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  • 1
    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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  • 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: 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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  • 6
    Keywords: APOPTOSIS ; CELL ; T-CELL ; LYMPHOMA ; resistance ; sensitivity ; USA
    Type of Publication: Journal article published
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  • 7
    Abstract: OBJECTIVE: This study evaluates the inter-site and intra-site reproducibility of 7 Tesla brain imaging and compares it to literature values for other field strengths. MATERIALS AND METHODS: The same two subjects were imaged at eight different 7 T sites. MP2RAGE, TSE, TOF, SWI, EPI as well as B1 and B0 field maps were analyzed quantitatively to assess inter-site reproducibility. Intra-site reproducibility was measured with rescans at three sites. RESULTS: Quantitative measures of MP2RAGE scans showed high agreement. Inter-site and intra-site reproducibility errors were comparable to 1.5 and 3 T. Other sequences also showed high reproducibility between the sites, but differences were also revealed. The different RF coils used were the main source for systematic differences between the sites. CONCLUSION: Our results show for the first time that multi-center brain imaging studies of the supratentorial brain can be performed at 7 T with high reproducibility and similar reliability as at 3T. This study develops the basis for future large-scale 7 T multi-site studies.
    Type of Publication: Journal article published
    PubMed ID: 27097904
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  • 8
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; SURVIVAL ; CELL ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; PROTEIN ; PROTEINS ; transcription ; TRANSDUCTION ; ACTIVATION ; FAMILY ; primary ; INDUCTION ; hepatocytes ; ACTIVATED PROTEIN-KINASE ; MEMBER ; SIGNAL ; CLEAVAGE ; CELL-SURVIVAL ; DAMAGE ; KAPPA-B ; RAT HEPATOCYTES ; CASPASE 8 ; Bcl-2 ; HUMAN HEPATOCYTES ; CD95 ; PHOSPHOINOSITIDE 3-KINASE ; MEDIATED APOPTOSIS ; SIGNAL TRANSDUCER ; ACID-INDUCED APOPTOSIS ; ACUTE LIVER-INJURY ; FULMINANT HEPATIC-FAILURE ; MITOCHONDRIAL RELEASE
    Abstract: CD95 (APO-1/Fas)-mediated apoptosis of hepatocytes plays a central role in the pathophysiology of various human liver diseases. Hepatocyte growth factor (HGF) was shown to exert antiapoptotic functions in rodent hepatocytes. We previously showed that primary human hepatocytes (PHH) are a valuable toot for the investigation of apoptotic processes in liver cells. In this study, we analyzed the influence of HGF on CD95-mediated apoptosis of PHH and its molecular determinants. HGF significantly inhibited CD95-mediated apoptosis of PHH as well as cleavage of caspase-8 and poly (ADP-ribose)polymerase. HGF transcriptionally induced the expression of the anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1). In contrary, HGF did not alter the expression levels of Bcl-2 or Bcl-(XL). HGF activated survival pathways such as the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK and the signal transducer and activator of transcription 3 (STAT3) pathway. Notably, HGF triggered serine(727)-but not tyrosine(705)-phosphorylation of STAT3. Pretreatment of PHH with the PI3K inhibitor LY294002 as well as adenoviral transduction of dominant negative Akt1 prevented HGF-mediated Mcl-1 induction and reversed the antiapoptotic effects of HGF. In conclusion, HGF confers survival of PHH by activation of the PI3K/Akt pathway. PI3K/Akt activation by HGF results in the induction of antiapoptotic proteins such as Mcl-1. Thus, application of HGF may be a therapeutic approach to prevent CD95-mediated hepatocellular damage in human liver diseases
    Type of Publication: Journal article published
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  • 9
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CELL ; Germany ; KINASE ; PATHWAY ; VITRO ; DEATH ; SITES ; PROTEIN ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; INDUCTION ; mechanisms ; T cells ; T-CELL ; T-CELLS ; PHOSPHORYLATION ; STIMULATION ; MUTATION ; LYMPHOCYTES ; REGION ; MUTATIONS ; BETA ; RECRUITMENT ; immune response ; IMMUNE-RESPONSE ; TCR ; REGULATOR ; REQUIREMENT ; PHOSPHORYLATION SITES ; ANTIGEN RECEPTORS ; HEMATOPOIETIC PROGENITOR KINASE-1 ; IKK ; CONSENSUS ; PKC ; USA ; A KINASE ; CBM complex ; IKK ACTIVATION ; MEDIATOR
    Abstract: Activation of the NF-kappa B pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-kappa B activation. Knock-down of HPK1 abrogates TCR-induced IKK beta and NF-kappa B activation, whereas active HPK1 leads to increased IKK beta activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-kappa B activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC theta consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kappa B activation and IL-2 expression in CARMA1-deficient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappa B response upon TCR stimulation
    Type of Publication: Journal article published
    PubMed ID: 19706536
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  • 10
    Abstract: Histone-deacetylase (HDAC) inhibitors (HDACi) can block proliferation and induce intrinsic apoptosis in human papillomavirus (HPV)-positive cervical carcinoma cells, independently of copy number and integration locus of the viral DNA. Using HPV18-positive HeLa cells as model systems, we provide evidence that HDAC inhibition leads to transcriptional suppression of c-FLIP, which negatively regulates extrinsic apoptosis by preventing the recruitment of caspase-8 to the death-inducing signaling complex. Consequently, HDACi pretreatment renders cervical cancer cells sensitive to TNFalpha and TRAIL-induced apoptosis. Already 5-hr incubation with TNFalpha or TRAIL was sufficient to eradicate more than 40% of pretreated cells, which are normally completely refractory against respective death-ligands alone even under long-term incubation. Ectopic expression of either short or long splicing variant of c-FLIP, c-FLIP(s) and c-FLIP(L), abrogates sensitization. Notably, combined HDACi/death ligand treatment did not result in eradication of HPV-negative cells, despite the fact that both c-FLIP isoforms were also downregulated. However, knocking down HPV18 E6/E7 transcription by siRNA prevents HDACi/death-ligand mediated apoptosis, indicating that continued viral oncogene expression favors sensitization. Here, the viral oncoprotein E7 seems to play a functional role, since only HPV16 E7-immortalized human keratinocytes underwent significant apoptosis on HDACi/TNFalpha treatment, whereas keratinocytes expressing only HPV16 E6 or primary keratinocytes were refractory under the same experimental conditions. Taken together, HDACi can be considered as an alternative therapeutic option in the treatment of premalignant and malignant lesions.
    Type of Publication: Journal article published
    PubMed ID: 20087862
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