Involvement of ERK1/2, p38 and PI3K in megakaryocytic differentiation of K562 cells
Involvement of ERK1/2, p38 and PI3K in megakaryocytic differentiation of K562 cells
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DOI：
10.1111/j.1600-0609.2010.01416.x
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发表时间：
2010-05-01
影响因子：
3.1
通讯作者：
Gonzalez-Manchon, Consuelo
中科院分区：
文献类型：
--
作者：
Conde, Isabel;Pabon, Dina;Gonzalez-Manchon, Consuelo
由许多化学化合物诱导的髓性白血病细胞系的巨核细胞分化部分模拟了响应于各种刺激而在骨髓中发生的生理过程。我们研究了促分裂原活化蛋白激酶（MAPK）[细胞外信号调节蛋白激酶（ERK 12）和p38]和磷酸肌醇3-激酶（PI 3 K）信号通路参与由佛波醇12-肉豆蔻酸酯13-乙酸酯，星形孢菌素（STA）和p38 MAPK抑制剂SB 202190促进的K562细胞分化表型。在我们的实验条件下，只有STA处理的细胞表现出成熟巨核细胞（MK）的表型，包括GPIb α表达，DNA核内复制和血小板样结构的形成。我们提供的证据支持ERK 1/2的基础活性，但不是持续激活，是MK表面标志物表达所必需的。此外，ERK 1/2信号传导不参与细胞内有丝分裂。PI 3 K通路对K562细胞分化具有双重调节作用：它与ERK 1/2级联密切相关，刺激表面标志物的表达，并且它也是多倍化所必需的，但不是充分的。最后，细胞凋亡和巨核细胞分化表现出不同的敏感性p38下调：它是所需的早期特异性标志物的表达，但不参与细胞凋亡。目前的工作与K562细胞提供了新的见解调节MK分化的分子机制。这些结果表明，包括ERK 1/2和p38 MAPK以及PI 3 K通路在内的信号的精确编排对于获得成熟MK的特征是必要的。
Megakaryocytic differentiation of myelogenous leukemia cell lines induced by a number of chemical compounds mimics, in part, the physiological process that takes place in the bone marrow in response to a variety of stimuli. We have investigated the involvement of mitogen-activated protein kinases (MAPKs) [extracellular signal-regulated protein kinase (ERK1/2) and p38] and phosphoinositide 3-kinase (PI3K) signaling pathways in the differentiated phenotypes of K562 cells promoted by phorbol 12-myristate 13-acetate, staurosporine (STA), and the p38 MAPK inhibitor SB202190. In our experimental conditions, only STA-treated cells showed the phenotype of mature megakaryocytes (MKs) including GPIb alpha expression, DNA endoreduplication, and formation of platelet-like structures. We provide evidence supporting that basal activity, but not sustained activation, of ERK1/2 is required for expression of MK surface markers. Moreover, ERK1/2 signaling is not involved in cell endomitosis. The PI3K pathway exerts dual regulatory effects on K562 cell differentiation: it is intimately connected with ERK1/2 cascade to stimulate expression of surface markers and it is also necessary, but not sufficient, for polyploidization. Finally, apoptosis and megakaryocytic differentiation exhibit different sensitivity to p38 down-regulation: it is required for expression of early specific markers but is not involved in cell apoptosis. The present work with K562 cells provides new insights into the molecular mechanisms regulating MK differentiation. The results indicate that a precise orchestration of signals, including ERK1/2 and p38 MAPKs as well as PI3K pathway, is necessary for acquisition of features of mature MKs.