SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.
SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.
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DOI：
10.1182/blood.v96.10.3422.h8003422_3422_3430
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发表时间：
2000-11
期刊：
影响因子：
20.3
通讯作者：
Rafael F Duarte;D. Frank
中科院分区：
文献类型：
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作者：
Rafael F Duarte;D. Frank
干细胞因子（SCF）是许多细胞因子的有效共刺激分子。它与粒细胞集落刺激因子（G-CSF）的协同作用产生了重要的生物学和临床效应，尽管其发生的机制仍然知之甚少。为了研究这种相互作用，本研究使用逆转录病毒载体将G-CSF受体转移到已知表达SCF受体的MO 7 e细胞中。转导的G-CSF受体是功能活性的，并且所得的MO 7 e-G细胞概括了SCF和G-CSF之间的增殖协同作用。当用两种细胞因子处理时，细胞周期的G（0）/G（1）期发生显著缩短，与细胞周期蛋白依赖性激酶抑制剂p27（kip-1）的抑制相关。此外，SCF和G-CSF诱导c-fos的协同激活，c-fos是一种参与造血细胞中促有丝分裂信号传播的原癌基因。G-CSF诱导STAT 1和STAT 3的酪氨酸磷酸化，而SCF不诱导，STAT 1和STAT 3是可介导c-fos诱导的转录因子。然而，SCF诱导STAT 3在serine 727（ser 727）上的磷酸化，这是最大STAT转录活性所必需的，并且SCF和G-CSF的组合导致STAT 3在ser 727上完全磷酸化。SCF和G-CSF导致STAT 3丝氨酸磷酸化的途径是不同的，并且部分依赖于磷脂酰肌醇-3激酶和ERK，这些途径也是SCF和G-CSF对增殖和c-fos诱导的协同作用所必需的。因此，MO 7 e-G细胞提供了一个强大的系统，其中SCF和G-CSF之间的协同作用的分子基础可以被解剖。
Stem cell factor (SCF) is a potent costimulatory molecule for many cytokines. Its synergy with granulocyte colony-stimulating factor (G-CSF) results in important biologic and clinical effects, although the mechanism by which this occurs remains poorly understood. To investigate this interaction, this study used a retroviral vector to transduce the G-CSF receptor into MO7e cells, which are known to express the SCF receptor. The transduced G-CSF receptor is functionally active, and the resultant MO7e-G cells recapitulate the proliferative synergy between SCF and G-CSF. When treated with both cytokines, a marked shortening of the G(0)/G(1) phase of the cell cycle occurs, associated with a suppression of the cyclin-dependent kinase inhibitor p27(kip-1). In addition, SCF and G-CSF induce the synergistic activation of c-fos, a proto-oncogene involved in propagation of mitogenic signals in hematopoietic cells. G-CSF, but not SCF, induces the tyrosine phosphorylation of STAT1 and STAT3, transcription factors that can mediate the induction of c-fos. However, SCF induces phosphorylation of STAT3 on serine727 (ser727), which is necessary for maximal STAT transcriptional activity, and the combination of SCF and G-CSF leads to complete STAT3 phosphorylation on ser727. The pathways by which SCF and G-CSF lead to serine phosphorylation of STAT3 are distinct and are partially dependent on phosphatidylinositol-3 kinase and ERKs, pathways that are also necessary for the synergistic effects of SCF and G-CSF on proliferation and c-fos induction. Thus, MO7e-G cells provide a powerful system in which the molecular basis of the synergy between SCF and G-CSF can be dissected.