Chk1 haploinsufficiency results in anemia and defective erythropoiesis.
Chk1 haploinsufficiency results in anemia and defective erythropoiesis.
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DOI：
10.1371/journal.pone.0008581
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发表时间：
2010-01-05
期刊：
影响因子：
3.7
通讯作者：
Rosen JM
中科院分区：
文献类型：
--
作者：
Boles NC;Peddibhotla S;Chen AJ;Goodell MA;Rosen JM
红细胞生成是一个高度调节和良好表征的发育过程，负责提供身体的氧运输系统。然而，很少有参与这一过程的机制已经阐明。检查点激酶1（Chk1）以其在细胞周期和DNA损伤途径中的作用而闻名，并且已被证明在几种途径中发挥作用，当被破坏时会导致贫血。在这里，我们发现Chk1的单倍不足导致30%的小鼠在生命的第一年内发生贫血。贫血Chk 1 +/−小鼠表现出扭曲的脾脏和骨髓结构，以及异常的红系祖细胞。此外，Chk1 +/−红系祖细胞表现出自发DNA损伤灶的增加和不适当的收缩肌动蛋白环形成，导致红细胞生成期间的异常去核。在具有过量原始细胞的难治性贫血患者中也观察到Chk1 RNA减少，进一步支持Chk1在临床贫血中的作用。Chk1抑制剂的临床试验目前正在进行中，以治疗癌症，因此，重要的是要跟踪这些药物对红细胞发育的影响，在一个较长的时期。我们的研究结果支持Chk 1在维持红系祖细胞和去核红系细胞之间的平衡分化过程中的作用。我们发现Chk1水平的破坏可能导致贫血。
Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia. Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/− mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/− erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia. Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia.
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影响因子：
6.5
作者：
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通讯作者：
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影响因子：
64.5
作者：
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DOI：
10.1007/978-1-59745-471-1_23
发表时间：
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期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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DOI：
10.1159/000130698
发表时间：
2008-01-01
期刊：
HEMODIALYSIS: FROM BASIC RESEARCH TO CLINICAL TRIALS
影响因子：
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作者：
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通讯作者：
Levin, Nathan W.
影响因子：
5.3
作者：
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通讯作者：
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