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  • APOPTOSIS  (72)
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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; PATHWAY ; PATHWAYS ; VITRO ; SYSTEM ; DEATH ; DISTINCT ; TIME ; COMPLEX ; COMPLEXES ; primary ; T cell ; T cells ; T-CELL ; T-CELLS ; culture ; activation-induced cell death ; CELL-DEATH ; UP-REGULATION ; CYCLE PROGRESSION ; DISPLAY ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; B-CELLS ; immune response ; IMMUNE-RESPONSE ; IL-2 ; INITIATION ; FAS-MEDIATED APOPTOSIS ; DISC ; SIGNALING COMPLEX ; ANTIGEN RECEPTOR ; C-FLIPSHORT ; CD95 ; COMPLEX DISC ; FLICE-INHIBITORY PROTEIN ; INTERLEUKIN-2 RECEPTOR
    Abstract: The CD95 (APO-1/Fas) system plays a critical role in activation-induced cell death (AICD) of T cells. We previously described two distinct CD95 (APO-1/Fas) signaling pathways: 1) type I cells show strong death-inducing signaling complex (DISC) formation and mitochondria-independent apoptosis and 2) DISC formation is reduced in type II cells, leading to mitochondria-dependent apoptosis. To investigate the relevance of these pathways, we set up an in vitro model that mimics the initiation and the down phase of an immune response, respectively. Freshly activated human T cells (initiation) are resistant toward CD95-mediated AICD despite high expression of CD95. We previously reported that these T cells show reduced DISC formation. In this study, we show that freshly activated T cells are CD95-type II cells that show high expression levels of Bcl-x(L) and display a block in the mitochondrial apoptosis pathway. Furthermore, we show that, upon prolonged culture (down phase), human T cells undergo a switch from type II to type I cells that renders T cells sensitive to CD95-mediated AICD. Finally, we demonstrate that this switch is dependent on the presence of IL-2. Our observations reveal for the first time that the existence of coexisting CD95 signaling pathways is of physiological relevance
    Type of Publication: Journal article published
    PubMed ID: 12960316
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; tumor ; KINASE ; DEATH ; PROTEIN ; MONOCLONAL-ANTIBODY ; DEATH DOMAIN ; TUMOR-NECROSIS-FACTOR ; COMPLEX ; LIGAND ; COMPLEXES ; DOMAIN ; mechanisms ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; treatment ; antibodies ; antibody ; INDUCED APOPTOSIS ; MODULATION ; PATHOGENESIS ; DISC ; SIGNALING COMPLEX ; ANTI-APOPTOTIC MOLECULE ; CASPASE-8 ACTIVATION ; DEATH-EFFECTOR DOMAIN ; FAS/TNFR1- INDUCED APOPTOSIS ; INHIBITORY PROTEIN ; INTEGRIN ACTIVATION ; INTRACELLULAR REGULATION ; SURFACE ANTIGEN
    Abstract: Fas, upon cross-linking with Fas ligand (FasL) or Fas agonistic antibody, transduces apoptotic yet also proliferative signals, which have been implicated in tumor pathogenesis. In this study, we investigated the molecular mechanisms that control Fas-mediated signaling in glioma cells. Fas agonistic antibody, CH-11, induced apoptosis in sensitive glioma cells through caspase-8 recruitment to the Fas-mediated death-inducing signaling complex (DISC) where caspase-8 was cleaved to initiate apoptosis through a systematic cleavage of downstream substrates. In contrast, CH-11 stimulated cell growth in resistant glioma cells through recruitment of c-FLIP (cellular Fas-associated death domain (FADD)-like interleukin-1beta- converting enzyme (FLICE)-inhibitory protein) to the Fas- mediated DISC. Three isoforms of long form c-FLIP were detected in glioma cells, but only the phosphorylated isoform was recruited to and cleaved into a p43 intermediate form in the Fas-mediated DISC in resistant cells. Calcium/calmodulin- dependent protein kinase II (CaMK II) activity was up-regulated in resistant cells. Treatment of resistant cells with the CaMK II inhibitor KN-93 inhibited CaMK II activity, reduced c-FLIP expression, inhibited c-FLIP phosphorylation, and rescued CH-11 sensitivity. Transfection of CaMK II cDNA in sensitive cells rendered them resistant to CH-11. These results indicated that CaMK 11 regulates c-FLIP expression and phosphorylation, thus modulating Fas-mediated signaling in glioma cells
    Type of Publication: Journal article published
    PubMed ID: 12496285
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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; DEATH ; PROTEIN ; PROTEINS ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; primary ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; DOWN-REGULATION ; culture ; IMMUNE-RESPONSES ; resistance ; CELL-DEATH ; UP-REGULATION ; immune response ; IMMUNE-RESPONSE ; CASPASE 8 ; FAS-MEDIATED APOPTOSIS ; SIGNALING COMPLEX ; EFFECTOR ; Bcl-2 ; FLICE-INHIBITORY PROTEIN ; CASPASE-8 ACTIVATION ; ACQUIRE
    Abstract: In the early phase of an immune response, T cells are activated and acquire effector functions. Whereas these short term activated T cells are resistant to CD95-mediated apoptosis, activated T cells in prolonged culture are readily sensitive, leading to activation-induced cell death and termination of the immune response. The translation inhibitor, cycloheximide, partially overcomes the apoptosis resistance of short term activated primary human T cells. Using this model we show in this study that sensitization of T cells to apoptosis occurs upstream of mitochondria. Neither death-inducing signaling complex formation nor expression of Bcl-2 proteins is altered in sensitized T cells. Although the caspase-8 inhibitor c-FLIPlong was only slightly down-regulated in sensitized T cells, c-FLIPshort became almost undetectable. This correlated with caspase-8 activation and apoptosis. These data suggest that c-FLIPshort, rather than c-FLIPlong, confers resistance of T cells to CD95-mediated apoptosis in the context of immune responses
    Type of Publication: Journal article published
    PubMed ID: 14764686
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  • 4
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; DEATH ; GENE ; PROTEIN ; RNA ; LINES ; gene transfer ; GENE-TRANSFER ; MECHANISM ; RAT ; CONTRAST ; mechanisms ; CELL-LINES ; PROTEIN-KINASE ; CLEAVAGE ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; MEMBRANE ; LINE ; KAPPA-B ; sensitivity ; OVEREXPRESSION ; cell lines ; CASPASE-8 CLEAVAGE ; SIGNALING COMPLEX ; CASPASE ; INHIBITORS ; RE ; GLIOMA ; CASPASE-8 ; OLIGONUCLEOTIDE ; NEURONS ; C-FLIP ; cell death ; ANTISENSE OLIGONUCLEOTIDE ; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME ; CEREBELLAR GRANULE NEURONS ; Fas/CD95 ; IMMUNE PRIVILEGE ; lifeguard ; PHOSPHATIDYLINOSITOL 3-KINASE ; PI3-kinase/ Akt
    Abstract: The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI3-kinase, overexpression of the inhibitory protein I kappa B, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e. g., inhibition of the PI3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL
    Type of Publication: Journal article published
    PubMed ID: 16033886
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; tumor ; Germany ; KINASE ; GENERATION ; DEATH ; PROTEIN ; MICE ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; SUPPRESSION ; ALPHA ; CLEAVAGE ; TRANSGENIC MICE ; activation-induced cell death ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; BETA ; T-LYMPHOCYTES ; sensitization ; TCR ; KAPPA-B ; sensitivity ; SIGNALING COMPLEX ; IMMUNOLOGICAL SYNAPSE ; T lymphocytes ; CD95 ; signaling ; PROGRAM ; RE ; INCREASE ; IMMUNE-SYSTEM ; cell death ; ANTIGEN RECEPTORS ; HPK1 ; progenitor ; INDUCE ; NEGATIVE REGULATION ; SWITCH ; AICD ; CD28 COSTIMULATION ; HEMATOPOIETIC PROGENITOR KINASE-1 ; IKK ; KINASE-C-THETA
    Abstract: Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous I kappa B kinase (IKK) complex and is crucial for TCR-mediated NF kappa B activation. While full-length HPK1 enhances IKK beta phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF kappa B activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NF kappa B upon TCR restimulation by binding to IKK alpha and IKK beta. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NF kappa B, and propose that HPK1 is a life/death switch in T lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 16341093
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  • 6
    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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  • 7
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; CELL ; Germany ; VITRO ; DEATH ; PATIENT ; MECHANISM ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUSCEPTIBILITY ; CD95 ligand ; CELL-DEATH ; LYMPHOCYTES ; INDIVIDUALS ; sensitivity ; MULTIPLE-SCLEROSIS ; GUIDELINES ; CD95 ; AUTOIMMUNE ENCEPHALOMYELITIS ; PROGRAM ; COSTIMULATION ; CD95-MEDIATED APOPTOSIS ; multiple sclerosis ; function ; DEFECT ; regulatory T cells ; EXPANSION ; regulatory T cell ; healthy individuals ; auto immunity ; DIAGNOSTIC-CRITERIA
    Abstract: Impaired suppressive function of CD4(+)CD25(high) regulatory T cells (T-reg) has been reported as a novel pathogenetic mechanism in Multiple sclerosis (MS). We addressed if high apoptosis sensitivity of MS-T-reg could explain this functional T-reg defect. T-reg from treatmentnaive MS patients showed high sensitivity towards CD95Ligand-mediated apoptosis and exhibited enhanced cell death to IL-2 and TCR-signal deprivation. Since susceptibility of T-reg to cell death was similar in MS patients and healthy controls, this cannot explain the inhibitory dysfunction of T-reg associated with MS. Furthermore, as cell death is not enhanced, therapeutic expansion of MS-T-reg in vitro should be a reasonable and novel therapeutic option. (c) 2006 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17092518
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  • 8
    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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  • 9
    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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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEINS ; RNA ; DRUG ; MONOCLONAL-ANTIBODY ; TUMORS ; RELEASE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; MECHANISM ; FAMILY ; DOMAIN ; INDUCTION ; mechanisms ; DOWN-REGULATION ; CYTOCHROME-C ; MITOCHONDRIA ; UNITED-STATES ; RECEPTORS ; OVEREXPRESSION ; TUMOR CELLS ; Bcl-2 ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CD95 ; CASPASE ; INHIBITORS ; signaling ; FAMILIES ; SOLID TUMORS ; CYCLOOXYGENASE-2 ; TUMOR-CELL ; death receptor ; downregulation ; function ; caspases ; DRUGS ; cyclooxygenase ; RELEVANCE ; NECROSIS ; MCL-1 ; CELECOXIB-INDUCED APOPTOSIS ; PRIMARY HUMAN HEPATOCYTES
    Abstract: Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNIF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cc leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release front mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small - interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria
    Type of Publication: Journal article published
    PubMed ID: 16849551
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