Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors
Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors
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DOI：
10.1038/sj.leu.2404448
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发表时间：
2006-12-01
期刊：
影响因子：
11.4
通讯作者：
Ward, A. C.
中科院分区：
文献类型：
--
作者：
Gits, J.;van Leeuwen, D.;Ward, A. C.
在一组极易患急性髓系白血病的中性粒细胞减少症患者中，已鉴定出粒细胞集落刺激因子受体（G - CSF - R）基因发生突变，导致产生截短的蛋白质。此类突变以显性方式起作用，导致对G - CSF的反应中细胞增殖过度但分化受损。这至少部分是由于内化缺陷以及几种负调节因子结合位点的缺失，从而导致受体持续激活。然而，那些负责介导过度增殖功能的信号通路仍不清楚。在这项研究中，对另外一种G - CSF - R突变体的分析证实了Box 2下游残基作为持续增殖的重要贡献因素的重要性。然而，最大增殖程度与持续强力激活信号转导和转录激活因子（STAT）5的能力相关，而显性负性STAT5（而非显性负性STAT3）的共表达能够抑制截短受体对G - CSF刺激的增殖。此外，一种Janus激酶（JAK）抑制剂也强烈降低增殖反应，而丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）或磷脂酰肌醇（PI）3 - 激酶抑制剂降低增殖的程度较小。这些数据表明，持续的JAK2/STAT5激活是截短的G - CSF受体过度增殖功能的主要因素，而涉及MEK和PI 3 - 激酶的通路所起作用较小。
Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF. This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree. These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role.