Department of Pediatrics, Herman B. Wells Center for Pediatric Research, University School of Medicine, Indianapolis, IN 46202, USA.
Blood. 2012 Oct 4;120(14):2868-78. doi: 10.1182/blood-2011-10-384172. Epub 2012 Aug 13.
Erythropoiesis is a dynamic, multistep process whereby hematopoietic stem cells differentiate toward a progressively committed erythroid lineage through intermediate progenitors. Although several downstream signaling molecules have been identified that regulate steady-state erythropoiesis, the major regulators under conditions of stress remain poorly defined. Rho kinases (ROCKs) belong to a family of serine/threonine kinases. Using gene-targeted ROCK1-deficient mice, we show that lack of ROCK1 in phenylhydrazine-induced oxidative stress model results in enhanced recovery from hemolytic anemia as well as enhanced splenic stress erythropoiesis compared with control mice. Deficiency of ROCK1 also results in enhanced survival, whereas wild-type mice die rapidly in response to stress. Enhanced survivability of ROCK1-deficient mice is associated with reduced level of reactive oxygen species. BM transplantation studies revealed that enhanced stress erythropoiesis in ROCK1-deficient mice is stem cell autonomous. We show that ROCK1 binds to p53 and regulates its stability and expression. In the absence of ROCK1, p53 phosphorylation and expression is significantly reduced. Our findings reveal that ROCK1 functions as a physiologic regulator of p53 under conditions of erythroid stress. These findings are expected to offer new perspectives on stress erythropoiesis and may provide a potential therapeutic target in human disease characterized by anemia.
红细胞生成是一个动态的多步骤过程，造血干细胞通过中间祖细胞向逐步特化的红细胞系分化。虽然已经鉴定出了几种下游信号分子来调节稳态红细胞生成，但在应激条件下的主要调节因子仍未得到很好的定义。Rho 激酶（ROCK）属于丝氨酸/苏氨酸激酶家族。使用基因靶向 ROCK1 缺陷小鼠，我们表明在苯肼诱导的氧化应激模型中缺乏 ROCK1 会导致溶血性贫血的恢复增强，并且与对照小鼠相比，脾应激红细胞生成增强。ROCK1 的缺乏也会导致存活率提高，而野生型小鼠在应激反应中迅速死亡。ROCK1 缺陷小鼠的高存活率与活性氧水平降低有关。BM 移植研究表明，ROCK1 缺陷小鼠的应激红细胞生成增强是干细胞自主的。我们表明 ROCK1 与 p53 结合并调节其稳定性和表达。在缺乏 ROCK1 的情况下，p53 磷酸化和表达显著降低。我们的发现表明，ROCK1 在红细胞应激条件下作为 p53 的生理调节剂发挥作用。这些发现有望为应激红细胞生成提供新的视角，并可能为以贫血为特征的人类疾病提供潜在的治疗靶点。
