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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; BLOOD ; CELL ; KINASE ; PATHWAY ; PATHWAYS ; liver ; DISTINCT ; PROTEIN ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSPLANTATION ; BINDING ; PROTEIN-KINASE ; SIGNAL ; DELETION ; FUSION ; DNA-BINDING ; SIGNALING PATHWAY ; STEM-CELLS ; CONSTITUTIVE ACTIVATION ; RECEPTORS ; HEMATOPOIETIC-CELLS ; ERYTHROPOIETIN ; STAT5A(-/-)5B(-/-) MICE ; C-KIT ; signaling ; HEMATOPOIESIS ; stem cells ; progenitor ; USA ; SELF-RENEWAL ; STEM ; MYELOPROLIFERATIVE DISORDERS ; TYROSINE KINASE JAK2 ; ERYTHROID PROGENITORS ; FETAL ; myeloid cells ; STEM-CELL-FACTOR ; STRESS ERYTHROPOIESIS
    Abstract: Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine-and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropolesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling
    Type of Publication: Journal article published
    PubMed ID: 18239084
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  • 2
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    Essays in Biochemistry 45 (), 109-120 
    Keywords: RECEPTOR ; CANCER ; GROWTH ; proliferation ; SURVIVAL ; CELL ; CELL-PROLIFERATION ; Germany ; human ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; NETWORKS ; SYSTEM ; SYSTEMS ; PROTEIN ; transcription ; DIFFERENTIATION ; TRANSDUCTION ; COMPLEX ; RESPONSES ; COMPLEXES ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; hepatocytes ; mechanisms ; SIMULATION ; BINDING ; BIOLOGY ; DOWN-REGULATION ; signal transduction ; SIGNAL ; TARGET ; TRANSCRIPTION FACTORS ; IDENTIFICATION ; MALIGNANCIES ; ASSAY ; PLASMA ; MEMBRANE ; SIGNAL-TRANSDUCTION ; PLASMA-MEMBRANE ; systems biology ; TARGETS ; RECEPTORS ; STAT1 ; CYTOKINE ; molecular ; MALIGNANCY ; review ; RE ; FAMILIES ; ARRAY ; cell proliferation ; MOLECULAR-MECHANISMS ; LEVEL ; analysis ; ASSAYS ; signalling ; SIGNALS ; ENGLAND ; quantitative ; response ; dynamic
    Abstract: Signalling in multicellular organisms is mediated by complex networks that integrate extracellular and intracellular signals to generate appropriate responses regulating cell proliferation, differentiation and Survival. Downstream of many cytokine and growth hormone receptors, receptor-associated JAKs (janus kinases) activate transcription factors of the STAT (signal transducer and activator of transcription) protein family and thereby mediate signal transduction from the plasma membrane to the nucleus. The JAK/STAT pathway has been shown to be Constitutively activated in a wide array of human malignancies. To elucidate mechanisms contributing to tumour formation and identify system properties of the JAK/STAT signalling pathway, a systems biology approach can be employed. So far the majority of studies available have focused on down-regulation of the signalling pathway based on simulations. However, a data-based model of the core module of the JAK2/STAT5 signalling pathway showed that rapid nucleocytoplasmic cycling of STAT5 is an essential pathway property. In the future, combining assays for quantitative analysis at different levels will be important to gain deeper insight into molecular mechanisms regulating Intracellular communication mediated by Such complex dynamic systems as signalling pathways and their targets
    Type of Publication: Journal article published
    PubMed ID: 18793127
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  • 3
    Keywords: SIMULATIONS ; Germany ; GENERATION ; NETWORKS ; SYSTEM ; SYSTEMS ; PROTEIN ; PROTEINS ; TIME ; TRANSDUCTION ; SIMULATION ; BIOLOGY ; signal transduction ; ACQUISITION ; SIGNAL-TRANSDUCTION ; PREDICTION ; systems biology ; STANDARD ; ACCURATE
    Abstract: Systems biology is an approach to the analysis and prediction of the dynamic behaviour of biological networks through mathematical modelling based on experimental data. The current lack of reliable quantitative data, especially in the field of signal transduction, means that new methodologies in data acquisition and processing are needed. Here, we present methods to advance the established techniques of immunoprecipitation and immunoblotting to more accurate and quantitative procedures. We propose randomisation of sample loading to disrupt lane correlations and the use of normalisers and calibrators for data correction. To predict the impact of each method on improving the data quality we used simulations. These studies showed that randomisation reduces the standard deviation of a smoothed signal by 55% +/- 10%. independently from most experimental settings. Normalisation with appropriate endogenous or external proteins further reduces the deviation from the true values. As the improvement strongly depends on the quality of the normaliser measurement, a criteria-based normalisation procedure was developed. Our approach was experimentally verified by application of the proposed methods to time course data obtained by the immunoblotting technique. This analysis showed that the procedure is robust and can significantly improve the quality of experimental data
    Type of Publication: Journal article published
    PubMed ID: 16986260
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  • 4
    Keywords: PEPTIDE ; RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; Germany ; IN-VIVO ; KINASE ; VITRO ; VIVO ; DISEASE ; DISEASES ; PROTEIN ; transcription ; DIFFERENTIATION ; ACTIVATION ; DOMAIN ; C-JUN ; PHOSPHORYLATION ; SIGNAL ; GLYCOPROTEIN ; PLASMA ; REGION ; PLASMA-MEMBRANE ; DOMAINS ; ERYTHROPOIETIN RECEPTOR ; CONSTITUTIVE EXPRESSION ; CYTOKINE ; BETA-SUBUNIT ; stem cells ; LEVEL ; function ; BLOCKADE ; in vivo ; TRANSMISSION ; EXTRACELLULAR DOMAINS ; MOUSE EMBRYOS ; LEUKEMIA INHIBITORY FACTOR ; IL-6 RECEPTOR ; INTERLEUKIN-6 FAMILY ; LEUCINE ZIPPERS ; ONCOSTATIN-M ; SIGNAL-TRANSDUCING RECEPTOR
    Abstract: The mode of activation of glycoprotein 130 kDa (gp130) and the transmission of the activation status through the plasma membrane are incompletely understood. In particular, the molecular function of the three juxtamembrane fibronectin III-like domains of gp130 in signal transmission remains unclear. To ask whether forced dimerization of gp130 is sufficient for receptor activation, we replaced the entire extracellular portion of gp130 with the c-jun leucine zipper region in the chimeric receptor protein L-gp130. On expression in cells, L-gp130 stimulates ligand-independent signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase 1/2 phosphorylation. gp130 activation could be abrogated by the addition of a competing peptide comprising the leucine zipper region of c-fos. When stably expressed in the interleukin-3-dependent Ba/F3 murine pre-B-cells, these cells showed constitutive STAT3 activation and cytokine-independent growth over several months. Because gp130 stimulation completely suppressed differentiation of murine embryonic stem cells in vitro, we also stably expressed L-gp130 in these cells, which completely blocked their differentiation in the absence of cytokine stimulation and was consistent with high constitutive expression levels of the stem cell factor OCT-4. Thus, L-gp130 can be used in vitro and in vivo to mimic constitutive and ligand-independent activation of gp130 and STAT3, the latter of Which is frequently observed in neoplastic diseases
    Type of Publication: Journal article published
    PubMed ID: 16624864
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  • 5
    Abstract: New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.
    Type of Publication: Journal article published
    PubMed ID: 29497170
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  • 6
    Keywords: PERSISTENT ; SUPPORT ; NEW-YORK ; ACTIVATION ; USA ; ERYTHROPOIESIS
    Type of Publication: Meeting abstract published
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