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  • Germany  (48)
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  • 11
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; GENE ; PROTEIN ; PROTEINS ; TISSUE ; MICE ; TUMOR-NECROSIS-FACTOR ; DNA ; MACROPHAGES ; MECHANISM ; CONTRAST ; DENDRITIC CELLS ; KERATINOCYTES ; mechanisms ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; treatment ; cytokines ; TARGET ; MUTANT ; inactivation ; DNA-BINDING ; BETA ; MOUSE MODEL ; TARGETS ; side effects ; REPRESSION ; DIMERIZATION ; chemokine ; TNF-ALPHA ; NEUTROPHILS ; CYTOKINE ; molecular ; PERSISTENT ; RECOMBINANT ; INFILTRATION ; MOLECULAR-MECHANISM ; RE ; keratinocyte ; allergy ; IMMUNE SUPPRESSION ; chemokines ; INFLAMMATORY CYTOKINES ; MOLECULAR-MECHANISMS ; PHASE ; USA ; corticosteroids ; GLUCOCORTICOIDS ; RESISTANT ; SKIN INFLAMMATION ; CONTACT ; MEDICINE ; INFLAMMATORY RESPONSE ; EPIDERMAL LANGERHANS CELLS ; HYPERSENSITIVITY REACTIONS ; INFLAMMATORY PROTEIN-2
    Abstract: Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the and inflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1 beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required
    Type of Publication: Journal article published
    PubMed ID: 17446934
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  • 12
    Keywords: RECEPTOR ; EXPRESSION ; proliferation ; Germany ; IN-VIVO ; MODEL ; VIVO ; SUPPORT ; liver ; GENE ; GENE-EXPRESSION ; microarray ; transcription ; DRUG ; METABOLISM ; MICE ; ACTIVATION ; LIGAND ; DNA ; MECHANISM ; DOMAIN ; mechanisms ; BINDING ; DISCOVERY ; RECOGNITION ; ACID ; TARGET ; MOUSE ; gene expression ; MICROARRAY DATA ; DISRUPTION ; WOMEN ; DNA-BINDING ; EXCHANGE ; LIGANDS ; PHENOTYPE ; MOUSE MODEL ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; expression profiling ; ER ; ESTROGEN-RECEPTOR ; TRANSCRIPTIONAL REGULATION ; MAMMARY-GLAND ; regulation ; AMINO-ACID ; DRUG DISCOVERY ; MOUSE-LIVER ; development ; ESTROGEN ; LOCUS ; estrogen receptor ; USA ; DNA binding ; AGREEMENT ; BREAST-CANCER CELLS ; ESTROGENS ; POSITION ; RECEPTOR-ALPHA ; Genetic ; ALPHA GENE ; ER-ALPHA ; HORMONE-THERAPY ; MUTATION PROVIDES EVIDENCE
    Abstract: The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER)alpha, which regulates transcription by several mechanisms. Because the tissue-specific effects of some ER alpha ligands may be caused by tissue-specific transcriptional mechanisms of ER alpha, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs. independent transcriptional regulation elicited by ER alpha. The EAAE mutant harbors amino acid exchanges at four positions of the DNA-binding domain (DBD) of ER alpha. This construct was knocked in the ER alpha gene locus to produce ER alpha((EAAE/ EAAE)) mice devoid of a functional ER alpha DBD. The phenotype of the ER alpha((EAAE/EAAE)) mice resembles the general loss-of-function phenotype of alpha ER knockout mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ER alpha((EAAE/EAAE)) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison with the wild type. Further gene expression analyses to validate the results of the microarray data were performed by quantitative RT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ER alpha rely on an intact DBD in vivo. (Molecular Endocrinology 23: 1544-1555, 2009)
    Type of Publication: Journal article published
    PubMed ID: 19574448
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  • 13
    Keywords: brain ; RECEPTOR ; ANGIOGENESIS ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; THERAPY ; LONG-TERM ; GENE ; transcription ; TISSUE ; TUMORS ; MICE ; TRANSCRIPTION FACTOR ; prognosis ; BIOLOGY ; LESIONS ; AGE ; genetics ; p53 ; B-CELLS ; MIGRATION ; STEM-CELLS ; MOUSE MODEL ; FREQUENT ; OVEREXPRESSION ; POOR-PROGNOSIS ; GLIOMAS ; brain tumor ; BRAIN-TUMORS ; TUMOR-SUPPRESSOR ; GLIOMA ; MALIGNANT GLIOMA ; development ; neurogenesis ; tailless ; MOUSE MODELS ; B-CELL ; EXPANSION ; GLIOBLASTOMA ; SELF-RENEWAL ; HUMAN GLIOBLASTOMA-MULTIFORME ; CELL BIOLOGY ; MAMMALIAN BRAIN ; Genetic ; GLIOBLASTOMAS ; BRAIN-TISSUE ; CONTRIBUTE ; ADULT SUBVENTRICULAR ZONE ; GLIAL TUMORS ; neural stem cells ; VASCULAR NICHE
    Abstract: Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors
    Type of Publication: Journal article published
    PubMed ID: 20360385
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  • 14
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; proliferation ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; LONG-TERM ; GENE-EXPRESSION ; METABOLISM ; DIFFERENTIATION ; TISSUE ; MICE ; NF-KAPPA-B ; MECHANISM ; CONTRAST ; mechanisms ; BIOLOGY ; CELL-CYCLE ; SUPPRESSION ; cytokines ; MOUSE ; hormone ; AGE ; MUTATION ; LINE ; DNA-BINDING ; PHENOTYPE ; NF-kappa B ; BONE-FORMATION ; CYTOKINE ; osteoblast ; development ; TECHNOLOGY ; BONE ; INHIBIT ; CELL BIOLOGY ; OSTEOBLASTS ; BONE FORMATION ; NF kappa B ; INDUCED OSTEOPOROSIS ; INTERLEUKIN-11 ; OSTEOCLAST
    Abstract: Development of osteoporosis severely complicates long-term glucocorticoid (GC) therapy. Using a Cre-transgenic mouse line, we now demonstrate that GCs are unable to repress bone formation in the absence of glucocorticoid receptor (GR) expression in osteoblasts as they become refractory to hormone-induced apoptosis, inhibition of proliferation, and differentiation. In contrast, GC treatment still reduces bone formation in mice carrying a mutation that only disrupts GR dimerization, resulting in bone loss in vivo, enhanced apoptosis, and suppressed differentiation in vitro. The inhibitory GC effects on osteoblasts can be explained by a mechanism involving suppression of cytokines, such as interleukin 11, via interaction of the monomeric GR with AP-1, but not NF-kappa B. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy
    Type of Publication: Journal article published
    PubMed ID: 20519123
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  • 15
    Keywords: brain ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; proliferation ; SURVIVAL ; CELL ; Germany ; DEATH ; POPULATION ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; DIFFERENTIATION ; NF-KAPPA-B ; TRANSCRIPTION FACTOR ; REDUCTION ; NERVOUS-SYSTEM ; STAGE ; gene expression ; CELL-DEATH ; NUMBER ; inactivation ; FACTOR-I ; ELIMINATION ; ADULT ; DEFICIENT MICE ; development ; cell death ; bcl-X ; NF kappa B ; CHOLINERGIC DIFFERENTIATION ; HOMEOBOX GENE PHOX2B ; NORADRENERGIC PHENOTYPE ; PRECURSOR CELLS ; SEROTONERGIC NEURONS
    Abstract: The transcription factor Gata3 is essential for the development of sympathetic neurons and adrenal chromaffin cells. As Gata3 expression is maintained up to the adult stage, we addressed its function in differentiated sympathoadrenal cells at embryonic and adult stages by conditional Gata3 elimination. Inactivation of Gata3 in embryonic DBH-expressing neurons elicits a strong reduction in neuron numbers due to apoptotic cell death and reduced proliferation. No selective effect on noradrenergic gene expression (TH and DBH) was observed. Interestingly, Gata3 elimination in DBH-expressing neurons of adult animals also results in a virtually complete loss of sympathetic neurons. In the Gata3-deficient population, the expression of anti-apoptotic genes (Bcl-2, Bcl-x(L), and NF kappa B) is diminished, whereas the expression of pro-apoptotic genes (Bik, Bok, and Bmf) was increased. The expression of noradrenergic genes (TH and DBH) is not affected. These results demonstrate that Gata3 is continuously required for maintaining survival but not differentiation in the sympathetic neuron lineage up to mature neurons of adult animals
    Type of Publication: Journal article published
    PubMed ID: 20702712
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  • 16
    Keywords: Germany ; DISEASE ; RNA ; transcription ; DNA ; CELL-DEATH ; UP-REGULATION ; p53 ; TIF-IA ; RIBOSOMAL-RNA SYNTHESIS ; MTOR PATHWAY ; PROTECTS MICE
    Abstract: The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.
    Type of Publication: Journal article published
    PubMed ID: 21228155
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  • 17
    Keywords: brain ; Germany ; LONG-TERM ; GENE ; PROTEIN ; transcription ; TRANSCRIPTION FACTOR ; REDUCTION ; WATER ; MEMORY ; FORM ; CAMP ; CELL-SURVIVAL ; conditioned taste aversion ; CONDITIONED TASTE-AVERSION ; CREB ; DEFICITS ; DELETION ; ELEMENT ; ELEMENT-BINDING PROTEIN ; ELEMENT-BINDING-PROTEIN ; fear conditioning ; hippocampus ; ISOFORM ; ISOFORMS ; knockout ; LATE-PHASE ; learning ; LONG-TERM POTENTIATION ; LTD ; LTP ; MAP KINASE ; MOUSE ; MOUSE-BRAIN ; MUTANT ; NERVOUS-SYSTEM ; NO ; PERFORMANCE ; PROBE ; RESPONSE ELEMENT ; score ; STAGE ; synaptic plasticity ; TARGETED MUTATION ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; TRIAL ; TRIALS ; WATER MAZE
    Abstract: Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors
    Type of Publication: Journal article published
    PubMed ID: 12867515
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  • 18
    Keywords: brain ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; MODEL ; VITRO ; SYSTEM ; NEW-YORK ; GENE ; GENOME ; PROTEIN ; recombination ; ALPHA ; MOUSE ; PROMOTER ; PROMOTERS ; inactivation ; BETA ; alpha complementation,iCre recombinase,IoxP ; COMPLEMENTATION ; POLYPEPTIDE ; SITE-SPECIFIC RECOMBINATION
    Abstract: The Cre-IoxP system is increasingly exploited for spatial and temporal gene inactivation. Here we present a novel approach to achieve this goal of selective gene inactivation. Following the model of complementation in the beta-galactosidase enzyme, where the enzyme is split into independent polypeptides which are able to associate and maintain the enzymatic activity, we divided the Cre recombinase into two independent polypeptides (one containing the NH2 terminus (alpha) and a second one containing the COOH-terminus (beta)). Individually, the two polypeptides have no detectable activity. However, when coexpressed the polypeptides are able to associate, giving rise to Cre enzymatic activity, which optimally is as high as 30% of that seen with wildtype Cre recombinase in vitro. We present this strategy as a modification of the traditional Cre-IoxP system, which could be used to obtain a highly specific recombination pattern by expressing the two halves under the control of separate promoters. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14502574
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  • 19
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; PROSTATE ; INFORMATION ; GENE ; HYBRIDIZATION ; microarray ; RNA ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; MESSENGER-RNA ; QUALITY ; TISSUES ; CYCLE ; AMPLIFICATION ; NUMBER ; REPRODUCIBILITY ; PCR ; STRATEGIES ; REVERSE TRANSCRIPTION ; CDNA SYNTHESIS ; linear RNA amplification-,laser-assisted microdissection,small-amount RNA,reverse transcription,olig ; SINGLE-CELL
    Abstract: Microarray-based gene profiling of laser-assisted microdissected tissues or clinical biopsies is still a challenge since the amount of total RNA in such samples is limited and amplification of RNA is mandatory. Representative amplification of mRNA is highly dependent on the reverse transcription reaction, which is error prone, and on the number of amplification cycles. To improve the accuracy of RNA amplification, we optimized, combined, and tested different amplification strategies for Affymetrix oligonucleotide array hybridization. We demonstrate that different protocols differ significantly in quality of mRNA amplification. To demonstrate the accuracy and reproducibility of our optimized protocol in a clinical setting, we analyzed total RNAs from laser-assisted, microdissected cells of human prostate tissues. On the basis of these results, we recommend a standard reverse transcription reaction for small-sample-transcriptome profiling experiments as part of the Minimal Information about a Microarray Experiment (MIAME) set of standards. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15028277
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  • 20
    Keywords: RECEPTOR ; EXPRESSION ; BLOOD ; CELL ; Germany ; IN-VIVO ; liver ; ENZYMES ; GENE ; GENES ; transcription ; METABOLISM ; MICE ; ACTIVATION ; kidney ; TRANSCRIPTION FACTOR ; INDUCTION ; hepatocytes ; MUTANT ; hormone ; DISRUPTION ; TANDEM MASS-SPECTROMETRY ; inactivation ; Jun ; GLUCOSE ; glucocorticoid receptor ; GLUCOCORTICOID-RECEPTOR ; ANTAGONIST ; insulin ; ABSENCE ; ADULT ; ENDOCRINE ; LEADS ; development ; CARBOXYKINASE GTP GENE ; HEPATIC GLUCONEOGENESIS ; PHOSPHOENOLPYRUVATE CARBOXYKINASE ; TYROSINE AMINOTRANSFERASE GENE
    Abstract: Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia
    Type of Publication: Journal article published
    PubMed ID: 15031319
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