Unexpected role for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis
Unexpected role for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis
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p19(INK4d) 在 GATA1 转录后调节和人类终末红细胞生成调节中的意外作用
DOI：
10.1182/blood-2016-09-739268
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发表时间：
2017-01-12
期刊：
影响因子：
20.3
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Han, Xu;Zhang, Jieying;Liu, Jing
终末红细胞分化与细胞周期退出密切协调，细胞周期退出受细胞周期蛋白、细胞周期蛋白依赖性激酶和细胞周期蛋白依赖性激酶抑制剂（CDKI）的调节，但它们在红细胞生成中的作用仍未完全确定。我们发现CDKI家族成员p19 （INK4d）在红母细胞中大量表达，p19 （INK4d）敲低会延迟红母细胞的分化，抑制细胞生长，导致凋亡增加和晚期成核异常红母细胞的产生。出乎意料的是，p19 （INK4d）敲低不影响细胞周期。相反，它导致GATA1蛋白的表达降低。重要的是，GATA1的异位表达挽救了分化和细胞核缺陷。由于GATA1蛋白受到核热休克蛋白家族（HSP）成员HSP70的保护，我们检测了p19 （INK4d）敲低对HSP70的影响，发现p19 （INK4d）敲低导致HSP70的表达降低及其核定位。HSP70水平的降低是细胞外信号调节激酶（ERK）激活减少的结果。进一步的生化分析表明，p19 （INK4d）直接结合Raf激酶抑制剂PEBP1， p19 （INK4d）敲低可增加PEBP1的表达，从而导致ERK活化降低。因此，我们已经通过新的PEBP1p- ERK-HSP70-GATA1途径确定了p19 INK4d的意想不到的作用。这些发现可能对改善对红细胞生成紊乱的理解有意义。
Terminal erythroid differentiation is tightly coordinated with cell-cycle exit, which is regulated by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors (CDKI), yet their roles in erythropoiesis remain to be fully defined. We show here that p19 (INK4d,) a member of CDKI family, is abundantly expressed in erythroblasts and that p19 (INK4d) knockdown delayed erythroid differentiation, inhibited cell growth, and led to increased apoptosis and generation of abnormally nucleated late-stage erythroblasts. Unexpectedly, p19 (INK4d) knockdown did not affect cell cycle. Rather, it led to decreased expression of GATA1 protein. Importantly, the differentiation and nuclear defects were rescued by ectopic expression of GATA1. Because the GATA1 protein is protected by nuclear heat shock protein family (HSP) member HSP70, we examined the effects of p19 (INK4d) knockdown on HSP70 and found that p19 (INK4d) knockdown led to decreased expression of HSP70 and its nuclear localization. The reduced levels of HSP70 are the result of reduced extracellular signal-regulated kinase (ERK) activation. Further biochemical analysis revealed that p19 (INK4d) directly binds to Raf kinase inhibitor PEBP1 and that p19 (INK4d) knockdown increased the expression of PEBP1, which in turn led to reduced ERK activation. Thus we have identified an unexpected role for p19 INK4d via a novel PEBP1p- ERK-HSP70-GATA1 pathway. These findings are likely to have implications for improved understanding of disordered erythropoiesis.