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首页> 外文期刊>Molecular and Cellular Biology >Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway.
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Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway.

机译：通过促分裂原活化的蛋白激酶途径控制血小板生成素诱导的巨核细胞分化。

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Thrombopoietin (TPO) is the major regulator of both growth and differentiation of megakaryocytes. We previously showed that both functions can be generated by TPO in the megakaryoblastic cell line UT7, in which murine Mpl was introduced, and are independently controlled by distinct regions of the cytoplasmic domain of Mpl. Particularly, residues 71 to 94 of this domain (deleted in the mutant mpl delta3) were found to be required for megakaryocytic maturation but dispensable for proliferation. We show here that TPO-induced differentiation in UT7 cells is tightly dependent on a strong, long-lasting activation of the mitogen-activated protein kinase (MAPK) pathway. Indeed, (i) in UT7-mpl cells, TPO induced a strong activation of extracellular signal-regulated kinases (ERK) which was persistent until at least 4 days in TPO-containing medium; (ii) a specific MAPK kinase (MEK) inhibitor inhibited TPO-induced megakaryocytic gene expression; (iii) the Mpl mutant mpl delta3, which displayed no maturation activity, transduced only a weak and transient ERK activation in UT7 cells; and (iv) TPO-induced megakaryocytic differentiation in UT7-mpl delta3 cells was partially restored by expression of a constitutively activated mutant of MEK. The capacity of TPO to trigger a strong and prolonged MAPK signal depended on the cell in which Mpl was introduced. In BAF3-mpl cells, TPO triggered a weak and transient ERK activation, similar to that induced in UT7-mpl delta3 cells. In these cells, no difference in MAPK activation was found between normal Mpl and mpl delta3. Thus, depending on the cellular context, several distinct regions of the cytoplasmic domain of Mpl and signaling pathways may contribute to generate quantitative variations in MAPK activation.
机译：血小板生成素（TPO）是巨核细胞生长和分化的主要调节剂。我们以前表明，这两种功能都可以在巨核母细胞系UT7（其中引入了鼠Mpl）中由TPO生成，并且受Mpl胞质域的不同区域独立控制。特别地，发现该结构域的71至94位残基（在突变体mpl del3中缺失）是巨核细胞成熟所必需的，但对于增殖是必需的。我们在这里显示，在UT7细胞中TPO诱导的分化紧密依赖有丝分裂原激活的蛋白激酶（MAPK）途径的强大，持久的激活。实际上，（i）在UT7-mpl细胞中，TPO诱导了细胞外信号调节激酶（ERK）的强激活，这种激活在含TPO的培养基中持续至少4天; （ii）特定的MAPK激酶（MEK）抑制剂抑制TPO诱导的巨核细胞基因表达; （iii）没有成熟活性的Mpl突变体mpl delta3，仅在UT7细胞中转导了弱而短暂的ERK激活; （iv）通过表达组成型活化的MEK突变体，部分恢复了TPO诱导的UT7-mpl del3细胞中的巨核细胞分化。 TPO触发强而延长的MAPK信号的能力取决于导入Mpl的细胞。在BAF3-mpl细胞中，TPO触发了短暂而短暂的ERK激活，类似于在UT7-mpl del3细胞中诱导的激活。在这些细胞中，在正常的Mpl和mpl delta3之间未发现MAPK激活的差异。因此，取决于细胞情况，Mpl的胞质结构域的几个不同区域和信号传导途径可能有助于产生MAPK激活的定量变化。

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