title: Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes.
abstract: Normal human erythroid cell maturation requests the transcription factor GATA-1 and a transient activation of caspase-3, with GATA-1 being protected from caspase-3-mediated cleavage by interaction with the chaperone heat shock protein 70 (Hsp70) in the nucleus. Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA-1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70 family. GATA-1 protein expression is decreased in MDS erythroblasts, but restores in the presence of a pan-caspase inhibitor. Expression of a mutated GATA-1 that cannot be cleaved by caspase-3 rescues the transcription of GATA-1 targets, and the erythroid differentiation, but does not improve survival. Hsp70 fails to protect GATA-1 from caspases because the protein does not accumulate in the nucleus with active caspase-3. Expression of a nucleus-targeted mutant of Hsp70 protects GATA-1 and rescues MDS erythroid cell differentiation. Alteration of Hsp70 cytosolic-nuclear shuttling is a major feature of MDS that favors GATA-1 cleavage and differentiation impairment, but not apoptosis, in dysplastic erythroblasts.
authors.affiliation: Département d'Immuno-Hématologie, Institut Cochin, 27 rue du Faubourg Saint-Jacques, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Frisan
authors.forename: Julie
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Thonel
authors.forename: Cécile
authors.initials: C
authors.lastname: Pierre-Eugène
authors.forename: Alexander
authors.initials: A
authors.lastname: Sternberg
authors.forename: Jean-Benoît
authors.initials: JB
authors.lastname: Arlet
authors.forename: Célia
authors.initials: C
authors.lastname: Floquet
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Gabet
authors.forename: Geneviève
authors.initials: G
authors.lastname: Courtois
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.forename: Yael
authors.initials: Y
authors.lastname: Zermati
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004900:Erythroblasts / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D018840:HSP70 Heat-Shock Proteins; C525621:HSPA1B protein, human; D049452:Green Fluorescent Proteins; D053148:Caspase 3