The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70

Abstract : Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome that exhibits an erythroid-specific phenotype. In at least 70% of cases, DBA is related to a haploinsufficient germ line mutation in a ribosomal protein (RP) gene. Additional cases have been associated with mutations in GATA1. We have previously established that the RPL11+/Mut phenotype is more severe than RPS19+/Mut phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11+/Mut erythroid progenitors. The HSP70 protein is known to protect GATA1, the major erythroid transcription factor, from caspase-3 mediated cleavage during normal erythroid differentiation. Here, we show that HSP70 protein expression is dramatically decreased in RPL11+/Mut erythroid cells while being preserved in RPS19+/Mut cells. The decreased expression of HSP70 in RPL11+/Mut cells is related to an enhanced proteasomal degradation of polyubiquitinylated HSP70. Restoration of HSP70 expression level in RPL11+/Mut cells reduces p53 activation and rescues the erythroid defect in DBA. These results suggest that HSP70 plays a key role in determining the severity of the erythroid phenotype in RP-mutation–dependent DBA.
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Blood Advances, The American Society of Hematology, 2017, 1 (22), pp.1959 - 1976. 〈http://www.bloodadvances.org/content/1/22/1959?sso-checked=true〉. 〈10.1182/bloodadvances.2017008078〉
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Soumis le : jeudi 14 décembre 2017 - 10:34:15
Dernière modification le : vendredi 8 juin 2018 - 14:50:25

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Marc Gastou, Sarah Rio, Michael Dussiot, Narjesse Karboul, Hélène Moniz, et al.. The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70. Blood Advances, The American Society of Hematology, 2017, 1 (22), pp.1959 - 1976. 〈http://www.bloodadvances.org/content/1/22/1959?sso-checked=true〉. 〈10.1182/bloodadvances.2017008078〉. 〈hal-01663646〉

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