PP2A-B56β在胎肝定向红系形成过程中的作用机制研究

Different with nutritional anemia, fetal hereditary anemia is induced by genetic disorders and is resistant to iron or nutrition supplements. We have reported that deletion of catalytic subunit α of protein phosphatase 2A (PP2Acα) perturbed fetal liver erythropoiesis with increased apoptosis of red blood cells. However with its comprehensive holoenzyme structure, the precise regulatory mechanism of its particular regulatory subunit remains to be elucidated. Our previous study using fetal liver cells revealed that within almost all of the PP2A regulatory subunits only PP2A-B56β was induced by erythropoietin (EPO) stimulation. Further bioinformatics analysis discovered three STAT5 binding sites in its promoter, exon1 and intron1 region, suggesting PP2A-B56β as a potential STAT5 downstream target in EPO/STAT5 signaling. We hypothesize that PP2A-B56β may function as a regulatory subunit of PP2A involved in fetal liver erythropoiesis. Our study will provide significant insights into the cellular mechanisms of PP2A-B56β in erythropoiesis and its relationship with fetal hereditary anemia.

与营养性贫血不同，补充铁剂或营养并不能缓解新生儿遗传性贫血，严重危急患儿健康。我们已经证实蛋白磷酸酶2A催化亚基PP2Acα基因缺失可导致胎肝定向红系形成受阻，红细胞凋亡增加。但是PP2A调节亚基众多且结构复杂，因此研究某个特定调节亚基的具体生物学功能至关重要。我们的前期实验显示在几乎所有PP2A调节亚基中，只有PP2A-B56β可以被促红细胞生成素(erythropoietin, EPO)诱导表达。生物信息学分析发现PP2A-B56β启动子、第1外显子和第1内含子区域共有3个STAT5结合位点，提示其可能作为STAT5下游因子受EPO/STAT5通路调控。由此我们推测PP2A-B56β可能作为功能性PP2A调节亚基参与胎肝造血形成。本项目将深入研究PP2A-B56β在胎肝红系形成中的功能并验证PP2A-B56β与遗传性贫血的临床相关性，为遗传性贫血治疗提供新线索。

红系分化障碍导致的遗传性贫血是血液系统的最常见疾病之一。本项目主要目的是寻找蛋白磷酸酶2A（PP2A）在红系分化过程中的功能性调节亚基。我们发现PP2A-B56β是唯一在两种红系体外分化体系中均可被诱导表达的PP2A调节亚基。沉默PP2A-B56β显著减弱hemin诱导的K562细胞红系分化，提示我们PP2A-B56β可能作为功能性PP2A调节亚基参与造血形成（Wu et al., 2016, BBRC），为遗传性贫血治疗提供新线索。另外，我们同时发现分泌蛋白Fstl1是红系分化的关键调控因子，并深入解析其调控机制（Wu et al., 2015, BBRC）。最后，我们也证实PP2A对间充质干细胞（MSCs）的迁移同样具有调控作用（Chen et al., 2016, Mol Cell Biochem）。

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