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  • 1
    Keywords: CELL-LINES ; DNA methylation ; 5-azacytidine ; PHASE-III ; ACUTE MYELOID-LEUKEMIA ; DEOXYCYTIDINE KINASE ; INTERNATIONAL WORKING GROUP ; METHYLATION PREDICTS ; DNMT INHIBITORS ; TET2 MUTATIONS
    Abstract: The nucleoside analog azacitidine (AZA) is used in the treatment of myelodysplastic syndromes (MDS), but 30-40% of patients fail to respond or relapse after treatment. Hence, to identify new molecular alterations that allow for identification of patients unlikely to respond to AZA could impact the utility of this therapy. We determined the expression levels of genes involved in AZA metabolism: UCK1, UCK2, DCK, hENT1, RRM1 and RRM2 using quantitative PCR in samples from 57 patients with MDS who received AZA. Lower expression of UCK1 was seen in patients without a response to AZA (median 0.2 vs 0.49 for patients with response to AZA, P = 0.07). This difference in UCK1 expression was not influenced by aberrant methylation of the UCK1 promoter. In addition, the seven polymorphic loci found in the coding sequence were not associated with UCK1 gene expression nor AZA response. Silencing of UCK1 by siRNA leads to blunted response to AZA in vitro. The univariate analysis revealed that patients expressing lower than median levels of UCK1 had a shorter overall survival (P = 0.049). Our results suggest that expression level of UCK1 is correlated with clinical outcome and may influence the clinical response to AZA treatment in patients with MDS.
    Type of Publication: Journal article published
    PubMed ID: 24192812
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  • 2
    ISSN: 0014-5793
    Keywords: Platelet-derived growth factor ; Rap1 ; Vascular smooth muscle cell
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 5
    Publication Date: 2014-08-27
    Description: beta-Thalassaemia major (beta-TM) is an inherited haemoglobinopathy caused by a quantitative defect in the synthesis of beta-globin chains of haemoglobin, leading to the accumulation of free alpha-globin chains that form toxic aggregates. Despite extensive knowledge of the molecular defects causing beta-TM, little is known of the mechanisms responsible for the ineffective erythropoiesis observed in the condition, which is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation. Although erythroid transcription factor GATA-1, the master transcriptional factor of erythropoiesis, is a caspase-3 target, it is not cleaved during erythroid differentiation. We have shown that, in human erythroblasts, the chaperone heat shock protein70 (HSP70) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA-1 from caspase-3 cleavage. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation. Here we show in vitro that during the maturation of human beta-TM erythroblasts, HSP70 interacts directly with free alpha-globin chains. As a consequence, HSP70 is sequestrated in the cytoplasm and GATA-1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA-1 mutant restores terminal maturation of beta-TM erythroblasts, which may provide a rationale for new targeted therapies of beta-TM.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arlet, Jean-Benoit -- Ribeil, Jean-Antoine -- Guillem, Flavia -- Negre, Olivier -- Hazoume, Adonis -- Marcion, Guillaume -- Beuzard, Yves -- Dussiot, Michael -- Moura, Ivan Cruz -- Demarest, Samuel -- de Beauchene, Isaure Chauvot -- Belaid-Choucair, Zakia -- Sevin, Margaux -- Maciel, Thiago Trovati -- Auclair, Christian -- Leboulch, Philippe -- Chretien, Stany -- Tchertanov, Luba -- Baudin-Creuza, Veronique -- Seigneuric, Renaud -- Fontenay, Michaela -- Garrido, Carmen -- Hermine, Olivier -- Courtois, Genevieve -- England -- Nature. 2014 Oct 9;514(7521):242-6. doi: 10.1038/nature13614. Epub 2014 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Service de Medecine Interne, Faculte de medecine Paris Descartes, Sorbonne Paris-Cite et Assistance publique - Hopitaux de Paris, Hopital Europeen Georges Pompidou, 15 rue Leblanc 75908 Paris, France [3] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [4] Laboratory of Excellence GR-Ex, 75015 Paris, France [5]. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France [4] Departement de Biotherapie, Faculte de medecine Paris Descartes, Sorbonne Paris-Cite et Assistance publique - Hopitaux de Paris, Hopital Necker, 149 rue de Sevres 75015 Paris, France [5]. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France. ; Commissariat a l'energie atomique (CEA), Institute of Emerging Diseases and Innovative Therapies (iMETI), 18 Route du Panorama, 92260 Fontenay-aux-Roses, France. ; 1] INSERM, unite mixte de recherche 866, Equipe labellisee Ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence Lipoproteines et sante (LipSTIC), 21033 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 7 boulevard Jeanne d'Arc, 21033 Dijon, France. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France [4] INSERM, unite mixte de recherche 699, Hopital Bichat, 46 rue Henri Huchard, 75018 Paris, France. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France [4] INSERM, unite mixte de recherche 699, Hopital Bichat, 46 rue Henri Huchard, 75018 Paris, France [5] Faculte de medecine and Universite Denis Diderot Paris VII, 5 Rue Thomas Mann, 75013 Paris, France. ; Centre national de la recherche scientifique (CNRS), unite mixte de recherche 8113, Ecole Normale Superieure de Cachan, 61 avenue du president Wilson, 94230 Cachan, France. ; 1] Centre national de la recherche scientifique (CNRS), unite mixte de recherche 8113, Ecole Normale Superieure de Cachan, 61 avenue du president Wilson, 94230 Cachan, France [2] Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LERMIT), Campus Paris Saclay, 5 rue Jean-Baptiste Clement 92296 Chatenay-Malabry, France. ; 1] Commissariat a l'energie atomique (CEA), Institute of Emerging Diseases and Innovative Therapies (iMETI), 18 Route du Panorama, 92260 Fontenay-aux-Roses, France [2] Women's Hospital and Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; INSERM, unite mixte de recherche 779, Universite Paris XI, Le Kremlin-Bicetre, France. ; University of Burgundy, Faculty of Medicine and Pharmacy, 7 boulevard Jeanne d'Arc, 21033 Dijon, France. ; 1] Laboratory of Excellence GR-Ex, 75015 Paris, France [2] Institut Cochin, INSERM, unite mixte de recherche 1016, centre national de la recherche scientifique (CNRS), unite mixte de recherche 8104, Universite Paris Descartes, and Assistance publique - Hopitaux de Paris, Hopitaux Universitaires Paris Centre, Hopital Cochin, Service d'hematologie biologique, 27 rue du Faubourg Saitn-Jacques, 75014 Paris, France. ; 1] INSERM, unite mixte de recherche 866, Equipe labellisee Ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence Lipoproteines et sante (LipSTIC), 21033 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 7 boulevard Jeanne d'Arc, 21033 Dijon, France [3] Centre anticancereux George Francois Leclerc, 1 rue professeur Marion, 21079 Dijon, France [4]. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France [4] Service d'hematologie, Faculte de medecine Paris Descartes, Sorbonne Paris-Cite et Assistance publique - Hopitaux de Paris Hopital Necker, 149 rue de Sevres, 75015 Paris, France [5]. ; 1] Laboratoire INSERM, unite mixte de recherche 1163, centre national de la recherche scientifique (CNRS) equipe de recherche labellisee 8254, 24 Boulevard de Montparnasse, 75015 Paris, France [2] Paris Descartes-Sorbonne Paris Cite University, Imagine Institute, Assistance publique - Hopitaux de Paris, Hopital Necker, 24 Boulevard de Montparnasse, 75015 Paris, France [3] Laboratory of Excellence GR-Ex, 75015 Paris, France [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25156257" target="_blank"〉PubMed〈/a〉
    Keywords: Apoptosis ; Bone Marrow/metabolism ; Caspase 3/metabolism ; Cell Nucleus/metabolism ; Cell Survival/genetics ; Cells, Cultured ; Cytoplasm/metabolism ; Enzyme Activation ; Erythroblasts/cytology/*metabolism/pathology ; *Erythropoiesis/genetics ; GATA1 Transcription Factor/genetics/metabolism ; Gene Expression Regulation ; HSP70 Heat-Shock Proteins/genetics/*metabolism ; Humans ; Kinetics ; Molecular Targeted Therapy ; Protein Binding ; Protein Refolding ; alpha-Globins/*metabolism ; beta-Thalassemia/*blood/*metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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