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  • MECHANISM  (44)
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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    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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  • 8
    Keywords: CELLS ; EXPRESSION ; IRRADIATION ; tumor ; CELL ; COMBINATION ; Germany ; DISEASE ; EXPOSURE ; TISSUE ; PATIENT ; NITRIC-OXIDE SYNTHASE ; NITRIC-OXIDE ; MECHANISM ; IMPACT ; mechanisms ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; FIELD ; LESIONS ; UP-REGULATION ; DAMAGE ; RECRUITMENT ; CLEARANCE ; FUTURE ; inflammation ; PROGRAM ; RE ; SYNTHASE ; chemokines ; REGULATORY T-CELLS ; SUBTYPES ; APOPTOTIC CELLS ; TESTS ; EVENTS ; SLE ; function ; nitric oxide ; regulatory T cells ; regulatory T cell ; PROTECTS ; CD4(+)CD25(+) ; ENVIRONMENTAL-FACTORS ; SKIN-LESIONS ; LUPUS-ERYTHEMATOSUS
    Abstract: The pathophysiology of cutaneous lupus erythematosus (CLE) has been investigated in numerous studies demonstrating that the combination of specific cellular and molecular events is leading to inflammation and tissue damage in this disease. However, a complete understanding of the diverse pathophysiological mechanisms and interactions does not exist. Various environmental factors influence the clinical expression of CLE and a striking relationship has emerged between sunlight exposure and the various subtypes of this disease. In the past years, photoprovocation tests with different ultraviolet (UV) wavelengths have been approved to be an optimal way to evaluate photosensitivity in patients with CLE. Furthermore, research on the pathogenetic mechanisms of UV-induced skin lesions has become an increasingly dynamic field and several new aspects of this disease could be identified. In this review, the impact of UV exposure that contributes to the manifestations of CLE is discussed and recently reported mechanisms in the pathophysiology of this disease are considered including the clearance of apoptotic cells, expression of inducible nitric oxide synthase, function of CD4(+)CD25(+) regulatory T cells, and the role of chemokines for lymphocyte recruitment. Elucidation of the relevant factors might lead to future development of effective strategies to prevent abnormal reactivity in patients with CLE
    Type of Publication: Journal article published
    PubMed ID: 16987823
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  • 9
    Keywords: APOPTOSIS ; CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; RNA ; MICE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; FAMILY ; primary ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; MEMBER ; MEMBERS ; TRANSGENIC MICE ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; Bcl-2 ; molecular ; MOLECULAR-BASIS ; RE ; FAMILIES ; LIFE ; LEVEL ; cell death ; ANTIGEN RECEPTORS ; progenitor ; SUPPRESSOR ; FAS LIGAND ; AICD ; HEMATOPOIETIC PROGENITOR KINASE-1 ; USA ; B-LYMPHOCYTES ; FATE ; FRAGMENT ; FAMILY-MEMBER BIM ; B-CELL ; KINASE-1 ; EXPANSION ; caspase-3 ; block ; B cells ; BCL-2 FAMILY ; COMPLEMENT ; FULL-LENGTH ; MEDIATED CLEAVAGE ; SMALL INTERFERING RNA
    Abstract: Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 17712048
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  • 10
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; GENERATION ; POPULATION ; PATIENT ; MECHANISM ; MARKER ; DONOR ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; DIFFERENCE ; resistance ; NUMBER ; AGE ; SURFACE ; BETA ; PHENOTYPE ; INDIVIDUALS ; TCR ; DE-NOVO ; PREVALENCE ; PERIPHERAL-BLOOD ; DECLINE ; MULTIPLE-SCLEROSIS ; GUIDELINES ; SUBPOPULATION ; DEFICIENCY ; SUBSET ; CAPACITY ; multiple sclerosis ; USA ; function ; correlation ; DEFECT ; immunology ; DEPLETION ; regulatory T cells ; HOMEOSTASIS ; EXPANSION ; DIAGNOSTIC-CRITERIA ; DYSFUNCTION ; GLATIRAMER ACETATE
    Abstract: The suppressive function of regulatory T cells (T-reg) is impaired in multiple sclerosis (MS) patients. The mechanism underlying the Treg functional defect is unknown. T-reg mature in the thymus and the majority of cells circulating in the periphery rapidly adopt a memory phenotype. Because our own previous findings suggest that the thymic output of T cells is impaired in MS, we hypothesized that an altered T-reg generation may contribute to the suppressive deficiency. We therefore determined the role of T-reg that enter the circulation as recent thymic emigrants (RTE) and, unlike their CD45RO(+) memory counterparts, express CD31 as typical surface marker. We show that the numbers of CD31(+)-coexpressing CD4(+)CD25(+)CD45RA(+)CD45RO-FOXP3(+) T-reg (RTE-T-g) within peripheral blood decline with age and are significantly reduced in MS patients. The reduced de novo generation of RTE-T-reg is compensated by higher proportions of memory T-reg, resulting in a stable cell count of the total T-reg population. Depletion of CD31(+) cells from T-reg diminishes the suppressive capacity of donor but not patient T-reg and neutralizes the difference in inhibitory potencies between the two groups. Overall, there was a clear correlation between T-reg-mediated suppression and the prevalence of RTE-T-reg, indicating that CD31-expressing naive T-reg contribute to the functional properties of the entire T-reg population. Furthermore, patient-derived T-reg, but not healthy T-reg, exhibit a contracted TCR V beta repertoire. These observations ggest that a shift in the homeostatic composition of T-reg subsets related to a reduced thymic-dependent de novo generation of RTE-T-reg with a compensatory expansion of memory Tmg may contribute to the Treg defect associated with MS
    Type of Publication: Journal article published
    PubMed ID: 17617625
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