de Koning J P, Ward A C, Caldenhoven E, de Groot R P, Löwenberg B, Touw I P
Institute of Hematology, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Hematol J. 2000;1(4):220-5. doi: 10.1038/sj.thj.6200041.
Activation of the signal transducer and activator of transcription protein STAT3 is a crucial step in granulocyte colony-stimulating factor (G-CSF)-mediated cell cycle exit and subsequent neutrophilic differentiation of myeloid precursor cells. We have recently demonstrated that this is mediated, at least in part, by upregulation of the cyclin-dependent kinase inhibitor p27(Kip1). The splice variant STAT3beta, that lacks a C-terminal serine residue implicated in the transcriptional activity of STAT3, has been shown to inhibit STAT3-mediated transcription in certain situations. STAT3beta is known to be expressed in hematopoietic cells, but its role in controlling the balance between proliferation and differentiation has not been established.
We ectopically introduced STAT3beta in differentiation-competent 32D cell transfectants expressing human wild type (WT) G-CSF receptors and studied the consequences for G-CSF-mediated responses.
Overexpression of STAT3beta did not alter the kinetics of G-CSF-mediated neutrophilic differentiation or p27 induction in 32D/G-CSF-R WT cells. In addition, we found that p27(Kip1) promoter activity was not inhibited by STAT3beta, while inhibition of p27 transactivation by a dominant-negative STAT3 mutant could in fact be alleviated by coexpression of the beta form.
These findings argue against a role of STAT3beta as a negative regulator of G-CSF-induced expression of p27 and myeloid differentiation.
信号转导子和转录激活蛋白STAT3的激活是粒细胞集落刺激因子（G-CSF）介导的细胞周期退出以及随后骨髓前体细胞嗜中性分化的关键步骤。我们最近证明，这至少部分是由细胞周期蛋白依赖性激酶抑制剂p27（Kip1）的上调介导的。剪接变体STAT3β缺乏与STAT3转录活性相关的C末端丝氨酸残基，已显示在某些情况下可抑制STAT3介导的转录。已知STAT3β在造血细胞中表达，但其在控制增殖与分化平衡中的作用尚未明确。
我们将STAT3β异位导入表达人野生型（WT）G-CSF受体且具有分化能力的32D细胞转染子中，并研究其对G-CSF介导反应的影响。
STAT3β的过表达并未改变32D/G-CSF-R WT细胞中G-CSF介导的嗜中性分化动力学或p27诱导。此外，我们发现p27（Kip1）启动子活性不受STAT3β抑制，而显性负性STAT3突变体对p27反式激活的抑制实际上可通过β形式的共表达得到缓解。
这些发现表明STAT3β并非G-CSF诱导的p27表达和骨髓分化的负调节因子。
