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  • 1
    Keywords: APOPTOSIS ; INHIBITION ; GENE ; DOWN-REGULATION ; COLORECTAL-CANCER ; CELL-GROWTH ; COLONY FORMATION ; OSTEOPONTIN ; EGR-1 EXPRESSION ; ACTIVATING TRANSCRIPTION FACTOR-3
    Abstract: Increased bone sialoprotein (BSP) serum levels are related to breast cancer skeletal metastasis, but their relevance is unknown. We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette containing a tet-regulated miRNA providing knockdown of BSP production. These clones were used to assess the effect of BSP on morphology, proliferation, migration, colony formation and gene expression in vitro, and on soft tissue and osteolytic lesions in a xenograft model by three imaging methods. BSP knockdown caused significant anti-proliferative, anti-migratory and anti-clonogenic effects in vitro (p〈0.001). In vivo, significant decreases of soft tissue and osteolytic lesions (p〈0.03) were recorded after 3 weeks of miRNA treatment, leading to complete remission within 6 weeks. Microarray data revealed that 0.3% of genes were modulated in response to BSP knockdown. Upregulated genes included the endoplasmic reticulum stress genes ATF3 and DDIT3, the tumor suppressor gene EGR1, ID2 (related to breast epithelial differentiation), c-FOS and SERPINB2, whereas the metastasis associated genes CD44 and IL11 were downregulated. Also, activation of apoptotic pathways was demonstrated. These results implicate that intracellular BSP is essential for breast cancer skeletal metastasis and a target for treating these lesions.
    Type of Publication: Journal article published
    PubMed ID: 24980816
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  • 2
    Keywords: TARGET ; CELL-LINE ; LINE ; ONCOLOGY ; GENES ; GENE ; CELL ; GENERATION ; TARGET GENES
    Type of Publication: Meeting abstract published
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  • 3
    Keywords: brain ; RECEPTOR ; CELLS ; PATHWAY ; PATHWAYS ; GENE ; GENES ; RELEASE ; RESPONSES ; MECHANISM ; FREQUENCY ; hormone ; STRESS ; inactivation ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; glucocorticoid receptor ; LIVING CELLS ; RECEPTORS ; GLUCOCORTICOID-RECEPTOR ; ANTAGONIST ; rodent ; SUBCELLULAR-LOCALIZATION ; signaling ; NEURONS ; LIFE ; ENHANCEMENT ; ESTROGEN ; corticosteroid ; mineralocorticoid receptor ; LEVEL ; function ; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor CA1 hippocampus ; glucocorticoid receptor knockout ; MICRODIALYSIS ; mineralocorticoid receptor knockout ; miniature excitatory postsynaptic current ; RAT HIPPOCAMPUS ; SYNAPSES
    Abstract: The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways
    Type of Publication: Journal article published
    PubMed ID: 16361444
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  • 4
    Keywords: CANCER ; EXPRESSION ; Germany ; GENE ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; SURGERY ; LINES ; PATIENT ; COMPLEX ; DOMAIN ; tumour ; CELL-LINES ; SEQUENCE ; PROGRESSION ; ASSAY ; Drosophila ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; LINE ; REGION ; MUTATIONS ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; cell lines ; CELL-MIGRATION ; BINDS ; CELL POLARITY ; MAPS ; colon cancer ; TUMORIGENESIS ; cell adhesion ; cell migration ; ASSAYS ; SUPPRESSOR ; tumour suppressor ; APC ; 17P11.2 ; Hugl-1 ; II HEAVY-CHAIN ; LETHAL-GIANT-LARVAE ; lgl
    Abstract: The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal( 2) giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression
    Type of Publication: Journal article published
    PubMed ID: 15735678
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  • 5
    Keywords: COHORT ; POPULATION ; RISK ; GENE ; DIFFERENTIATION ; AIR-POLLUTION ; SKIN ; T-CELLS ; ASSOCIATION ; polymorphism ; DESIGN ; PREVALENCE ; asthma ; ATOPY ; CYTOKINE ; REGISTRY ; IL-18 ; INTERVAL ; single-nucleotide ; single-nucleotide polymorphism ; haplotype-tagging ; allergic rhinitis ; cohort analysis ; RISK-FACTOR ; population-based ; general population ; BRONCHIAL-ASTHMA ; IGE LEVELS ; IL18 GENE ; LUNG-DISEASES
    Abstract: IL-18 is a pleiotrophic cytokine involved in both, T-helper type 1 (Th1) and Th2 differentiation. Recently genetic variants in the IL-18 gene have been associated with increased risk of atopy and asthma. To examine the relationship of a genetic, haplotype-tagging promotor variant -137G/C in the IL-18 gene with atopic asthma in a large, well-characterized and population-based study of adults. Prospective cohort study design was used to collect interview and biological measurement data at two examination time-points 11 years apart. Multivariate logistic regression analysis was used to assess the association of genotype with asthma and atopy. The G-allele of the IL-18 promotor variant (-137G/C) was associated with a markedly increased risk for the prevalence of physician-diagnosed asthma with concomitant skin reactivity to common allergens. Stratification of the asthma cases by skin reactivity to common allergens revealed an exclusive association of IL-18 -137 G-allele with an increased prevalence of atopic asthma (adjusted odds ratio (OR): 3.63; 95% confidence interval: (1.64-8.02) for GC or GG carriers vs. CC carriers), and no according association with asthma and concomitant negative skin reactivity (adjusted OR: 1.13; 0.66-1.94). The interaction between IL-18 -137G/C genotype and positive skin prick test was statistically significant (P=0.029). None of 74 incident asthma cases with atopy at baseline exhibited the CC genotype. Our results strongly suggest that this variant of the IL-18 gene is an important genetic determinant involved in the development of atopic asthma
    Type of Publication: Journal article published
    PubMed ID: 16433859
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  • 6
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; proliferation ; SURVIVAL ; CELL ; Germany ; INHIBITION ; SYSTEM ; DEATH ; GENE ; GENES ; RNA ; transcription ; MICE ; ACTIVATION ; TRANSCRIPTION FACTOR ; INDUCTION ; hippocampus ; NERVOUS-SYSTEM ; TRANSCRIPTIONAL ACTIVITY ; DISRUPTION ; CELL-DEATH ; STRESS ; inactivation ; p53 ; STRATEGIES ; INTERACTS ; HEALTHY ; molecular ; ADULT ; RE ; FACTOR TIF-IA ; NEURONS ; ABLATION ; LEVEL ; cell death ; nucleolus ; RNA polymerase I ; progenitor ; INDUCE ; USA ; LOSSES ; neurodegeneration ; PROGENITORS ; DEGENERATION ; NOV ; response ; synthesis ; POLYMERASE ; STATE ; RNA-POLYMERASE ; neural progenitors ; rRNA transcription ; TRANSCRIPTION ACTIVITY
    Abstract: Transcription of rRNA genes is essential for maintaining nucleolar integrity, a hallmark for the healthy state and proliferation rate of a cell. Inhibition of rRNA synthesis leads to disintegration of the nucleolus, elevated levels of p53, and induction of cell suicide, identifying the nucleolus as a critical stress sensor. Whether deregulation of rRNA synthesis is causally involved in neurodegeneration by promoting cell death and/or by inhibiting cellular growth has however not been addressed. The transcription factor TIF-IA plays a central role in mammalian rRNA synthesis, regulating the transcriptional activity of RNA polymerase I. To investigate the consequences of nucleolar perturbation in the nervous system, we have chosen to specifically ablate the gene encoding the transcription factor TIF-IA in two different contexts: neural progenitors and hippocampal neurons. Here, we show that ablation of TIF-IA leads to impaired nucleolar activity and results in increased levels of the proapoptotic transcription factor p53 in both neural progenitors and hippocampal neurons but induces rapid apoptosis only in neural progenitors. Nondividing cells of the adult hippocampus are more refractory to loss of rRNA transcription and face a protracted degeneration. Our study provides an unexploited strategy to initiate neurodegeneration based on perturbation of nucleolar function and underscores a novel perspective to study the cellular and molecular changes involved in the neurodegenerative processes
    Type of Publication: Journal article published
    PubMed ID: 19036968
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  • 7
    Keywords: brain ; RECEPTOR ; EXPRESSION ; GROWTH ; evaluation ; Germany ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VIVO ; SUPPORT ; SYSTEM ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; PROTEINS ; transcription ; MICE ; ACTIVATION ; RESPONSES ; DNA ; TRANSCRIPTION FACTOR ; hepatocytes ; INTERVENTION ; MR ; BINDING ; MEMORY ; TARGET ; MOUSE ; TRANSCRIPTION FACTORS ; hormone ; IDENTIFICATION ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; DISRUPTION ; MUTATION ; DISPLAY ; DNA-BINDING ; MUTATIONS ; US ; MOUSE MODEL ; glucocorticoid receptor ; BODY ; side effects ; RECEPTORS ; INSIGHTS ; CRE RECOMBINASE ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; DIMERIZATION ; immunosuppression ; DISSECTION ; steroid ; signaling ; targeting ; BODIES ; molecular ; RE ; INTERFERENCE ; RESOURCE ; regulation ; gene targeting ; GENE-REGULATION ; GENE-TRANSCRIPTION ; MOUSE MODELS ; TARGET GENE ; corticosteroid ; gene regulation ; mineralocorticoid receptor ; SI
    Abstract: Functional genomic technologies, including artificial chromosome-based transgenesis and conditional gene targeting, allowed us to generate mouse models harboring genes with loss-of-function mutations, gain-of-function mutations, spatially and/or temporally restricted mutations, tissue-specific mutations, and function-selective mutations. This kind of "allelic series" for corticosteroid receptors in mouse models provides a very useful resource for the molecular understanding of corticosteroid function in vivo. These models will also support the identification of steroid receptor target genes in order to define a steroid signaling cascade in molecular terms. They provide opportunities for the identification of compounds that regulate steroid receptors in a tissue-specific and function-selective manner. For example, selective glucocorticoid receptor modulators preventing receptor dimerization and DNA binding can be expected to reduce osteoporotic and/or diabetogenic side effects, but to display partial or full anti-inflammatory potential. Thus, these mouse models will help to evaluate distinct steroid receptor functions for therapeutic intervention.
    Type of Publication: Journal article published
    PubMed ID: 15241729
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  • 8
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; INHIBITOR ; Germany ; GENE ; GENE-EXPRESSION ; microarray ; PROTEIN ; PROTEINS ; TISSUE ; DNA ; treatment ; gene expression ; microarrays ; ARRAYS ; DEGRADATION ; protein expression ; INHIBITORS ; FEATURES ; ONCOLOGY ; ARRAY ; RHEUMATOID-ARTHRITIS ; LEVEL ; analysis ; OSTEOPONTIN ; IMMUNOHISTOCHEMICAL ANALYSIS ; bone sialoprotein ; comparison ; GIANT-CELL TUMOR ; HORMONE-RELATED PROTEIN ; PVNS ; RANKL
    Abstract: Protein expression of osteopontin (OPN), osteoprotegerin (OPG), bone sialoprotein (BSP), osteocalcin (OC), RANK L and PTHrP was determined by use of immunohistochemical analysis on tissue arrays (48 cases of PVNS, 20 cases of active (a-RA), non-active rheumatoid arthritis (na-RA), and osteoarthritis (OA)). Additionally, gene expression was analysed using complimentary DNA (cDNA) microarrays. All PVNS cases showed a higher level of both protein and gene expression of RANKL, OPN and BSP in comparison with OA cases. Expression of OPG was not significantly different in PVNS compared to CIA. The RANKL/OPG expression ratio was significantly higher in PVNS than in OA. High expressions level of proteins involved in bone degradation in PVNS may promote an intra-osseous propagation of the lesion. This evidence suggests that PVNS might respond to treatment using specific inhibitors of RANKL, OPN and BSP. (c) 2007 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17601661
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  • 9
    Keywords: RECEPTOR ; EXPRESSION ; NETWORK ; GENE ; GENE-EXPRESSION ; GENES ; MICE ; MESSENGER-RNA ; primary ; MR ; culture ; MOUSE ; IDENTIFICATION ; gene expression ; CELL-DEATH ; genetics ; INVOLVEMENT ; glucocorticoid receptor ; specificity ; heredity ; genomics ; HEART-FAILURE ; mineralocorticoid receptor ; analysis ; USA ; corticosteroids ; GLUCOCORTICOIDS ; genomic ; microbiology ; SET ; transcriptome ; biotechnology ; PERIPHERAL-TISSUES ; aldosterone ; CA2+ CURRENT ; cardiomyocytes ; gene networks ; NEONATAL-RAT ; SODIUM-TRANSPORT
    Abstract: Corticosteroids (aldosterone, cortisol/corticosterone) exert direct functional effects on cardiomyocytes. However, gene networks activated by corticosteroids in cardiomyocytes, as well as the involvement of the mineralocorticoid receptor (MR) vs the glueocorticoid receptor (GR) in these effects, remain largely unknown. Here we characterized the corticosteroid-dependent transcriptome in primary culture of neonatal mouse cardiomyocytes treated with 10(-6) M aldosterone, a concentration predicted to occupy both MR and GR. Serial analysis of gene expression revealed 101 alclosterone-regulated genes. The MR/GR specificity was characterized for one regulated transcript, namely ecto-ADP-ribosyltransferase-3 (Art3). Using cardiomyocytes from GR(null/null) or MR(null/null) mice we demonstrate that in GR(null/null) cardiomyocytes the response is abrogated, but it is fully maintained in MR(null/null) cardiomyocytes. We conclude that Art3 expression is regulated exclusively via the GR. Our study identifies a new set of corticosteroid-regulated genes in cardiomyocytes and demonstrates a new approach to studying the selectivity of MR- vs GR-dependent effects. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17174066
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  • 10
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; Germany ; neoplasms ; THERAPY ; FOLLOW-UP ; DISEASE ; GENE ; TISSUE ; TUMORS ; PATIENT ; chromosome ; PROGRESSION ; AMPLIFICATION ; DESIGN ; resistance ; STRESS ; chemotherapy ; RESECTION ; PRODUCT ; MULTIVARIATE ; PROGNOSTIC VALUE ; sensitivity ; experimental design ; 1p ; CHROMOSOMES ; GENE-PRODUCT ; ONCOLOGY ; RE ; PRODUCTS ; THERAPIES ; END ; GRADE ; biomarker ; oligodendroglioma ; ANAPLASTIC OLIGODENDROGLIOMAS ; HISTOLOGY ; USA ; LOSSES ; OLIGODENDROGLIAL TUMORS ; cancer research ; EXTENT ; - ; PROGRESSION-FREE SURVIVAL ; outcome ; PHASE-III TRIAL
    Abstract: Purpose: The combined loss of genetic material on chromosomes 1p and 19q is strongly associated with favorable outcome in patients with WHO grade 3 anaplastic oligodendroglial tumors. The prognostic value of 1p/19q loss in WHO grade 2 oligodendroglial tumors is less well defined. Importantly, the possible effect of combined 1p/19q loss has not been studied in patients who were! not treated with radiotherapy or chemotherapy. Experimental Design: Seventy-six patients with oligodendroglioma (n = 33), oligoastrocytoma (n = 30), anaplastic oligodendroglioma (n = 6), or anaplastic oligoastrocytoma (n = 7) were identified who had not received radiotherapy or chemotherapy after their first operation until the end of follow-up or until the first progression and had tissue for 1p/19q status available. 1p/19q status was assessed by multiplex ligation - dependent probe amplification. Results: After a median follow-up of 3.8 years, progressive disease was documented in 34 patients. The estimated median progression-free survival was 4.6 years. Fifty-eight of the 76 patients had a combined loss of 1p and 19q. The absence or presence of combined 1p/19q loss was not prognostic for progression-free survival using multivariate adjustment for histology, extent of resection, and gender. Conclusions: Combined 1p/19q loss is not a sensitive prognostic biomarker in patients with oligodendroglial tumors who do not receive radiotherapy or chemotherapy. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress
    Type of Publication: Journal article published
    PubMed ID: 18056167
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