Lyn kinase promotes erythroblast expansion and late-stage development
Lyn kinase promotes erythroblast expansion and late-stage development
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DOI：
10.1182/blood-2005-09-008243
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发表时间：
2006-09-01
期刊：
影响因子：
20.3
通讯作者：
Wojchowski, Don M.
中科院分区：
文献类型：
--
作者：
Karur, Vinit G.;Lowell, Clifford A.;Wojchowski, Don M.
Lyn 激酶已知可调节 B 细胞、单核细胞和肥大细胞的形成和功能。然而，Lyn(-/-) 小鼠也会出现红细胞脾肿大，并且最近已经概述了 Lyn 的负性和正性红细胞生成作用的病例。在苯肼治疗的Lyn(-/-)小鼠中，髓外脾脏红细胞生成过度激活，但这并没有导致贫血加速恢复。此外，对骨髓源性 Lyn(-/-) 成红细胞在独特的原代培养系统中发育的离体分析表明，Lyn 在两个阶段都具有积极作用。晚期Lyn(-/-)成红细胞表现出Ter119(pos)细胞形成缺陷，同时细胞凋亡增加（和Bcl-xL表达减少）。在早期发育过程中，Lyn(-/-)成红细胞在Kit(pos)CD71(high)阶段积累，增殖能力下降，并在进入明显的G1/S细胞周期阶段时减弱。在所提出的补偿反应中，Lyn(-/-)成红细胞表达的活化Akt和p60-Src水平升高，而死亡相关蛋白激酶2水平降低。相反，Stat5 激活和 Bcl-xL 表达显着降低，与存活和发育潜力的降低保持一致。因此，Lyn 被认为通过红系细胞内在机制发挥作用，促进祖细胞扩增超出 Kit(pos)CD71(high) 阶段，并支持随后的后期发育。
Lyn kinase is known to modulate the formation and function of B cells, monocytes, and mast cells. However, Lyn(-/-) mice also develop erythrosplenomegaly, and cases for both negative and positive erythropoietic actions of Lyn recently have been outlined. In phenylhydrazine-treated Lyn(-/-) mice, extramedullary splenic erythropoiesis was hyperactivated, but this did not lead to accelerated recovery from anemia. Furthermore, ex vivo analyses of the development of bone marrow-derived Lyn(-/-) erythroblasts in unique primary culture systems indicated positive roles for Lyn at 2 stages. Late-stage Lyn(-/-) erythroblasts exhibited deficit Ter119(pos) cell formation, and this was paralleled by increased apoptosis (and decreased Bcl-xL expression). During early development, Lyn(-/-) erythroblasts accumulated at a Kit(pos)CD71(high) stage, possessed decreased proliferative capacity, and were attenuated in entering an apparent G1/S cell-cycle phase. In proposed compensatory responses, Lyn(-/-) erythroblasts expressed increased levels of activated Akt and p60-Src and decreased levels of death-associated protein kinase-2. Stat5 activation and Bcl-xL expression, in contrast, were significantly decreased in keeping with decreased survival and developmental potentials. Lyn, therefore, is proposed to function via erythroid cell-intrinsic mechanisms to promote progenitor cell expansion beyond a Kit(pos)CD71(high) stage and to support subsequent late-stage development.