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  • 1
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; THERAPY ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; SACCHAROMYCES-CEREVISIAE ; DRUG ; NEUROBLASTOMA-CELLS ; FAMILY ; PROTEIN FAMILY ; DOMAIN ; CONTRAST ; MEMBER ; MEMBERS ; SEQUENCE ; SIGNAL ; BREAST-CANCER ; cytokines ; ACID ; ACIDS ; PROGRESSION ; ENCODES ; YEAST ; resistance ; CELL-DEATH ; PLASMA ; MEMBRANE ; INTERFERON ; sensitization ; AMINO-ACIDS ; OVEREXPRESSION ; MYCN ; neuroblastoma ; DRUG-INDUCED APOPTOSIS ; MAPS ; DISULFIDE BOND FORMATION ; EGG-WHITE ; INDUCED CELL DEATH ; QUIESCIN Q6 ; RETINOID COMBINATION ; THIOREDOXIN REDUCTASE
    Abstract: In neuroblastoma cells, apoptotic programs can be activated by cytokines and cytostatic drugs. Apoptotic dysfunction confers resistance against therapeutic drugs and is a major complication for achieving optimal therapy response. Deregulated expression of the MYCN gene is a critical determinant in neuroblastoma progression, and one of the pleiotropic functions of the MYCN protein is cellular sensitization to cytokine-induced and drug-induced apoptosis. By using the functional approach of technical knockout (TKO), we have identified five genes that regulate sensitization for IFN-gamma-induced cell death. Most efficient among them is the newly identified SOXN (neuroblastoma-derived sulfhydryl oxidase), which comprises 12 exons and maps to 9q34.3. SOXN encodes a putative protein of 698 amino acids that contains a signal sequence, a protein-disulfide-isomerase-type thioredoxin and a yeast ERV1 domain and is highly homologous to members of the sulfhydryl oxidase/Quiescin6 family. The SOXN protein is predominantly located in the plasma and in the nuclear membrane. Antisense SOXN confers resistance to IFN-gamma-induced apoptosis. In contrast, ectopic overexpression of sense-SOXN sensitizes the cells to induced cell death. These results identify SOXN as a major player in regulating the sensitization of neuroblastoma cells for IFN-gamma-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 14633699
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; AGENTS ; Germany ; MODEL ; MODELS ; THERAPY ; POPULATION ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; HYBRIDIZATION ; TISSUE ; TUMORS ; gene therapy ; MICE ; INFECTION ; MARKER ; ANTIGEN ; DENDRITIC CELLS ; SUPPRESSION ; VARIANTS ; cytokines ; virus ; DELETION ; IN-SITU ; LYMPHOMA ; gene expression ; VECTOR ; MARKERS ; MELANOMA ; LYMPHOCYTES ; DERIVATIVES ; SURVEILLANCE ; MINUTE VIRUS ; GENE-THERAPY ; AUTONOMOUS PARVOVIRUSES ; autonomous parvovirus ; AGENT ; in situ hybridization ; INFILTRATION ; PROGRAM ; targeted ; PROTOCOL ; INTERLEUKIN-12 ; dendritic cell ; ABILITY ; parvovirus minute virus of mice
    Abstract: Due to their oncolytic properties and apathogenicity, autonomous parvoviruses have attracted significant interest as possible anticancer agents. Recent preclinical studies provided evidence of the therapeutic potential of minute virus of mice prototype strain (MVMp) and its recombinant derivatives. In a murine model of hemangiosarcoma, positive therapeutic outcome correlated with high intratumoral expression of MVMp-encoded genes in tumors and lymphoid organs, especially in tumor-draining lymph nodes. The source and relevance of this extratumoral expression, which came as a surprise because of the known fibrotropism of MVMp, remained unclear. In the present study, we investigated (i) whether the observed expression pattern occurs in different tumor models, (ii) which cell population is targeted by the virus, and (iii) the immunological consequences of this infection. Significant MVMp gene expression was detected in lymphoid tissues from infected tumor-free as well as melanoma-, lymphoma-, and hemangiosarcoma-bearing mice. This expression was especially marked in lymph nodes draining virus-injected tumors. Fluorescent in situ hybridization analysis, multicolor fluorescence-activated cell sorting, and quantitative reverse transcription-PCR revealed that MVMp was expressed in rare subpopulations of CD11b (Mac1)-positive cells displaying CD11c(+) (myeloid dendritic cells [MDC]) or CD45B (B220(+) [131 lymphocytes]) markers. Apart from the late deletion of cytotoxic memory cells (CD8(+) CD44(+) CD62L(-)), this infection did not lead to significant alteration of the immunological profile of cells populating lymphoid organs. However, subtle changes were detected in the production of specific proinflammatory cytokines in lymph nodes from virus-treated animals. Considering the role of 131 lymphocytes and MDC in cancer and immunological surveillance, the specific ability of these cell types to sustain parvovirus-driven gene expression may be exploited in gene therapy protocols
    Type of Publication: Journal article published
    PubMed ID: 15731246
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  • 3
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; human ; POPULATION ; SITE ; GENE ; MOLECULAR CHARACTERIZATION ; DNA ; NERVOUS-SYSTEM ; HOMOZYGOUS DELETIONS ; CANCER-CELLS ; REGIONS ; MUTATIONS ; gene amplification ; common fragile sites ; RENAL-CELL CARCINOMA ; CHROMOSOMES ; DISORDERS ; RE ; PREFERENTIAL INTEGRATION ; function ; fragile sites ; FRA13A ; HUMAN-CHROMOSOME 7 ; NBEA ; neurobeachin ; RECESSIVE JUVENILE PARKINSONISM ; DELTA-2 GLUTAMATE-RECEPTOR ; neuropsychiatric disorders ; TRINUCLEOTIDE REPEAT
    Abstract: Common fragile sites are unstable chromosomal regions that predispose chromosomes to breakage and rearrangements Recombinogenic DNA sequences encompassing these sites may contribute to both germinal and somatic genomic mutations, and the genomic instability at these regions might cause severe inherited disorders or predispose to cancer. In this review, we discuss the characterization of common fragile site FRA13A within the neurobeachin gene, which is involved in development and function of the central nervous system. We raise the possibility of an implication of common fragile sites in neuropsychiatric disorders and overview previous and recent reports concerning individual variability of expression of common fragile sites in human populations. (c) 2005 Published by Elsevier Ireland Ltd
    Type of Publication: Journal article published
    PubMed ID: 16298041
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  • 4
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; CELL ; Germany ; VITRO ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; ACTIVATION ; primary ; CELL-LINES ; ANTITUMOR-ACTIVITY ; culture ; ACID ; RATES ; CELL-LINE ; acetylation ; HIGH-RISK ; HISTONE DEACETYLASE ; Ras ; retinoids ; neuroblastoma ; N-MYC ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; LEVEL ; HISTONE DEACETYLASE INHIBITORS ; SUPPRESSOR ; SODIUM VALPROATE ; retinoblastoma ; tumor suppressor ; HC-TOXIN ; RB tumor suppressor network ; E2F-1 ; HIGH-RISK NEUROBLASTOMA ; SUPPRESSES
    Abstract: Treatment of high-risk neuroblastoma (NB) is difficult. Novel therapeutics improving survival rates are urgently required. We have previously shown that the histone deacetylase inhibitor (HDACI) Helminthosporium carbonum (HC)toxin induces differentiation of neuroblastoma (NB) cells. Here, we show that HC-toxin inhibits the growth of both established NB cell lines and primary cultures with and without amplified MYCN stronger than retinoids (RAs) and other HDACIs (MS-275, n-butyric acid, suberoylanilide hydroxamic acid, trichostatin A, valproic acid). Nanomolar dosages suppress E2F-1, N-myc, Skp2, Mad2 and survivin proteins, found at high levels in high-risk NBs, more efficiently than both RAs and other HDACIs. The level of hypophosphorylated active retinoblastoma (RB) tumor suppressor protein is increased most effectively. HC-toxin's epoxy group is essential for inhibiting HDACs and promoting anti-NB activity. Without this functional group, those cellular effects are not observed. In conclusion, the anti-NB activity of HC-toxin is superior to that of RAs and that of all other HDACIs tested. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18262346
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  • 5
    Keywords: CANCER ; CELL ; IDENTIFICATION ; REGION ; REPLICATION ; MOLECULAR-BASIS ; FRA3B ; FHIT GENE ; CHROMOSOME BREAKAGE ; DNA INSTABILITY
    Abstract: Common fragile sites (cFSs) are non-random chromosomal regions that are prone to breakage under conditions of replication stress. DNA damage and chromosomal alterations at cFSs appear to be critical events in the development of various human diseases, especially carcinogenesis. Despite the growing interest in understanding the nature of cFS instability, only a few cFSs have been molecularly characterised. In this study, we fine-mapped the location of FRA2H using six-colour fluorescence in situ hybridisation and showed that it is one of the most active cFSs in the human genome. FRA2H encompasses approximately 530 kb of a gene-poor region containing a novel large intergenic non-coding RNA gene (AC097500.2). Using custom-designed array comparative genomic hybridisation, we detected gross and submicroscopic chromosomal rearrangements involving FRA2H in a panel of 54 neuroblastoma, colon and breast cancer cell lines. The genomic alterations frequently involved different classes of long terminal repeats and long interspersed nuclear elements. An analysis of breakpoint junction sequence motifs predominantly revealed signatures of microhomology-mediated non-homologous recombination events. Our data provide insight into the molecular structure of cFSs and sequence motifs affected by their activation in cancer. Identifying cFS sequences will accelerate the search for DNA biomarkers and targets for individualised therapies.
    Type of Publication: Journal article published
    PubMed ID: 22476624
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  • 6
    Keywords: PHASE-I ; p53 ; CANCER-THERAPY ; N-MYC ; CYCLE ARREST ; HIGH-RISK NEUROBLASTOMA ; DEPENDENT KINASE 4/6 ; DIRECT TRANSCRIPTIONAL TARGET ; PHARMACOLOGICAL INHIBITION ; PD 0332991
    Abstract: Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. MYCN-amplified neuroblastoma cells in vitro are characterized by a failure to arrest at the G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several MYCN-amplified cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions or TP53 mutations. Cells with these additional aberrations undergo significantly lower levels of cell death after doxorubicin treatment compared with MYCN-amplified cells, with no additional mutations in these pathways. In MYCN-amplified cells CDK4 expression is elevated, increasing the competition between CDK4 and CDK2 for binding p21. This results in insufficient p21 to inhibit CDK2, leading to high CDK4 and CDK2 kinase activity upon doxorubicin treatment. CDK4 inhibition by siRNAs, selective small compounds or p19 (INK4D) overexpression partly restored G(1)-S arrest, delayed S-phase progression and reduced cell viability upon doxorubicin treatment. Our results suggest a specific function of p19 (INK4D) , but not p16 (INK4A) , in sensitizing MYCN-amplified cells with a functional p53 pathway to doxorubicin-induced cell death. In summary, the CDK4/cyclin D-pRB axis is altered in MYCN-amplified cells to evade a G(1)-S arrest after doxorubicin-induced DNA damage. Additional chromosomal aberrations affecting the p53-p21 and CDK4-pRB axes compound the effects of MYCN on the G(1) checkpoint and reduce sensitivity to cell death after doxorubicin treatment. CDK4 inhibition partly restores G(1)-S arrest and sensitizes cells to doxorubicin-mediated cell death in MYCN-amplified cells with an intact p53 pathway.
    Type of Publication: Journal article published
    PubMed ID: 23462184
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  • 7
    Keywords: GENE ; neuroblastoma ; ENHANCERS ; LANDSCAPE ; TERT REARRANGEMENTS
    Abstract: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
    Type of Publication: Journal article published
    PubMed ID: 26466568
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  • 8
    Keywords: COLORECTAL-CANCER ; HUMAN GENOME ; DNA-DAMAGE ; COPY NUMBER CHANGES ; MULTIPLE-MYELOMA ; RENAL-CELL CARCINOMA ; PREFERENTIAL INTEGRATION ; VIRAL INTEGRATION ; HUMAN-CHROMOSOME 7 ; REPLICATION DYNAMICS
    Abstract: The cytogenetic hypothesis that common fragile sites (cFSs) are hotspots of cancer breakpoints is increasingly supported by recent data from whole-genome profiles of different cancers. cFSs are components of the normal chromosome structure that are particularly prone to breakage under conditions of replication stress. In recent years, cFSs have become of increasing interest in cancer research, as they not only appear to be frequent targets of genomic alterations in progressive tumors, but also already in precancerous lesions. Despite growing evidence of their importance in disease development, most cFSs have not been investigated at the molecular level and most cFS genes have not been identified. In this review, we summarize the current data on molecularly characterized cFSs, their genetic and epigenetic characteristics, and put emphasis on less-studied cFS genes as potential contributors to cancer development.
    Type of Publication: Journal article published
    PubMed ID: 25231336
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  • 9
    Keywords: CANCER ; CELLS ; Germany ; GENE ; GENES ; PROTEIN ; MICE ; DNA ; FAMILY ; recombination ; fibroblasts ; MEMBER ; MEMBERS ; chromosome ; FREQUENCY ; SUSCEPTIBILITY ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; DELETION ; NUMBER ; CHROMOSOMAL-ABERRATIONS ; DNA-REPAIR ; MUTATION ; REPAIR ; TUMOR PROGRESSION ; RATES ; DELETIONS ; DAMAGE ; LYMPHOCYTES ; WILD-TYPE ; INSTABILITY ; MUTATIONS ; EXCHANGE ; STABILITY ; DUPLICATION ; CARRIERS ; INDIVIDUALS ; GERM-LINE ; FLUORESCENCE ; CLUSTERS ; GENOMIC INSTABILITY ; HOMOLOGOUS RECOMBINATION ; CLUSTER ; BRCA2 ; fibroblast ; REARRANGEMENT ; MUTATION CARRIERS ; CANCER SUSCEPTIBILITY ; DOUBLE-STRAND BREAK ; familial breast cancer clusters ; fluorescence in situ hybridisation ; GERM-LINE MUTATIONS ; haploinsufficiency ; INVERSION ; sister chromatid exchange
    Abstract: Heterozygous carriers of germ-line mutations of the BRCA2 breast cancer susceptibility gene are predisposed to breast, ovarian, pancreatic and other cancers. The BRCA2 protein is implicated in the maintenance of chromosome stability through its essential function in double-strand DNA repair and recombination. Our previous studies had revealed multiple intrachromosomal rearrangements, duplications, inversions and deletions on 9p23-24 in lymphocytes and fibroblasts of BRCA2(+/-) members from independently ascertained familial breast cancer clusters. In pursuit of evaluating if there is a subtle genomic instability in BRCA2(+/-) individuals, we have determined frequencies of spontaneous sister chromatid exchanges (SCEs) in BRCA2 wild-types and BRCA2 mutation carriers of two familial breast cancer clusters. Here, we demonstrate an average increase of 65% of spontaneous SCEs in BRCA2(+/-) versus BRCA2(+/+) family members. In one cluster, the number of metaphases with multiple SCEs was 5-times higher in BRCA2(+/-) compared to wild-type members, while in the second cluster BRCA2(+/-) members had 8.9% of metaphases with multiple SCEs compared to a level below detection in BRCA2 wild types. To investigate the correlation between SCE and genomic instability in 9p, we performed fluorescence detection of SCEs and FISH analysis with 9p probes. The frequency of SCE in 9p of BRCA2 mutation carriers was 3-4 fold (P=0.005) higher compared to BRCA2 wild-types. Collectively, the increased rates of SCE in BRCA2 heterozygous mutation carriers indicate a BRCA2 haploinsufficiency, which might be an important factor for the accumulation of structural chromosomal alterations with the consequence of damage in as yet unidentified genes. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15172125
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  • 10
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; human ; INHIBITION ; COMMON ; incidence ; POPULATION ; SITE ; SITES ; GENE ; GENOME ; RESOLUTION ; DNA ; MECHANISM ; recombination ; OPEN READING FRAME ; SEQUENCE ; chromosome ; FORM ; IDENTIFICATION ; AMPLIFICATION ; HUMANS ; NUMBER ; MUTATION ; genetics ; COMPONENT ; DATABASE ; HUMAN GENOME ; REGION ; INSTABILITY ; STABILITY ; CARRIERS ; INDIVIDUALS ; heredity ; LOCATION ; common fragile sites ; MAPS ; CHROMOSOMES ; DNA-SEQUENCE ; ONCOLOGY ; DISORDERS ; RE ; BRCA2 ; INCREASE ; TUMORIGENESIS ; MUTATION CARRIERS ; BREAKPOINTS ; analysis ; USA ; genomic ; CHROMOSOME-9 ; BRCA2 MUTATION ; CHROMOSOME BREAKAGE ; FRA16D
    Abstract: Common fragile sites represent a component of normal chromosome structure that form gaps and breaks on metaphase chromosomes after partial inhibition of DNA synthesis. In humans, cytogenetic locations of 89 common fragile sites are listed in the Genome Database; however, the exact number of fragile sites remains unknown. The application of high resolution mapping approaches continues to reveal new common fragile sites in the human genome. Here, we identified a novel aphidicolin-inducible common fragile site FRA9G which maps to chromosomal band 9p22.2. We have characterized the structure of the fragile DNA sequence that extends over a genomic region of similar to 300 kb within the C9orf39 (chromosome 9 open reading frame 39) gene. Analysis of incidence in healthy individuals showed that FRA9G is commonly expressed in the population. Heterozygous BRCA2 mutation carriers exhibit an almost sevenfold increase of FRA9G expression compared to an unrelated control population group. Identification of a novel aphidicolin-inducible common fragile site at 9p22 may have implications for understanding the mechanism of genetic instability in tumorigenesis and other genetic disorders. (C) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17668870
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