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  • 1
    Keywords: CELLS ; INHIBITOR ; Germany ; GENERATION ; SYSTEM ; PROTEIN ; FAMILY ; CONTRAST ; fibroblasts ; MOLECULE ; RECOGNITION ; CLEAVAGE ; NERVOUS-SYSTEM ; synaptic plasticity ; MEMBRANE ; NECROSIS-FACTOR-ALPHA ; ADHESION ; MIGRATION ; SUPERFAMILY ; L1 ; NEURITE OUTGROWTH ; ADHESION MOLECULE ; MEDIATED RELEASE ; AMYLOID PRECURSOR PROTEIN ; CELL-MIGRATION ; PHORBOL ESTER ; protease ; INHIBITORS ; ADULT ; immunoglobulin ; NEURONS ; MOLECULE L1 ; cell adhesion ; CONVERTING-ENZYME ; INTRAMEMBRANE PROTEOLYSIS ; cell migration ; ROLES ; MOUSE CEREBELLUM ; N-CADHERIN ; POTENTIAL ROLE
    Abstract: The immunoglobulin superfamily recognition molecule L1 plays important functional roles in the developing and adult nervous system. Metalloprotease-mediated cleavage of this adhesion molecule has been shown to stimulate cellular migration and neurite outgrowth. We demonstrate here that L1 cleavage is mediated by two distinct members of the disintegrin and metalloprotease family, ADAM10 and ADAM17. This cleavage is differently regulated and leads to the generation of a membrane bound C-terminal fragment, which is further processed through gamma-secretase activity. Pharmacological approaches with two hydroxamate-based inhibitors with different preferences in blocking ADAM10 and ADAM17, as well as loss of function and gain of function studies in murine embryonic fibroblasts, showed that constitutive shedding of L1 is mediated by ADAM10 while phorbol ester stimulation or cholesterol depletion led to ADAM17-mediated L1 cleavage. In contrast, N-methyl-D-aspartate treatment of primary neurons stimulated ADAM10-mediated L1 shedding. Both proteases were able to affect L1-mediated adhesion and haptotactic migration of neuronal cells. In particular, both proteases were involved in L1-dependent neurite outgrowth of cerebellar neurons. Thus, our data identify ADAM10 and ADAM17 as differentially regulated L1 membrane sheddases, both critically affecting the physiological functions of this adhesion protein
    Type of Publication: Journal article published
    PubMed ID: 16199880
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  • 2
    Keywords: RECEPTOR ; GROWTH ; COMBINATION ; Germany ; SITE ; PROTEIN ; PROTEINS ; SACCHAROMYCES-CEREVISIAE ; COMPLEX ; COMPLEXES ; DOMAIN ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; ACID ; IDENTIFICATION ; YEAST ; MUTATION ; MUTATIONS ; RECEPTORS ; MATRIX PROTEIN ; BINDS ; MEMBRANE-PROTEIN ; molecular biology ; molecular ; MATRIX ; FRACTION ; interaction ; CORE ; function ; BIOGENESIS ; docking ; PEX5P INTERACTS ; PTS1 RECEPTOR ; SH3 DOMAIN ; TARGETING SIGNAL RECEPTOR ; TRANSLOCATION MACHINERY
    Abstract: The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. Associated with this complex is a fraction of Pex13, another essential component of the import machinery. Here we demonstrate that Pex13 directly binds Pex14 not only via its SH3 domain but also via a novel intraperoxisomal site. Furthermore, we demonstrate that Pex5 also contributes to the association of Pex13 with Pex14. Peroxisome function was affected only mildly by mutations within the novel Pex14 interaction site of Pex13 or by the non-Pex13-interacting mutant Pex5(W204A). However, when these constructs were tested in combination, PTS1-dependent import and growth on oleic acid were severely compromised. When the SH3 domain-mediated interaction of Pex13 with Pex14 was blocked on top of that, PTS2-dependent matrix protein import was completely compromised and Pex13 was no longer copurified with the docking complex. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import that is enabled by two direct interactions and by one that is mediated by Pex5, a result which indicates a novel, receptor-independent function of Pex5
    Type of Publication: Journal article published
    PubMed ID: 15798189
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  • 3
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; Germany ; INHIBITION ; KINASE ; GENERATION ; DEATH ; PROTEIN ; RNA ; DRUG ; TIME ; COMPLEX ; COMPLEXES ; DNA ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; BIOLOGY ; PROTEIN-KINASE ; SIGNAL ; MITOCHONDRIA ; SUPEROXIDE ; OXYGEN ; FAS LIGAND EXPRESSION ; MULTIPLE-SCLEROSIS ; reactive oxygen species ; signaling ; PROGRAM ; RE ; assembly ; SUPEROXIDE-PRODUCTION ; HYDROGEN-PEROXIDE ; REACTIVE OXYGEN ; AICD ; CHAPERONE ; USA ; ROS ; PREVENTS ; CD95L ; block ; SMALL INTERFERING RNA ; superoxide dismutase ; COMPLEX-I ; DOPAMINERGIC-NEURONS ; HEART-MITOCHONDRIA ; LYMPHOCYTE-ACTIVATION ; RECEPTOR STIMULATION ; ROTENONE INHIBITION
    Abstract: Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), IAT (linker of activated T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), PLC gamma 1 (phospholipase C gamma 1), and PKC theta (protein kinase C theta), are crucial for ROS production. PKC theta is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA) -mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKC theta-dependent ROS generation by mitochondrial complex I is essential for AICD
    Type of Publication: Journal article published
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  • 4
    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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  • 5
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; CELL ; IN-VIVO ; PATHWAY ; VIVO ; SUPPORT ; DEATH ; SAMPLE ; SAMPLES ; cell line ; TUMORS ; LINES ; MICE ; ACTIVATION ; cell signaling ; MARKER ; REDUCTION ; DOMAIN ; animals ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; signal transduction ; treatment ; TYPE-1 ; PROGRESSION ; HUMANS ; CELL-DEATH ; CYCLE PROGRESSION ; CELL-LINE ; MARKERS ; SIGNALING PATHWAY ; OUTCOMES ; ABNORMALITIES ; cell lines ; Ras ; signaling ; PERIPHERAL-NERVE ; RNA INTERFERENCE ; cell proliferation ; LEVEL ; TRANSCRIPTIONAL ACTIVATION ; cell death ; NERVE ; USA ; INVASIVENESS ; Male ; Cell Line,Tumor ; outcome ; neurofibromatosis ; MESENCHYMAL TRANSITION ; STATE ; MPNST ; SCHWANN-CELLS ; Schwann cell ; ras Proteins/metabolism ; Base Sequence ; Mice,SCID ; Neoplasm Invasiveness ; Nerve Sheath Neoplasms/genetics/*metabolism/pathology ; ral GTP-Binding Proteins/antagonists & inhibitors/genetics/*metabolism ; RNA,Small Interfering/genetics ; Schwann Cells/metabolism
    Abstract: Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.
    Type of Publication: Journal article published
    PubMed ID: 19414599
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  • 6
    Keywords: CANCER ; cell line ; DNA-DAMAGE ; STABILITY ; INDUCE APOPTOSIS ; REGULATES P73 ; HUMAN TUMORS ; C-ABL ; APOPTOTIC RESPONSE ; IKK-BETA ; P53-RELATED PROTEIN
    Abstract: Delta Np73 alpha, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of Delta Np73 alpha protein levels in normal and cancer cells are poorly characterized. Here, we show that that I kappa B kinase beta (IKK beta) increases Delta Np73 alpha protein stability independently of its ability to activate NF-kappa B. IKK beta associates with and phosphorylates Delta Np73 alpha at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in Delta Np73 alpha abolished IKK beta-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKK beta activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in Delta Np73 alpha destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKK beta and Delta Np73 alpha cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network
    Type of Publication: Journal article published
    PubMed ID: 21482671
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  • 7
    Keywords: EXPRESSION ; KINASE ; PATHWAY ; GENE ; ELEMENT-BINDING PROTEIN ; EMBRYO ; TUMOR-GROWTH ; MICE LACKING ; HUMAN-MELANOMA CELLS ; MESODERM FORMATION
    Abstract: Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1(-/-) CREB(-/-) embryos die before implantation due to developmental arrest. ATF1(+/-) CREB(-/-) embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.
    Type of Publication: Journal article published
    PubMed ID: 11865068
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  • 8
    Keywords: CANCER ; EXPRESSION ; THERAPY ; ACTIVATION ; COMPLEXES ; Drosophila ; MUTATION ; CAENORHABDITIS-ELEGANS ; AKT ; MAMMALIAN TARGET ; TUBEROUS SCLEROSIS COMPLEX ; RAPTOR ; BINDING PARTNER ; RHEB ; RICTOR-MTOR COMPLEX
    Abstract: The evolutionarily conserved serine/threonine protein kinase target-of-rapamycin (TOR) controls cell growth as a core component of TOR complexes 1 (TORC1) and 2 (TORC2). Although TORC1 is the more central growth regulator, TORC2 has also been shown to affect cell growth. Here, we demonstrate that Drosophila LST8, the only conserved TOR-binding protein present in both TORC1 and TORC2, functions exclusively in TORC2 and is not required for TORC1 activity. In mutants lacking LST8, expression of TOR and RAPTOR, together with their upstream activator Rheb, was sufficient to provide TORC1 activity and stimulate cell and organ growth. Furthermore, using an lst8 knockout mutation, we show that TORC2 regulates cell growth cell autonomously. Surprisingly, however, TORC2 does not regulate cell growth via its best-characterized target, AKT. Our findings support the possible application of TORC2-specific drugs in cancer therapy
    Type of Publication: Journal article published
    PubMed ID: 22493059
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  • 9
    Keywords: IN-VIVO ; transcription ; DYNAMICS ; LIVING CELLS ; GLUCOCORTICOID-RECEPTOR ; fluorescence correlation spectroscopy ; ANOMALOUS DIFFUSION ; intranuclear mobility ; NUCLEAR HORMONE-RECEPTORS ; HETERODIMERS
    Abstract: Retinoid X receptor (RXR) is a promiscuous nuclear receptor forming heterodimers with several other receptors, which activate different sets of genes. Upon agonist treatment, the occupancy of its genomic binding regions increased, but only a modest change in the number of sites was revealed by chromatin immunoprecipitation followed by sequencing, suggesting a rather static behavior. However, such genome-wide and biochemical approaches do not take into account the dynamic behavior of a transcription factor. Therefore, we characterized the nuclear dynamics of RXR during activation in single cells on the subsecond scale using live-cell imaging. By applying fluorescence recovery after photobleaching and fluorescence correlation spectroscopy (FCS), techniques with different temporal and spatial resolutions, a highly dynamic behavior could be uncovered which is best described by a two-state model (slow and fast) of receptor mobility. In the unliganded state, most RXRs belonged to the fast population, leaving similar to 15% for the slow, chromatin-bound fraction. Upon agonist treatment, this ratio increased to similar to 43% as a result of an immediate and reversible redistribution. Coactivator binding appears to be indispensable for redistribution and has a major contribution to chromatin association. A nuclear mobility map recorded by light sheet microscopy-FCS shows that the ligand-induced transition from the fast to the slow population occurs throughout the nucleus. Our results support a model in which RXR has a distinct, highly dynamic nuclear behavior and follows hit-and-run kinetics upon activation.
    Type of Publication: Journal article published
    PubMed ID: 24449763
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  • 10
    Keywords: GENE-EXPRESSION ; PLAQUE PROTEIN ; CELL-ADHESION ; EPITHELIAL-CELLS ; STRESS GRANULES ; EXON JUNCTION COMPLEX ; POLY(A)-BINDING PROTEIN ; EUKARYOTIC TRANSLATION ; STIMULATE TRANSLATION ; TUMOR-PROGRESSION
    Abstract: Plakophilins 1 and 3 (PKP1/3) are members of the arm-repeat family of catenin proteins and serve as structural components of desmosomes important for cell-cell-adhesion. In addition, PKP1/3 occur as soluble proteins outside of desmosomes, yet their role in the cytoplasm is not known so far. We found that cytoplasmic PKP1/3 were co-precipitated with the RNA-binding proteins FXR1, G3BP, PABPC1 and UPF1 and these PKP1/3 complexes also comprised desmoplakin and PKP2 mRNAs. Moreover, we showed that the interaction of PKP1/3 with G3BP, PABPC1 and UPF1 but not with FXR1 was RNase-sensitive. To address the cytoplasmic function of PKP1/3 we performed gain and loss of function studies. Both PKP1 and PKP3 knock down cell lines showed reduced protein and mRNA levels for desmoplakin and PKP2. Whereas global rates of translation were unaffected, desmoplakin and PKP2 mRNA were destabilized. Furthermore, binding of PKP1/3 to FXR1 was RNA-independent, and both PKP3 and FXR1 stabilized PKP2 mRNA. Our results demonstrate that cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression.
    Type of Publication: Journal article published
    PubMed ID: 25225333
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