Team: Heat Shock Protein, Cell Death cellular differentiation and tumorigenic properties

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Role of Heat Shock Factor and GATA-1 in HSP70 expression in erythroid cells
Project to be performed by my team in collaboration with the team of O Hermine (Necker Hospital) and M Fontenay (Cochin Institute). (ANR 2013-2016)
In association with two teams of the GR-Ex (O Hermine’s and M Fontenay’s teams) we previously demonstrated that erythroid differentiation required a wave of caspase activation and that the heat shock protein HSP70 is constitutively expressed and exerts a protective effect on the transcription factor GATA-1 within the nucleus thereby preventing apoptosis and maturation arrest of erythroid cells. In contrast, during apoptosis HSP70 was exported from the nucleus and cells were dying by apoptosis. Thus, the localization of HSP70 (cytosol versus nucleus) determines at least in part the fate of erythroblasts (differentiation vs apoptosis) (Ribeil et al, Nature, 2007). In patients with Myelodysplastic syndromes despite high levels of HSP70 mRNA and protein, HSP70, thought to protect GATA-1 from cleavage, was poorly localized in the nucleus in most MDS with cytological features of dyserythropoiesis. Finally, the lentiviral transfer of a nucleus-targeted mutant HSP70 rescued erythroid cell differentiation (Frisan, Vandekerckhove et al. Blood, 2012).

In Thalassemia major, an α-hemoglobin–stabilizing protein (AHSP) has recently been identified that specifically binds to and stabilizes free α chains (Yu, Kong et al. 2007). We have recently demonstrated that beta-globin is chaperoned by HSP70 in the cytosol. The association results in a cytosolic sequestration of HSP70 and thereby inhibition of erythroblasts’ differentiation (Arlet et al, Nature).