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  • IN-VIVO  (30)
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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: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; VIVO ; DISEASE ; SITE ; SITES ; GENE ; transcription ; DIFFERENTIATION ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; TRANSCRIPTION FACTOR ; AP-1 ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; PROMOTER ; BETA ; immune response ; IMMUNE-RESPONSE ; LIVING CELLS ; CD28 ; C-REL ; T lymphocyte,transcription factor,cytokine
    Abstract: IL-4 plays a pivotal role in the development of the Th2 cell mediated humoral immune response and causes IgE-dependent allergic inflammatory diseases. Expression of IL-4 in differentiated Th2 cells is regulated by transcription factors such as NF-AT AP-1 and NF-IL6. Recently, increasing evidence indicates that the pro-inflammatory transcription factor NF-kappaB,13 may also participate in IL-4 expression. In this study, we show that the IL-4 promoter is synergistically activated by NF-kappaB, NF-AT and NF-IL6 at the NF-kappaB/NF-AT/NF-IL6 composite sites. In addition, we performed the chromatin immunoprecipitation technique to determine the functional relevance of NF-kappaB in the activation of the IL-4 gene in vivo. We demonstrate that NF-kappaB binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappaB nuclear translocation in living cells blocked binding of NF-kappaB to the IL-4 promoter. The data provide first evidence that NF-kappaB is directly involved in IL-4 transcription
    Type of Publication: Journal article published
    PubMed ID: 15048722
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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: Germany ; IN-VIVO ; THERAPY ; VIVO ; imaging ; QUANTIFICATION ; SYSTEM ; TOOL ; MICE ; ACTIVATION ; INJURIES ; MRI ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; MOUSE-BRAIN ; DAMAGE ; magnetic resonance imaging (MRI) ; RAT-BRAIN ; CD95 ; RE ; INCREASE ; RECOVERY ; manganese ; in vivo ; EXTENT ; CORD ; therapy monitoring ; CONNECTIONS ; MEMRI ; MNCL2 ; spinal cord injury (SCI)
    Abstract: In past decades, much effort has been invested in developing therapies for spinal injuries. Lack of standardization of clinical read-out measures, however, makes direct comparison of experimental therapies difficult. Damage and therapeutic effects in vivo are routinely evaluated using rather subjective behavioral tests. Here we show that manganese-enhanced magnetic resonance imaging (MEMRI) can be used to examine the extent of damage following spinal cord injury (SCI) in mice in vivo. Injection of MnCl2 solution into the cerebrospinal fluid leads to manganese uptake into the spinal cord. Furthermore, after injury MEMRI-derived quantitative measures correlate closely with clinical locomotor scores. Improved locomotion due to treating the detrimental effects of SCI with an established therapy (neutralization of CD95Ligand) is reflected in an increase of manganese uptake into the injured spinal cord. Therefore, we demonstrate that MEMRI is a sensitive and objective tool for in vivo visualization and quantification of damage and functional improvement after SCI. Thus, MEMRI can serve as a reproducible surrogate measure of the clinical status of the spinal cord in mice, potentially becoming a standard approach for evaluating experimental therapies
    Type of Publication: Journal article published
    PubMed ID: 16602070
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; Germany ; IN-VIVO ; DEATH ; DISEASE ; GENE ; PROGRAMMED CELL-DEATH ; FAS-LIGAND ; SIGNALING COMPLEX DISC ; CD95 ; TAU-PROTEIN ; SYSTEMIC-LUPUS-ERYTHEMATOSUS ; brain development ; death receptor ; branching ; CD95 ( Fas/Apo-1) ; LPR MICE ; neurite remodeling
    Type of Publication: Journal article published
    PubMed ID: 16003386
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; IN-VITRO ; tumor ; CELL ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; VIVO ; SYSTEM ; SYSTEMS ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; transcription ; EPITHELIA ; TUMORS ; validation ; MICE ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; SKIN ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; TARGET ; ISOFORM ; ENCODES ; PROMOTER ; PROMOTERS ; REQUIRES ; DNA-DAMAGE ; BAX ; HUMAN KERATINOCYTES ; SQUAMOUS-CELL CARCINOMA ; TARGETS ; RECEPTORS ; MICROARRAY ANALYSIS ; epidermis ; TRAIL ; DEATH RECEPTORS ; tetramer ; CD95 ; chemoresistance ; review ; TUMOR-SUPPRESSOR ; keratinocyte ; LIGHT ; TUMORIGENESIS ; development ; STRATIFIED EPITHELIA ; TARGET GENES ; analysis ; P63 ; death receptor ; EPITHELIUM ; EPITHELIAL TUMORS ; KINASE C-ABL ; P53-DEPENDENT APOPTOSIS ; REGULATES P73 ; USA ; function ; in vivo ; E ; PROTECTS ; MAINTENANCE ; inactive ; cornification ; FAMILY-MEMBER GENES ; GENE ENCODES ; IKK alpha ; ISOFORM EXPRESSION ; P53 HOMOLOG P63
    Abstract: The epidermis is a multilayered stratified epithelium, continuously regenerated by differentiating keratinocytes, that requires the transcription factor p63 for its development and maintenance. The TP63 gene encodes two major protein isoforms, TAp63 and Delta Np63, which have both transactivating and transcriptional repressing activities and regulate a wide range of target genes. TAp63 shows clear pro-apoptotic activity, mediated both by death receptors (CD95, TNF, TRAIL) and mitochondrial (bax, puma) pathways. Conversely, DNp63 protects from apoptosis by directly competing for TAp63 target promoters or sequestering it, forming inactive tetramers. Accordingly, p63 is expressed in epithelial tumors, contributing to both tumorigenesis and chemoresistance. However, the predominant physiological role of p63 is in epithelial development, as demonstrated by the lack of epidermis and other epithelia in p63-deficient mice. The specific role of TAp63 and DNp63 isoforms in epithelial development remains mostly unclear. Nevertheless, recent work utilizing in vivo genetic complementation of TAp63 and/or DNp63 into a p63 null background has shed new light into the specific functions of the two isoforms and allowed the in vivo validation of several p63 transcriptional targets, originally identified by microarray analysis in in vitro systems. However, despite concerted efforts to address the role of p63 isoforms, several questions remain unanswered. The main aim of this review is to critically discuss the data available in the literature and thoroughly analyze the models proposed
    Type of Publication: Journal article published
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  • 8
    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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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; CELL ; IN-VIVO ; MODEL ; VITRO ; VIVO ; SYSTEM ; DEATH ; MICE ; NEUROBLASTOMA-CELLS ; NITRIC-OXIDE SYNTHASE ; NITRIC-OXIDE ; IFN-GAMMA ; DONOR ; INDUCTION ; tumour ; DOWN-REGULATION ; INDUCED APOPTOSIS ; UP-REGULATION ; SIGNALING PATHWAYS ; KAPPA-B ; FACTOR-I ; TNF-ALPHA ; CD95 ; INCREASE ; FAS ; SYNTHASE ; MEDIATED APOPTOSIS ; death receptor ; function ; CANDIDATE ; nitric oxide ; in vivo ; immunology
    Abstract: Both the function and regulation of Fas expression in tumours is poorly understood. Our laboratory has reported that cultured, low Fas-expressing tumours undergo massive, yet reversible, up-regulation of cell surface Fas expression when injected into mice. The present study was aimed at determining what causes this enhanced Fas expression and whether the newly expressed Fas functions as a death receptor. Newly expressed Fas is indeed capable of inducing apoptosis. Based on our observation that Fas induction is reduced when tumour cells are injected into immune-deficient mice, we propose that Fas up-regulation in vivo involves the host's immune system. Accordingly, Fas up-regulation occurs in vitro when low Fas-expressing tumour cells are cocultured with lymphoid cells. Furthermore ascitic fluid extracted from tumour-bearing mice trigger Fas up-regulation in low Fas expressing tumours. This last finding suggests that a soluble factor(s) mediates induction of Fas expression. The best candidate for this soluble factor is nitric oxide (NO) based on the following observations: the factor in the ascites is unstable; Fas expression is induced to a lesser degree after injection into inducible NO synthase (NOS)-deficient (iNOS(-/-)) mice when compared to control mice; similarly, coculture with iNOS(-/-) splenocytes induces Fas less effectively than coculture with control splenocytes; and finally, the NO donor SNAP induces considerable Fas up-regulation in tumours in vitro. Our model is that host lymphoid cells in response to a tumour increase NO synthesis, which in turn causes enhanced Fas expression in the tumour
    Type of Publication: Journal article published
    PubMed ID: 17343612
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; tumor ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; SAMPLES ; TUMORS ; TIME ; PATIENT ; INDUCTION ; cell cycle ; CELL-CYCLE ; CYCLE ; treatment ; PROGRESSION ; resistance ; INDUCED APOPTOSIS ; PLASMA ; prostate cancer ; PROSTATE-CANCER ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DERIVATIVES ; HEPATOMA-CELLS ; EPITHELIAL-CELLS ; CARCINOMAS ; PHARMACOKINETICS ; AGENT ; SINGLE ; ONCOLOGY ; RE ; EX-VIVO ; SOLID TUMORS ; MEDIATED APOPTOSIS ; MOLECULAR-MECHANISMS ; LEVEL ; analysis ; methods ; PLASMA-LEVELS ; dexamethasone ; PROMOTION ; USA ; GLUCOCORTICOIDS ; prospective ; in vivo ; clinical study
    Abstract: Background: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. Material and Methods: We performed an overall statistical analysis of our new and recent data obtained with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. Results: New in vivo results demonstrate glucocorticoid - induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid - induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid - derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti - emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti - emetic agents did not counteract anticancer treatment and may be sufficient to replace gluco corticoids in cotreatment of carcinoma patients. Conclusion: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC - induced cell - type specific pro - and anti - apoptotic signalling
    Type of Publication: Journal article published
    PubMed ID: 17224649
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