Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes
Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes
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DOI：
10.1182/blood-2011-03-343475
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发表时间：
2012-02-09
期刊：
影响因子：
20.3
通讯作者：
Fontenay, Michaela
中科院分区：
文献类型：
--
作者：
Frisan, Emilie;Vandekerckhove, Julie;Fontenay, Michaela
正常的人红系细胞成熟需要转录因子GATA-1和caspase-3的瞬时激活，GATA-1通过与细胞核中的伴侣热休克蛋白70(Hsp70)相互作用而免受caspase-3介导的切割。在早期骨髓增生异常综合征(MDS)中观察到的红系细胞异常增殖症包括分化障碍和过度凋亡，并伴随caspase的突然激活。通过体外培养获得的MDS红细胞的基因表达分析表明，一组GATA-1转录靶基因下调，包括编码血糖素A(GPA)的GypA，以及HSP70家族成员的上调。MDS红细胞中GATA-1蛋白表达降低，但在泛半胱氨酸氨基转移酶抑制剂存在下恢复。表达不能被caspase-3切割的突变的GATA-1可以挽救GATA-1靶标的转录和红系分化，但不能提高存活率。HSP70不能保护GATA-1不受caspase的影响，因为该蛋白不会随着caspase-3的激活而积聚在细胞核中。Hsp70核靶向突变体的表达保护GATA-1并挽救MDS红系细胞分化。Hsp70胞质核穿梭的改变是MDS的一个主要特征，它有利于发育不良的红细胞中GATA-1的切割和分化障碍，而不是凋亡。(血。2012年；119(6)：1532-1542)
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 ofGATA-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 cytosolicnuclear shuttling is a major feature of MDS that favors GATA-1 cleavage and differentiation impairment, but not apoptosis, in dysplastic erythroblasts. (Blood. 2012; 119(6): 1532-1542)