUMBER ; CELL-LINE ; LINE ; CANCER-CELLS ; CYTOCHROME-C ; cell lines ; DISC ; SIGNALING COMPLEX ; CD95 ; signaling ; PROGRAM ; RE ; FAS ; MEDIATED APOPTOSIS ; SIGNALING COMPLEXES ; ADAPTER MOLECULE
    Abstract: Caspase-2 was reported to be involved in a number of apoptotic pathways triggered by various stimuli. However, the molecular mechanism of procaspase-2 activation in the course of apoptosis remains poorly defined. In this report, we demonstrate that procaspase-2 is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex (DISC) in human T- and B-cell lines. We show that procaspase-2 is activated at the DISC on CD95 stimulation. Despite its presence at the DISC, caspase-2 does not initiate apoptosis on CD95 stimulation in caspase-8-deficient cell lines. Taken together, our data reveal that caspase-2 is activated at the DISC but does not play an initiating role in the CD95-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16822901
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; CELL ; Germany ; MODEL ; PATHWAY ; DEATH ; MONOCLONAL-ANTIBODY ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; INDUCTION ; T-CELLS ; BIOLOGY ; MOLECULAR-BIOLOGY ; SEQUENCE ; STIMULATION ; CLEAVAGE ; SUBUNIT ; CELL-DEATH ; INDUCED APOPTOSIS ; DOMAINS ; SIGNALING COMPLEX DISC ; SIGNALING COMPLEX ; CASPASE-8 ACTIVATION ; signaling ; molecular biology ; CASPASE-8 ; FAS ; EVENTS ; USA ; caspases ; OCCURS ; death-receptor
    Abstract: Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Procaspase-8 is activated at the death-inducing signaling complex (DISC). Previous studies suggested a two-step model of procaspase-8 activation. The first cleavage step occurs between the protease domains p18 and p10. The second cleavage step takes place between the prodomain and the large protease subunit (p18). Subsequently, the active caspase-8 heterotetramer p18(2)-p10(2) is released into the cytosol, starting the apoptotic signaling cascade. In this report, we have further analyzed procaspase-8 processing upon death receptor stimulation directly at the DISC and in the cytosol. We have found an alternative sequence of cleavage events for procaspase-8. We have demonstrated that the first cleavage can also occur between the prodomain and the large protease subunit (p18). The resulting cleavage product, p30, contains both the large protease subunit (p18) and the small protease subunit (p10). p30 is further processed to p10 and p18 by active caspases. Furthermore, we show that p30 can sensitize cells toward death receptor-induced apoptosis. Taken together, our data suggest an alternative mechanism of procaspase-8 activation at the DISC
    Type of Publication: Journal article published
    PubMed ID: 19528225
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; SURVIVAL ; CELL ; COMBINATION ; Germany ; KINASE ; MODEL ; DEATH ; PROTEIN ; MONOCLONAL-ANTIBODY ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; INDUCTION ; BIOLOGY ; PROTEIN-KINASE ; SIGNAL ; VARIANTS ; antibodies ; antibody ; MEMBRANE ; US ; MONOCLONAL-ANTIBODIES ; RECRUITMENT ; REGULATOR ; CD95 ; COMPLEX DISC ; CASPASE-8 ACTIVATION ; signaling ; PROGRAM ; RE ; CD95-MEDIATED APOPTOSIS ; analysis ; monoclonal antibodies ; USA ; - ; modeling
    Abstract: Recently we generated a mathematical model (Bentele, M., Lavrik, I., Ulrich, M., Stosser, S., Heermann, D. W., Kalthoff, H., Krammer, P. H., and Eils, R. ( 004) J. Cell Biol. 166, 839 - 851) of signaling in CD95(Fas/ APO-1)-mediated apoptosis. Mathematical modeling in combination with experimental data provided new insights into CD95-mediated apoptosis and allowed us to establish a threshold mechanism of life and death. Here, we further assessed the predictability of the model experimentally by a detailed analysis of the threshold behavior of CD95 signaling. Using the model predictions for the mechanism of the threshold behavior we found that the CD95 DISC (death-inducing signaling complex) is formed at the cell membrane upon stimulation with low concentrations of agonistic anti-APO-1 monoclonal antibodies; however, activation of procaspase-8 at the DISC is blocked due to high cellular FLICE-inhibitory protein recruitment into the DISC. Given that death signaling does not occur upon CD95 stimulation at low (threshold) anti-APO-1 concentrations, we also analyzed survival signaling, focusing on mitogen-activated protein kinase activation. Interestingly, we found that mitogen-activated protein kinase activation takes place under threshold conditions. These findings show that triggering of CD95 can signal both life or death, depending on the strength of the stimulus
    Type of Publication: Journal article published
    PubMed ID: 17347143
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  • 8
    Keywords: tumor ; CELL ; Germany ; DEATH ; PROTEIN ; PROTEINS ; LINES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; LIGAND ; DOMAIN ; BIOLOGY ; CELL-LINES ; MOLECULAR-BIOLOGY ; STIMULATION ; AMPLIFICATION ; MEMBRANE ; CELL-LINE ; TRAIL ; DISC ; FLICE ; SIGNALING COMPLEX ; INDUCED-PROXIMITY MODEL ; CASPASE-8 ACTIVATION ; CASPASE ; signaling ; molecular biology ; molecular ; RE ; C-FLIP ; USA ; B-CELL ; RECEPTOR-INDUCED APOPTOSIS ; FADD ; DEATH EFFECTOR DOMAIN ; cFLIP
    Abstract: Stimulation of CD95(APO-1/Fas) by its natural ligand CD95L (APO-1L/FasL) leads to the formation of the death-inducing signaling complex. Here we report that upon CD95 stimulation in several T and B cell lines, a novel signaling complex is formed, which we term complex II. Complex II is composed of the death effector domain proteins as follows: procaspase-8a/b, three isoforms of c-FLIP (c-FLIPL, c-FLIPS, c-FLIPR), and FADD. Notably, complex II does not contain CD95. Based on our findings we suggest that CD95 signaling includes two steps. The first step involves formation of the death-inducing signaling complex at the cell membrane. The second step involves formation of the cytosolic death effector domain protein-containing complex that may play an important role in amplification of caspase activation
    Type of Publication: Journal article published
    PubMed ID: 18635548
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  • 9
    Keywords: CANCER ; EXPRESSION ; tumor ; human ; NEW-YORK ; ENZYMES ; PROTEIN ; PROTEINS ; TUMORS ; RELEASE ; PATIENT ; RESPONSES ; MESSENGER-RNA EXPRESSION ; ANTIGEN ; T cell ; T-CELL ; antibodies ; TARGET ; ASSAY ; poly(ADP-ribose) polymerase ; COLON-CANCER ; CD8(+) ; ELISPOT ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; DOMAINS ; protein expression ; ONCOLOGY ; RECOMBINANT ; humoral immune response ; SEREX ; LEVEL ; biomarker ; methods ; ASSAYS ; TELOMERASE ACTIVITY ; USA ; B-CELL ; immunology ; quantitative ; ANTIBODY-RESPONSE ; epitope mapping ; HUMAN AUTOANTIBODIES ; HUMAN GASTRIC CARCINOMAS ; POLY(ADENOSINE DIPHOSPHATE-RIBOSE) POLYMERASE ; REPEAT-BINDING FACTOR-1 ; STERILE ALPHA-MOTIF ; telomerase-interacting proteins
    Abstract: Purpose Tankyrases 1 and 2 are telomere-associated poly(ADP-ribose) polymerases (PARP) that can positively regulate telomere elongation and interact with multiple cellular proteins. Recent reports implicated tankyrases as tumor antigens and potential targets of anticancer treatment. We examined expression of tankyrases in colon tumors and immune response to these enzymes in patients with different types of cancer. Methods mRNA and protein expression was evaluated by quantitative real-time RT-PCR and Western blotting, respectively. Humoral immune response to recombinant tankyrases was investigated by modified enzyme-linked immunoassays. Cellular immune response was analysed by ELISPOT and Cr-51 release assays. Results We found that both mRNA and protein levels of tankyrase 2 (TNKL) are upregulated in colon tumors. In contrast, protein level of tankyrase 1 (TNKS) is downregulated, while mRNA level shows variable changes. More than a quarter of colon cancer patients develop humoral immune response to at least one of the two tankyrases. In this study we mapped common and unique B-cell epitopes located in different domains of the two proteins. Additionally, we present evidence for T-cell responses both to epitopes that are unique for TNKL and to those shared between TNKL and TNKS. Conclusion Our study favors a biomarker usage of antibody response to tankyrases. Spontaneous CD8(+) T-cell responses to these enzymes are rare and further investigation is needed to evaluate tankyrases as potential targets for cancer immunotherapy
    Type of Publication: Journal article published
    PubMed ID: 18026951
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  • 10
    Keywords: SYSTEM ; DEATH ; LIFE
    Type of Publication: Journal article published
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