Thrombopoietin stimulates Hoxb4 expression:: an explanation for the favorable effects of TPO on hematopoietic stem cells
Thrombopoietin stimulates Hoxb4 expression:: an explanation for the favorable effects of TPO on hematopoietic stem cells
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DOI：
10.1182/blood-2003-03-0944
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发表时间：
2003-11-01
期刊：
影响因子：
20.3
通讯作者：
Kaushansky, K
中科院分区：
文献类型：
--
作者：
Kirito, K;Fox, N;Kaushansky, K
血小板生成素 (TPO) 是血小板生成的主要调节因子，在造血干细胞 (HSC) 生物学中也发挥着重要作用。在之前的研究中，我们证明 tpo(-/-) 小鼠的 HSC 自我更新和扩张能力比对照组低 10 至 20 倍。为了探索这种效应的分子基础，我们假设 Hoxb4 可能至少介导了这些细胞上的部分 TPO 效应。我们首先分析了TPO对原始造血细胞系中Hoxb4表达的影响； TPO 使 EML 和 UT-7/TPO 细胞中该基因的表达增加 2 至 3 倍。我们还比较了来自 tpo(-/-) 小鼠和对照小鼠的候选 HSC 群体中的 Hoxb4 水平； Hoxb4 表达在无效 HSC 中低 2 至 5 倍。在 TPO 诱导的众多信号转导分子中，我们发现 p38 丝裂原激活蛋白激酶 (MAPK) 是 TPO 诱导的 Hoxb4 升高的原因。我们还证明上游刺激因子 1 (USF-1)（一种先前显示调节 Hoxb4 表达的转录因子）也以 p38 依赖性方式被 TPO 诱导。这些数据共同提供了一种分子途径，生长因子可以通过该途径调节转录因子，从而帮助指导关键的发育过程。 (C) 2003 年，美国血液学会。
Thrombopoietin (TPO), the primary regulator of platelet production, also plays an important role in hematopoietic stem cell (HSC) biology. In previous studies we demonstrated that the self-renewal and expansion of HSCs is 10 to 20 times less robust in tpo(-/-) mice than in controls. To explore the molecular basis of this effect, we postulated that Hoxb4 might mediate at least part of the TPO effect on these cells. We first analyzed the effects of TPO on Hoxb4 expression in primitive hematopoietic cell lines; TPO increased expression of the gene 2- to 3-fold in EML and UT-7/TPO cells. We also compared Hoxb4 levels in a candidate HSC population derived from tpo(-/-) and control mice; Hoxb4 expression was 2- to 5-fold lower in null HSCs. Of the numerous signal transduction molecules induced by TPO, we found that p38 mitogen-activated protein kinase (MAPK) was responsible for the TPO-induced Hoxb4 elevation. We also demonstrated that upstream stimulating factor 1 (USF-1), a transcription factor previously shown to regulate Hoxb4 expression, is also induced by TPO in a p38-dependent manner. Together, these data provide a molecular pathway by which a growth factor can modulate a transcription factor and thereby help direct a critical developmental process. (C) 2003 by The American Society of Hematology.