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Mécanismes de régulation de GATA-1 par les protéines de choc thermique Hsp27 et Hsp70 au cours de la différenciation érythroïde terminale.

Abstract : Erythropoiesis is a process leading to red cells production. This differentiation program is mainly under control of the transcription factor GATA-1 that controls the expression of erythroid genes and the anti-apoptotic protein Bcl-xL. During apoptosis, GATA-1 is cleaved by activated caspase-3, leading to decreased Bcl-xL expression. During terminal erythroid differentiation, transient caspase-3 activation is required but GATA-1 remains uncleaved. In this study we demonstrated that during differentiation but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase 3-mediated proteolysis. At the onset of caspase activation, Hsp70 translocates into nucleus and protects GATA-1, allowing Bcl-xL. In contrast, EPO starvation induces the nuclear export of Hsp70 and the cleavage of GATA-1 leading to apoptosis. On the other hand, GATA-1 overexpression induces a blocage of maturation, then GATA-1 expression must be tighly regulated for proper erythroid differentiation. Here, we showed that Hsp27 is accumulated into nucleus of differentiating erythroblasts through p38 MAPPK phosphorylation. Nuclear Hsp27 interacts with acetylated GATA-1 to favor it's ubiquitinylation and proteasomal degradation. Those results show a new role for Hsp70 and Hsp27 along terminal erythroid differentiation through the fine tuning of GATA-1 expression. Further, we determined the mechanisms of nuclear accumulation during terminal erythroid differentiation. Erythropoiesis is positively regulated by two factors necessary for proliferation and survival of erythroid progenitors, SCF from early stage until the stage of basophilic erythroblast and Epo since CFU-E until erythroblast. Before c-Kit (SCF receptor) down-modulation at basophilic stage, Hsp70 is mainly localized into cytoplasm. Indeed, SCF induced Hsp70 nuclear export via S400 Hsp70 AKT phosphorylation resulting in a weak nuclear Hsp70. At the onset of c-Kit down-modulation, SCF induced Hsp70 nuclear export was decreased. On the other hand, Epo activated Lyn induced Hsp70 nuclear accumulation. Then, we described here a new mechanism of c-Kit erythroid blocage since it's down modulation is necessary for caspase-3 GATA-1 protection by Hsp70. Moreover, we highlighted a new survival and differentiating role for Lyn kinase under Epo. We tested if our model could be applicated to low grade myelodysplastic syndrome (MDS), characterized by anemia, associated with excessive caspase activation leading to apoptosis and delayed expression of the glycophorin A marker of erythroid progenitors. Here, we demonstrated that a defect in nuclear localization of Hsp70 is partially responsible for the observed phenotype since expression of nuclear Hsp70 partially rescues phenotype observed in differentiating cells of MDS patients. These results confirm our physiologic model. Moreover, c-Kit could be a new therapeutic target in MDS.
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https://tel.archives-ouvertes.fr/tel-00432780
Contributor : Catherine Slama <>
Submitted on : Tuesday, November 17, 2009 - 11:53:01 AM
Last modification on : Friday, March 27, 2020 - 2:52:53 AM
Long-term archiving on: : Thursday, June 17, 2010 - 6:29:09 PM

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  • HAL Id : tel-00432780, version 1

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Julie Vandekerckhove. Mécanismes de régulation de GATA-1 par les protéines de choc thermique Hsp27 et Hsp70 au cours de la différenciation érythroïde terminale.. Biologie cellulaire. Université Paris Sud - Paris XI, 2009. Français. ⟨tel-00432780⟩

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