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  • 1
    Keywords: EXPRESSION ; KINASE ; PATHWAY ; GENE ; ELEMENT-BINDING PROTEIN ; EMBRYO ; TUMOR-GROWTH ; MICE LACKING ; HUMAN-MELANOMA CELLS ; MESODERM FORMATION
    Abstract: Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1(-/-) CREB(-/-) embryos die before implantation due to developmental arrest. ATF1(+/-) CREB(-/-) embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.
    Type of Publication: Journal article published
    PubMed ID: 11865068
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; IRRADIATION ; proliferation ; SURVIVAL ; CELL ; COMBINATION ; IN-VIVO ; VIVO ; GENERATION ; PROTEIN ; PROTEINS ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSCRIPTION FACTOR ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; CELL-SURVIVAL ; ELEMENT ; ELEMENT-BINDING PROTEIN ; knockout ; MUTANT ; NO ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; PROMOTER ; transgenic ; RESPONSIVE ELEMENT ; T lymphocyte ; OVEREXPRESSION ; rodent ; T lymphocytes ; BINDING PROTEIN ; thymus ; BINDING-PROTEIN ; IL-2 PRODUCTION ; MOLECULAR-BASIS
    Abstract: Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (CAMP responsive element binding protein) and the related proteins CREM (CAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo
    Type of Publication: Journal article published
    PubMed ID: 15214044
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  • 3
    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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  • 4
    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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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; Germany ; IN-VIVO ; INHIBITION ; PATHWAY ; PATHWAYS ; VITRO ; DEATH ; GENE ; MICE ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; T-CELL ; T-CELLS ; BINDING ; signal transduction ; CD95 ligand ; CELL-DEATH ; PROMOTER ; MUTATION ; SIGNAL-TRANSDUCTION ; inactivation ; FACTOR-KAPPA-B ; glucocorticoid receptor ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; CROSS-TALK ; CD95 ; signaling ; molecular ; PROGRAM ; RE ; PH ; regulation ; RHEUMATOID-ARTHRITIS ; INFLAMMATORY RESPONSES ; cell death ; ABILITY ; APOPTOTIC CELLS ; FAS LIGAND ; NEGATIVE REGULATION ; THYMOCYTE DEVELOPMENT
    Abstract: Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs
    Type of Publication: Journal article published
    PubMed ID: 15802531
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  • 6
    Keywords: brain ; RECEPTOR ; EXPRESSION ; Germany ; MODEL ; MODELS ; SYSTEM ; EXPOSURE ; GENE ; PROTEIN ; MICE ; PATIENT ; MECHANISM ; MESSENGER-RNA ; RECEPTOR EXPRESSION ; chromosome ; MOUSE ; TRANSGENIC MICE ; hormone ; YEAST ; STRESS ; PATHOGENESIS ; DNA-BINDING ; Jun ; glucocorticoid receptor ; sensitivity ; BEHAVIOR ; OVEREXPRESSION ; GLUCOCORTICOID-RECEPTOR ; signaling ; molecular ; regulation ; KNOCKOUT MICE ; NEUROTROPHIC FACTOR ; FOREBRAIN ; RAT HIPPOCAMPUS ; depression ; DEXAMETHASONE-CRH TEST ; helplessness
    Abstract: Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR(+/-)) with a 50% GRgene dose reduction, and (2) mice overexpressingGR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR(+/-) mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR(+/-) mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression
    Type of Publication: Journal article published
    PubMed ID: 15987954
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  • 7
    Keywords: EXPRESSION ; IN-VITRO ; SURVIVAL ; MODEL ; GENE-EXPRESSION ; MICE ; ACTIVATION ; MAP KINASE ; DNA-BINDING ; KAPPA-B ; REPRESSION ; INFLAMMATORY RESPONSES ; dexamethasone ; CLP ; GR ; IL-1 beta ; PHOSPHATASE-1
    Abstract: Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-alpha is normally regulated in these mice, but down-regulation of IL-6 and IL-1 beta is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1 beta in macrophages by GCs is pivotal to control sepsis.-Kleiman, A., Hubner, S., Rodriguez Parkitna, J. M., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schutz, G., Libert, C., Reichardt, H. M., Tuckermann, J. P. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.
    Type of Publication: Journal article published
    PubMed ID: 22042221
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  • 8
    Keywords: RECEPTOR ; EXPRESSION ; CELL ; Germany ; GENERATION ; SYSTEM ; GENE-EXPRESSION ; RNA ; EFFICIENCY ; MICE ; TRANSCRIPTION FACTOR ; BIOLOGY ; MOLECULAR-BIOLOGY ; ACIDS ; TRANSGENIC MICE ; NUCLEAR-FACTOR ; DESIGN ; VECTOR ; LINE ; DELIVERY ; MAMMALIAN-CELLS ; STEM-CELLS ; NETHERLANDS ; molecular biology ; molecular ; RE ; INTERFERENCE ; RNA INTERFERENCE ; GAMMA ; LENTIVIRAL VECTOR ; methods ; NUCLEAR ; function ; TRANSMISSION ; microbiology ; lentiviral vectors ; MicroRNAs ; mosaicism ; biotechnology ; INTERFERING RNAS ; SIRNAS ; Transgenesis ; TRANSGENIC RATS
    Abstract: We have used a lentiviral delivery system (LentiLox3.7) to generate transgenic mice harbouring RNA interference (RNAi) against the hepatocyte nuclear factor 4 gamma (HNF4(gamma)). HNF4(gamma) is a nuclear receptor with unknown function. Our analyses performed on founder (F-0) and first generation (F-1) mice revealed mosaicism in F-0 founders and a low efficiency of transgenesis (6%) in F-1 mice. These data, together with the observation of multiple silenced transgenes, do not favour the use of LentiLox3.7 lentivirus for transgenesis. Despite the low efficiency of transgenesis, we achieved a tissue-dependent knockdown of HNF4(gamma) expression in some mice
    Type of Publication: Journal article published
    PubMed ID: 17682835
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