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  • CELLS  (38)
  • 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: CELLS ; EXPRESSION ; CELL ; Germany ; human ; MODEL ; THERAPY ; T-CELL ; BONE-MARROW ; antibodies ; antibody ; MOUSE ; leukemia ; STEM-CELLS ; MOUSE MODEL ; ACUTE MYELOGENOUS LEUKEMIA ; REARRANGEMENT ; LINEAGE ; stem cells ; B-CELL ; DEPLETION ; ABILITY IN-VITRO ; BETHESDA PROPOSALS ; MULTIPOTENT HEMATOPOIETIC PROGENITORS ; SELF-RENEWAL ; stem cell ; STEM-CELL
    Abstract: A challenge for the development of therapies selectively targeting leukemic stem cells in acute myeloid leukemia (AML) is their similarity to normal hematopoietic stem cells (HSCs). Here we demonstrate that the leukemia-propagating cell in murine CALM/AF10-positive AML differs from normal HSCs by B220 surface expression and immunoglobulin heavy chain rearrangement. Furthermore, depletion of B220+ cells in leukemic transplants impaired development of leukemia in recipients. As in the murine model, human CALM/AF10-positive AML was characterized by CD45RA (B220)-positive, IG DH-JH rearranged leukemic cells. These data demonstrate in a murine leukemia model that AIVIL can be propagated by a transformed progenitor with lymphoid characteristics, which can be targeted by antibodies that do not crossreact with normal HSCs
    Type of Publication: Journal article published
    PubMed ID: 17097559
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  • 3
    Keywords: CELLS ; Germany ; IN-VIVO ; VITRO ; PROTEIN ; PROTEINS ; transcription ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; BINDING ; ASSOCIATION ; ASSAY ; LOCALIZATION ; NUCLEUS ; MAMMALIAN-CELLS ; INVOLVEMENT ; LIVING CELLS ; ORGANIZATION ; SC-35 DOMAINS ; DOMAINS ; LOSSES ; NUCLEAR-PORE COMPLEX ; EXON JUNCTION COMPLEX ; FLUORESCENCE COMPLEMENTATION
    Abstract: The bimolecular fluorescence complementation (BiFC) assay, which allows the investigation of interacting molecules in vivo, was applied to study complex formation between the splicing factor Y14 and nuclear export factor 1 (NXF1), which evidence indicates are functionally associated with nuclear mRNA. Y14 linked to the COOH terminus of yellow fluorescent protein (YFP; YC-Y14), and NXF1 fused to the NH2 terminus of YFP (YN-NXF1) expressed in MCF7 cells yielded BiFC upon specific binding. Fluorescence accumulated within and around nuclear speckles, suggesting the involvement of speckles in mRNA processing and export. Accordingly, BiFC depended on transcription and full-length NXF1. Coimmunoprecipitation of YC-Y14 with YN-NXF1, NXF1, Y14, and RNA indicated that YC-Y14 and YN-NXF1 functionally associate with RNA. Fluorescence recovery after photobleaching and fluorescence loss in photobleaching revealed that roughly half of the accumulated BiFC complexes were immobile in vivo. This immobile fraction was readily depleted by adenosine triphosphate (ATP) administration in permeabilized cells. These results suggest that a fraction of RNA, which remains in the nucleus for several hours despite its association with splicing and export proteins, accumulates in speckles because of an ATP-dependent mechanism
    Type of Publication: Journal article published
    PubMed ID: 16431928
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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: CELLS ; EXPRESSION ; CELL ; human ; INFORMATION ; SYSTEM ; SYSTEMS ; TOOL ; GENE-EXPRESSION ; GENOME ; RNA ; TISSUE ; TISSUES ; BIOLOGY ; MOLECULAR-BIOLOGY ; SEQUENCE ; SEQUENCES ; MATURATION ; TARGET ; IDENTIFICATION ; PATTERNS ; DIFFERENCE ; STABILITY ; Jun ; TARGETS ; FUTURE ; HEMATOPOIETIC-CELLS ; LOCATION ; POSTTRANSCRIPTIONAL REGULATION ; molecular biology ; molecular ; PATTERN ; LIBRARIES ; C-ELEGANS ; LINEAGE ; TRANSLATION ; analysis ; PROFILES ; EXPRESSION PROFILES ; rodents ; USA ; CAENORHABDITIS-ELEGANS/ ; UNIT ; PRECURSOR ; TOOLS ; SET ; MENTAL-RETARDATION PROTEIN ; MicroRNAs ; ZEBRAFISH ; MICRORNA ; miRNAs ; ANIMAL DEVELOPMENT
    Abstract: MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. In order to identify miRNAs and to assess their expression patterns, we sequenced over 250 small RNA libraries from 26 different organ systems and cell types of human and rodents that were enriched in neuronal as well as normal and malignant hematopoietic cells and tissues. We present expression profiles derived from clone count data and provide computational tools for their analysis. Unexpectedly, a relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues. This broad survey also provides detailed and accurate information about mature sequences, precursors, genome locations, maturation processes, inferred transcriptional units, and conservation patterns. We also propose a subclassification scheme for miRNAs for assisting future experimental and computational functional analyses
    Type of Publication: Journal article published
    PubMed ID: 17604727
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  • 6
    Keywords: CELLS ; GROWTH ; CELL ; Germany ; IN-VIVO ; MICROSCOPY ; GENES ; PROTEINS ; TIME ; DNA ; MECHANISM ; mechanisms ; BIOLOGY ; WATER ; CHROMATIN ; NUCLEUS ; PHENOTYPE ; FLUORESCENCE ; CHROMOSOME TERRITORIES ; INSITU HYBRIDIZATION ; ORGANIZATION ; DOMAINS ; ARCHITECTURE ; molecular ; FEATURES ; ELECTRON-MICROSCOPY ; INCREASE ; HELA-CELLS ; SUPPLEMENTATION ; interaction ; NUCLEAR ; SIZE ; function ; LOSSES ; COMPOUND ; ENGLAND ; PROMOTES ; MEDIA ; SHAPE ; evidence ; macromolecular crowding ; INTEGRITY ; chromatin compaction ; excluded volume effect ; INDUCED ORGANIZATION ; microcompartmentalization
    Abstract: Many compounds in the cell nucleus are structurally organized. To assess the influence of structural organization on nuclear function, we investigated the physical mechanisms of structure formation by using molecular crowding as a parameter for nuclear integrity. Molecular crowding promotes compaction of macromolecular compounds depending on their size and shape without the need for site-specific interactions. HeLa and MCF7 cells were incubated with hypertonic medium to increase crowding of their macromolecular content as a result of the osmotic loss of water. Supplementation of sucrose, sorbitol or NaCl to the growth medium shifted nuclear organization, observed by fluorescence and electron microscopy, towards compaction of chromatin and segregation of other nuclear compounds. With increasing hypertonic load and incubation time, this nuclear reorganization proceeded gradually, irrespective of the substances used, and reversibly relaxed to a regular phenotype upon re-incubation of cells in isotonic growth medium. Gradual and reversible re-organization are major features of controlled de-mixing by molecular crowding. Of fundamental importance for nuclear function, we discuss how macromolecular crowding could account for the stabilization of processes that involve large, macromolecular machines
    Type of Publication: Journal article published
    PubMed ID: 17430977
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; proliferation ; tumor ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; HEPATOCELLULAR-CARCINOMA ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; ACTIVATION ; DNA ; INFECTION ; MECHANISM ; prognosis ; mechanisms ; BREAST-CANCER ; TARGET ; virus ; TRANSGENIC MICE ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; NUMBER ; etiology ; RATES ; REGION ; ONCOGENE ; ALCOHOL ; OVEREXPRESSION ; gene expression profiling ; ALCOHOL-CONSUMPTION ; CONSUMPTION ; molecular ; RE ; ARRAY ; CANDIDATE GENES ; USA ; CANDIDATE ; CANCERS ; viral ; CHROMOSOME-ABERRATIONS ; ELONGATION-FACTOR EEF1A2
    Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized by aggressive tumor behavior coupled with poor prognosis. Various etiologies have been linked to HCC development, most prominently chronic hepatitis B and C virus infections as well as chronic alcohol consumption. In approximately 10% of HCCs, the etiology remains cryptic; however, recent epidemiological data suggest that most of these cryptogenic HCCs develop due to nonalcoholic steatohepatitis. To identify etiology-dependent DNA copy number aberrations and genes relevant to hepatocarcinogenesis, we performed array based comparative genomic hybridization of 63 HCCs of well-defined etiology and 4 HCC cell lines followed by gene expression profiling and functional analyses of candidate genes. For a 10-megabase chromosome region on 8q24, we observed etiology-dependent copy number gains and MYC overexpression in viral and alcohol-related HCCs, resulting in up-regulation of MYC target genes. Cryptogenic HCCs showed neither 8q24 gains, nor MYC overexpression, nor target gene activation, suggesting that tumors of this etiology develop by way of a distinct MYC-independent pathomechanism. Furthermore, we detected several etiology-independent small chromosome aberrations, including amplification of MDM4 on 1q32.1 and frequent gains of EEF1A2 on 20q13.33. Both genes were overexpressed in approximately half the HCCs examined, and gene silencing reduced cell viability as well as proliferation and increased apoptosis rates in HCC cell fines. Conclusion: Our findings suggest that MDM4 and EEF1A2 act as etiology-independent oncogenes in a significant percentage of HCCs
    Type of Publication: Journal article published
    PubMed ID: 18161050
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  • 8
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; MICROSCOPY ; MODEL ; THERAPY ; VITRO ; VIVO ; POPULATION ; GENE-EXPRESSION ; DIFFERENTIATION ; cytokines ; ACID ; TARGET ; DESIGN ; resistance ; EFFICACY ; STEM-CELLS ; PPAR-GAMMA ; RETINOIC ACID ; PHASE-II ; chemoresistance ; TRANS-RETINOIC ACID ; CYTOKINE ; ONCOLOGY ; secretion ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMAS ; TUMORIGENICITY ; MOTILITY ; GLIOBLASTOMA ; STEM ; TUMOR-INITIATING CELLS ; MARKER CD133
    Abstract: Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications. Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model. Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo. Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715-28. (C) 2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20442299
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  • 9
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; INHIBITION ; MODEL ; PATHWAY ; PATHWAYS ; THERAPY ; VITRO ; EXPOSURE ; GENE ; microarray ; PROTEIN ; RNA ; DIFFERENTIATION ; MECHANISM ; INDUCTION ; mechanisms ; BIOLOGY ; ACID ; TARGET ; PROGRESSION ; AMPLIFICATION ; ASSAY ; PROMOTER ; genetics ; ONCOGENE ; STEM-CELLS ; PROGENITOR CELLS ; CANCER-THERAPY ; GLIOMAS ; RETINOIC ACID ; TRANS-RETINOIC ACID ; INHIBITORS ; signaling ; ONCOLOGY ; GLIOMA ; GLIOMA-CELLS ; MOLECULAR-MECHANISMS ; LOCUS ; GLIOBLASTOMA ; MicroRNAs ; MICRORNA ; CELL BIOLOGY ; TUMOR-INITIATING CELLS ; Genetic ; tumor grade ; Molecular mechanisms ; CTGF ; miR-17-92 ; NEURAL PRECURSORS ; spheroid culture
    Abstract: All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response to exposure to differentiation-promoting conditions in such cultures. Microarray analyses of five independent cultures showed that after induction of differentiation, inhibitors of transforming growth factor beta/bone morphogenetic protein, Wnt/beta-catenin and IGF signaling were upregulated, whereas expression of several microRNAs decreased, particularly that of the miR-17-92 cluster. In primary astrocytic gliomas (n = 82), expression of several members of miR-17-92 was significantly higher relative to those of normal brain (n = 8) and significantly increased with tumor grade progression (P 〈 0.05). A high-level amplification of the miR-17-92 locus was detected in one glioblastoma specimen. Transfection of inhibitors of miR-17-92 induced increased apoptosis and decreased cell proliferation in glioblastoma spheroids. Mir-17-92 inhibition was also associated with increased messenger RNA (mRNA) and/or protein expression of CDKN1A, E2F1, PTEN and CTGF. The CTGF gene was shown to be a target of miR-17-92 in glioblastoma spheroids by luciferase reporter assays. Our results suggest that miR-17-92 and its target CTGF mediate effects of differentiation-promoting treatment on glioblastoma cells through multiple regulatory pathways. Oncogene (2010) 29, 3411-3422; doi:10.1038/onc.2010.83; published online 22 March 2010
    Type of Publication: Journal article published
    PubMed ID: 20305691
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  • 10
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; DIFFERENTIATION ; TISSUE ; MICE ; NITRIC-OXIDE SYNTHASE ; MECHANISM ; MESSENGER-RNA ; PROGRESSION ; genetics ; inactivation ; MUTATIONS ; LOCALIZATION ; HUMAN HOMOLOG ; NEURITE OUTGROWTH ; CHILDREN ; PRECURSORS ; MORPHOGENESIS ; POSTTRANSCRIPTIONAL REGULATION ; TUMORIGENESIS ; SUBVENTRICULAR ZONE ; TUMOR SUPPRESSORS ; CEREBELLAR DEVELOPMENT ; GROWTH-ASSOCIATED PROTEIN-43 ; REGULATES PROLIFERATION
    Abstract: Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression
    Type of Publication: Journal article published
    PubMed ID: 22438824
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