Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBPε
Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBPε
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DOI：
10.1111/j.1365-3083.2006.01827.x
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发表时间：
2006-09-01
影响因子：
3.7
通讯作者：
Oberg, F.
中科院分区：
文献类型：
--
作者：
Dimberg, A.;Karehed, K.;Oberg, F.
单核细胞分化是通过多个信号通路的有序激活来协调的，控制调节成熟表型发育的特定基因子集的转录。为了确定参与这一过程的关键转录因子，我们使用人类单核细胞 U-937 细胞系作为单核细胞分化的模型。 U-937 细胞可以通过全反式视黄酸 (ATRA) 和 1,25 α-二羟基胆钙化醇 (VitD3) 处理来分化，从而产生表达单核细胞表面标记的 G(0)/G(1) 停滞细胞。我们之前已经表明，ATRA 诱导的分化和细胞周期停滞特别需要通过酪氨酸 701 和丝氨酸 727 的磷酸化来激活 Stat1。在本报告中，我们使用表达 Stat1 磷酸化缺陷突变体（Stat1Y701F 和 Stat1S727A）的 U-937 细胞来确定在诱导单核细胞分化过程中 Stat1 下游被激活的骨髓特异性转录因子。我们证明，ATRA 诱导的 Stat2、ICSBP/IRF8 和 C/EBP epsilon（与骨髓单核细胞分化相关的关键转录因子）的上调在表达突变 Stat1 的细胞中选择性受损。相反，ATRA 诱导的 PU.1、C/EBP α、C/EBP β 和 IRF-1 表达不受影响。综上所述，我们的数据表明，ATRA 诱导的 Stat2、ICSBP 和 C/EBP epsilon 调节依赖于活性 Stat1，并且未能正确调节这些转录因子与单核细胞分化的抑制有关。
Monocytic differentiation is coordinated through the ordered activation of multiple signalling pathways, controlling transcription of specific subsets of genes that regulate the development of the mature phenotype. To identify key transcription factors involved in this process, we used the human monoblastic U-937 cell line as a model of monocytic differentiation. U-937 cells can be differentiated by treatment with all-trans retinoic acid (ATRA) and 1,25 alpha-dihydroxycholecalciferol (VitD3), resulting in G(0)/G(1)-arrested cells expressing monocytic surface markers. We have previously shown that ATRA-induced differentiation and cell cycle arrest specifically requires Stat1 activation, through phosphorylation of tyrosine 701 and serine 727. In this report, we used U-937 cells expressing phosphorylation-deficient mutants of Stat1 (Stat1Y701F and Stat1S727A) to determine myeloid-specific transcription factors that are activated downstream of Stat1 during induced monocytic differentiation. We demonstrate that ATRA-induced upregulation of Stat2, ICSBP/IRF8 and C/EBP epsilon, key transcription factors linked to myelomonocytic differentiation, is selectively impaired in cells expressing mutant Stat1. In contrast, ATRA-induced expression of PU.1, C/EBP alpha, C/EBP beta and IRF-1 was unaffected. Taken together, our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBP epsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation.