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  • 1
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; Germany ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; transcription ; PATIENT ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; chromosome ; DELETION ; LYMPHOMA ; gene expression ; DISRUPTION ; UP-REGULATION ; MUTATION ; leukemia ; DELETIONS ; inactivation ; TUMOR-SUPPRESSOR GENE ; REGION ; B-CELLS ; point mutation ; TRANSCRIPTS ; molecular ; TUMOR-SUPPRESSOR ; ACUTE MYELOID-LEUKEMIA ; regulation ; ATM MUTATIONS ; B-CLL ; tumor suppressor gene ; transcript ; 11Q23 ; ATM ; CYCLIN-E ; GENOMIC REGION ; GTPASE-ACTIVATING PROTEIN ; INDUCED SKIN TUMORS ; MLL
    Abstract: Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis. (C) 2004 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15543602
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  • 2
    Keywords: SIMULATIONS ; CELLS ; CELL ; Germany ; MODEL ; DEATH ; PROTEINS ; cell line ; LINES ; COMPLEX ; COMPLEXES ; CELL-LINES ; treatment ; SPECTROSCOPY ; CELL-DEATH ; CELL-LINE ; LINE ; KINETICS ; LIVING CELLS ; FLUORESCENCE ; cell lines ; MONTE-CARLO ; TRANSLATIONAL DIFFUSION ; fluorescence correlation spectroscopy ; RE ; ENVIRONMENTS ; cell death ; ANOMALOUS DIFFUSION ; USA ; correlation ; compartment ; CYTOPLASM ; SUBDIFFUSION
    Abstract: We have used fluorescence correlation spectroscopy to determine the anomalous diffusion properties of. fluorescently tagged gold beads in the cytoplasm and the nucleus of living cells. From the extracted mean-square displacement v( t); t a, wehave determined the complex shear modulus G(v); v a for both compartments. Without treatment, all tested cell lines showed a strong viscoelastic behavior of the cytoplasm and the nucleoplasm, highlighting the crowdedness of these intracellular. fluids. We also found a similar viscoelastic response in frog egg extract, which tended toward a solely viscous behavior upon dilution. When cells were osmotically stressed, the diffusion became less anomalous and the viscoelastic response changed. In particular, the anomality changed from a approximate to 0.55 to a approximate to 0.66, which indicates that the Zimm model for polymer solutions under varying solvent conditions is a good empirical description of the material properties of the cytoplasm and the nucleoplasm. Since osmotic stress may eventually trigger cell death, we propose, on the basis of our observations, that intracellular. fluids are maintained in a state similar to crowded polymer solutions under good solvent conditions to keep the cell viable. We have used fluorescence correlation spectroscopy to determine the anomalous diffusion properties of fluorescently tagged gold beads in the cytoplasm and the nucleus of living cells. From the extracted mean- square displacement v(tau)similar to tau(alpha), we have determined the complex shear modulusG(omega)similar to omega(alpha) for both compartments. Without treatment, all tested cell lines showed a strong viscoelastic behavior of the cytoplasm and the nucleoplasm, highlighting the crowdedness of these intracellular. uids. We also found a similar viscoelastic response in frog egg extract, which tended toward a solely viscous behavior upon dilution. When cells were osmotically stressed, the diffusion became less anomalous and the viscoelastic response changed. In particular, the anomality changed from a approximate to 0.55 to a approximate to 0.66, which indicates that the Zimm model for polymer solutions under varying solvent conditions is a good empirical description of the material properties of the cytoplasm and the nucleoplasm. Since osmotic stress may eventually trigger cell death, we propose, on the basis of our observations, that intracellular. uids are maintained in a state similar to crowded polymer solutions under good solvent conditions to keep the cell viable
    Type of Publication: Journal article published
    PubMed ID: 17416631
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  • 3
    Keywords: CELLS ; tumor ; CELL ; Germany ; PROTEIN ; PROTEINS ; cell line ; LINES ; CONTRAST ; BIOLOGY ; CELL-LINES ; MOLECULAR-BIOLOGY ; METASTASIS ; CELL-LINE ; LINE ; NUCLEUS ; MAMMALIAN-CELLS ; NETHERLANDS ; LIVING CELLS ; BEHAVIOR ; cell lines ; DIFFUSION ; fluorescence correlation spectroscopy ; molecular biology ; molecular ; RE ; SCALE ; SIZE ; ANOMALOUS DIFFUSION ; LATERAL DIFFUSION ; cell size ; compartment ; CYTOPLASM ; ANOMALOUS SUBDIFFUSION ; ARCHIPELAGO ; FLUIDS ; FORCE MICROSCOPY ; macromolecular crowding ; viscoelastic ; VISCOELASTICITY
    Abstract: Macromolecular crowding provides the cytoplasm and the nucleoplasm with strongly viscoelastic properties and renders the diffusion of soluble proteins in both fluids anomalous. Here, we have determined the nanoscale viscoelasticity of the cytoplasm and the nucleoplasm in different mammalian cell lines. In contrast to the cell-specific response on the macroscale the nanoscale viscoelasticity (i.e. the behavior on length scales about 100-fold smaller than the cell size) only showed minor variations between different cell types. Similarly, the associated anomalous diffusion properties varied only slightly. Our results indicate a conserved state of macromolecular crowding in both compartments for a variety of mammalian cells with the cytoplasm being somewhat more crowded than the nucleus. (C) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17923125
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; CELL ; Germany ; GENE ; GENES ; PROTEIN ; SAMPLES ; cell cycle ; CELL-CYCLE ; DOWN-REGULATION ; TARGET ; DELETION ; LYMPHOMA ; MUTATION ; COMPONENT ; inactivation ; PATHOGENESIS ; MUTATIONS ; B-CELLS ; DEGRADATION ; POLYMERASE-CHAIN-REACTION ; point mutation ; REGULATOR ; TRANSCRIPTS ; ONCOLOGY ; TUMOR-SUPPRESSOR ; CLL ; ATM MUTATIONS ; POINT MUTATIONS ; LEVEL ; TARGET GENES ; analysis ; leukaemia ; ATM ; PP2A ; PHOSPHATASE ; CONFORMATION ; B-CELL ; apoptosis regulation ; B-cell chronic lymphocytic ; 11q22-q23 ; CUL5 ; NPAT ; PHOSPHATASE 2A ; PPP2R1B
    Abstract: Deletion of 11q22-q23 is associated with an aggressive course of B-cell chronic lymphocytic leukaemia (B-CLL). Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NFAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction. Though none of the genes were affected by deleterious mutations, we observed a significant down-regulation of NPAT in B-CLL versus CD19+ B cells and of CUL5 in 11q deletion versus non-deletion B-CLL samples and measured reduced PPP2R1B transcript levels in a subset of B-CLL cases. Alternative splicing of PPP2R1B transcripts (skipping of exons 2/3, 3, 9) was associated with a reduced activity of protein phosphatase 2A. Together, these results implicate deregulation of the cell-cycle and apoptosis regulators NPAT, CUL5 and PPP2R1B and a role for these genes in the pathogenesis of B-CLL. (C) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17449237
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  • 5
    Keywords: CANCER ; IRRADIATION ; Germany ; EXPOSURE ; MORTALITY ; RISK ; GENE ; PROTEIN ; MICE ; radiation ; PATIENT ; LYMPHOMA ; MALIGNANCIES ; ENCODES ; MUTATION ; REPAIR ; leukemia ; inactivation ; MANTLE CELL LYMPHOMA ; ATAXIA-TELANGIECTASIA ; MALIGNANCY ; ATM ; ionising radiation ; predisposition of heterozygotes ; somatic mutation
    Abstract: Predisposition to lymphomagenesis is a well-known phenomenon of ataxia-telangiectasia, a recessive disorder caused by germline inactivation of ATM. ATM encodes a protein implicated in the repair of radiation induced double-strand breaks. Biallelic ATM inactivation was described also in sporadic lymphoid malignancies, supporting a role of ATM as a tumour suppressor gene. It is, however, still unclear whether ATM heterozygotes are at higher risk of tumours. We describe an ATM heterozygous patient, who developed a mantle cell lymphoma (MCL) after occupational exposure to ionising radiation and somatic mutation of the second ATM allele supporting the contention that heterozygous germline ATM alterations in combination with irradiation exposure predisposes to sporadic MCL. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16387360
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  • 6
    Keywords: CELL ; Germany ; MICROSCOPY ; MODEL ; PATHWAY ; SITE ; SITES ; PROTEIN ; PROTEINS ; COMPONENTS ; RESOLUTION ; COMPLEXES ; DOMAIN ; DYNAMICS ; BINDING ; BIOLOGY ; TRANSPORT ; MEMBRANE ; NUMBER ; PREDICTION ; KINETICS ; LIVING CELLS ; systems biology ; FLUORESCENCE ; SPATIAL-ORGANIZATION ; ORGANIZATION ; DOMAINS ; ENDOPLASMIC-RETICULUM ; ER ; RE ; PATTERN ; VESICLES ; INCREASE ; LEADS ; FLUORESCENCE MICROSCOPY ; COPII ; endoplasmic reticulum ; EXPORT ; PREDICTS ; ENGLAND ; PREDICT ; AGREEMENT ; PICHIA-PASTORIS ; TURNOVER ; SECRETORY PATHWAY ; CELL BIOLOGY ; biophysical modelling ; COOPERATIVE BINDING ; COPII-COATED VESICLE ; domain formation ; membrane traffic
    Abstract: Exit sites (ES) are specialized domains of the endoplasmic reticulum (ER) at which cargo proteins of the secretory pathway are packaged into COPII-coated vesicles. Although the essential COPII proteins (Sar1p, Sec23p-Sec24p, Sec13p-Sec31p) have been characterized in detail and their sequential binding kinetics at ER membranes have been quantified, the basic processes that govern the self-assembly and spatial organization of ERES have remained elusive. Here, we have formulated a generic computational model that describes the process of formation of ERES on a mesoscopic scale. The model predicts that ERES are arranged in a quasi-crystalline pattern, while their size strongly depends on the cargo-modulated kinetics of COPII turnover - that is, a lack of cargo leads to smaller and more mobile ERES. These predictions are in favorable agreement with experimental data obtained by fluorescence microscopy. The model further suggests that cooperative binding of COPII components, for example mediated by regulatory proteins, is a key factor for the experimentally observed organism-specific ERES pattern. Moreover, the anterograde secretory flux is predicted to grow when the average size of ERES is increased, whereas an increase in the number of (small) ERES only slightly alters the flux
    Type of Publication: Journal article published
    PubMed ID: 18073241
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  • 7
    Keywords: Germany ; GENE ; recombination ; IDENTIFICATION
    Type of Publication: Journal article published
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  • 8
    Keywords: CELLS ; COMBINATION ; Germany ; SYSTEM ; GENE ; GENES ; RNA ; MESSENGER-RNA ; MARKER ; DOMAIN ; chromosome ; FREQUENCY ; NUCLEI ; resistance ; PROMOTER ; IN-SITU HYBRIDIZATION ; REGION ; MAMMALIAN-CELLS ; PARAMETERS ; LIVING CELLS ; TERRITORIES ; CHROMOSOME TERRITORIES ; INSITU HYBRIDIZATION ; INTERCHROMOSOMAL-DOMAIN COMPARTMENT ; ORGANIZATION ; INTERPHASE NUCLEI ; TRANSCRIPTS ; COMPARTMENTS ; INACTIVE GENES ; transcript ; HIV-1 REV PROTEIN ; nuclear RNA ; PARTICLE FORMATION ; reticular compartment ; RNAS
    Abstract: RNA polymerase II transcripts are confined to nuclear compartments. A detailed analysis of the nuclear topology of RNA from individual genes was performed for transcripts from the marker gene coding for chloramphenicol acetyltransferase, expressed at a high level from the HTLV-1 LTR promoter. The construct was transfected into A293 cells where the RNA was organized as an extensive reticular network. We also studied the RNA distribution from combinations of neighboring HIV and bacterial resistance genes that co-integrated within the genome of COS-7 cells-revealing spherical or track-like accumulations of RNA that were extensively branched. There were many nuclei with distinct but overlapping RNA accumulations. Since the coding genes localized at the overlapping points, the RNAs are synthesized at a common region and diverge. The correlation between the frequency of the separation of the transcripts and the physical distance of the respective genes suggests a subcompartmentalization in the microenvironment of genes on the basis of geometric parameters. Thus, the more distant the genes are on the same chromosome, the more likely they are confined to separated subcompartments of an extensive reticular system. Co-delineation of the RNA transcripts with Cajal bodies and chromosome territories indicated the organization of nuclear RNA transcripts in a reticular interchromosome domain compartment. (C) 2004 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15561100
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  • 9
    Keywords: ACTIVATION, BIOLOGY, CELL, DIFFUSION, DYNAMICS, EXPORT, FACTOR TIF-IA, fluorescence correlation spec
    Abstract: TIF-IA is a basal transcription factor of RNA polymerase I (Pol I) that is a major target of the JNK2 signaling pathway in response to ribotoxic stress. Using advanced fluorescence microscopy and kinetic modeling we elucidated the subcellular localization of TIF-IA and its exchange dynamics between the nucleolus, nucleoplasm and cytoplasm upon ribotoxic stress. In steady state, the majority of (GFP-tagged) TIF-IA was in the cytoplasm and the nucleus, a minor portion (7%) localizing to the nucleoli. We observed a rapid shuttling of GFP-TIF-IA between the different cellular compartments with a mean residence time of similar to 130 s in the nucleus and only similar to 30 s in the nucleoli. The import rate from the cytoplasm to the nucleus was similar to 3-fold larger than the export rate, suggesting an importin/exportin-mediated transport rather than a passive diffusion. Upon ribotoxic stress, GFP-TlF-IA was released from the nucleoli with a half-time of similar to 24 min. Oxidative stress and inhibition of protein synthesis led to a relocation of GFP-TIF-IA with slower kinetics while osmotic stress had no effect. The observed relocation was much slower than the nucleo-cytoplasmic and nucleus-nucleolus exchange rates of GFP-TIF-IA, indicating a time-limiting step upstream of the JNK2 pathway. In support of this, time-course experiments on the activity of JNK2 revealed the activation of the JNK kinase as the rate-limiting step. (C) 2009 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19450626
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  • 10
    Keywords: brain ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INVASION ; IN-VIVO ; VITRO ; QUANTIFICATION ; VOLUME ; DISEASE ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; HEART ; COMPLEX ; TISSUES ; ALZHEIMERS-DISEASE ; culture ; antibodies ; antibody ; MOUSE ; COMPARATIVE GENOMIC HYBRIDIZATION ; ASSAY ; WHITE-MATTER ; GLIOMA ; CORTEX ; human brain ; COLONY FORMATION ; MOTILITY ; CELL MOTILITY ; GLIOBLASTOMAS ; white matter ; CELL MORPHOLOGY ; focal adhesion complex ; functional characterization ; tumour relevant gene ; VINCULIN
    Abstract: In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration
    Type of Publication: Journal article published
    PubMed ID: 22427331
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