ALBERT

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〉

Description: Oceanic rocks in the Ankara Mélange along the Izmir–Ankara–Erzincan suture zone (IAESZ) in North-Central Anatolia include locally coherent ophiolite complexes (~179 Ma and ~80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (~67–63 Ma). All but the arc rocks occur in a shaly-graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the Middle to Late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant LILE enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syeno-dioritic plutons exhibit high-K shoshonitic to medium-to high-K calc-alkaline compositions with strong enrichment in LILE, REE and Pb, and initial ϵNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syeno-dioritic plutons) in the southern part. The Early to Late Jurassic and Late Cretaceous epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the Northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the Northern Neotethys was an open ocean with its MORB-type oceanic lithosphere by the Early Triassic. The Latest Cretaceous–Early Paleocene island arc volcanic, dike and plutonic rocks with subalkaline to alkaline geochemical affinities represent intraoceanic magmatism that developed on and across the subduction-accretion complex above a N-dipping, southward-rolling subducted lithospheric slab within the Northern Neotethys. The Ankara Mélange thus exhibits the record of ~120–130 million years of oceanic magmatism in geological history of the Northern Neotethys.

Description: Oceanic rocks in the Ankara Mélange along the Izmir–Ankara–Erzincan suture zone (IAESZ) in north-central Anatolia include locally coherent ophiolite complexes (~ 179 Ma and ~ 80 Ma), seamount or oceanic plateau volcanic units with pelagic and reefal limestones (96.6 ± 1.8 Ma), metamorphic rocks with ages of 256.9 ± 8.0 Ma, 187.4 ± 3.7 Ma, 158.4 ± 4.2 Ma, and 83.5 ± 1.2 Ma indicating northern Tethys during the late Paleozoic through Cretaceous, and subalkaline to alkaline volcanic and plutonic rocks of an island arc origin (~ 67–63 Ma). All but the arc rocks occur in a shale–graywacke and/or serpentinite matrix, and are deformed by south-vergent thrust faults and folds that developed in the middle to late Eocene due to continental collisions in the region. Ophiolitic volcanic rocks have mid-ocean ridge (MORB) and island arc tholeiite (IAT) affinities showing moderate to significant large ion lithophile elements (LILE) enrichment and depletion in Nb, Hf, Ti, Y and Yb, which indicate the influence of subduction-derived fluids in their melt evolution. Seamount/oceanic plateau basalts show ocean island basalt (OIB) affinities. The arc-related volcanic rocks, lamprophyric dikes and syenodioritic plutons exhibit high-K shoshonitic to medium- to high-K calc-alkaline compositions with strong enrichment in LILE, rare earth elements (REE) and Pb, and initial εNd values between +1.3 and +1.7. Subalkaline arc volcanic units occur in the northern part of the mélange, whereas the younger alkaline volcanic rocks and intrusions (lamprophyre dikes and syenodioritic plutons) in the southern part. The late Permian, Early to Late Jurassic, and Late Cretaceous amphibole-epidote schist, epidote-actinolite, epidote-chlorite and epidote-glaucophane schists represent the metamorphic units formed in a subduction channel in the northern Neotethys. The Middle to Upper Triassic neritic limestones spatially associated with the seamount volcanic rocks indicate that the northern Neotethys was an open ocean with its MORB-type oceanic lithosphere by the early Triassic (or earlier). The latest Cretaceous–early Paleocene island arc volcanic, dike and plutonic rocks with subalkaline to alkaline geochemical affinities represent intraoceanic magmatism that developed on and across the subduction–accretion complex above a N-dipping, southward-rolling subducted lithospheric slab within the northern Neotethys. The Ankara Mélange thus exhibits the record of ~ 120–130 million years of oceanic magmatism in geological history of the northern Neotethys.