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G-CSF-induced proliferation and differentiation of neutrophils

G-CSF诱导中性粒细胞增殖和分化

基本信息

批准号：
07457014
负责人：
NAGATA Shigekazu
金额：
$ 4.61万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Neutrophils in blood are generated from stem cells through various intermediate cells. Proliferation and differentiation of the progenitor cells of neutrophils are specifically regulated by granulocyte colony-stimulating factor (G-CSF). Previously, we have isolated cDNA for G-CSF and G-CSF receptor, and elucidated their structure. By introducing the cloned G-CSF receptor cDNA in mouse myeloid precursor cells which normally do not express the G-CSF receptor, we identified two distinct functional domains in the G-CSF receptor for proliferation and differentiation. The differentiation signal included the specific gene induction of myeloperoxidase or leukocyte elastase which are normally expressed in neutrophils. The cytoplasmic region of the G-CSF receptor contains 4 tyrosine residues, which are phosphorylated upon binding of G-CSF.Mutational analysis of these tyrosine residues indicated that each tyrosine residue has a distinct role to transduce the signals which lead to the neutrophil differentation. We showed that Jak1 and Jak2 kinases as well as STAT3 transcription factor are specifically activated upon binding of G-CSF to the receptor. Using the dominant-negative form of STAT3, we could show that STAT3 is involved in the G-CSF-induced differentiation signal, in particular, in the G-CSF-induced morphological changes of the neutrophilic granulocytes. Development and differentiation of cell are often determined by transcription factors containing zinc-finger domains. We have isolated a novel form of myeloid zinc-finger protein (MZF).

血液中的中性粒细胞由干细胞通过各种中间细胞产生。粒细胞集落刺激因子（G-CSF）特异性地调节中性粒细胞祖细胞的增殖和分化。在此之前，我们已经分离了G-CSF和G-CSF受体的cDNA，并阐明了它们的结构。通过在通常不表达G-CSF受体的小鼠骨髓前体细胞中引入克隆的G-CSF受体cDNA，我们确定了G-CSF受体中用于增殖和分化的两个不同的功能域。分化信号包括髓过氧化物酶或白细胞弹性蛋白酶的特异性基因诱导，这些基因通常在中性粒细胞中表达。G-CSF受体的胞浆区含有4个酪氨酸残基，它们在与G-CSF结合时被磷酸化，对这些酪氨酸残基的突变分析表明，每一个酪氨酸残基对中性粒细胞分化的信号传导都有不同的作用。我们发现，Jak 1和Jak 2激酶以及STAT 3转录因子在G-CSF与受体结合后被特异性激活。利用STAT 3的显性负性形式，我们可以表明STAT 3参与G-CSF诱导的分化信号，特别是参与G-CSF诱导的嗜中性粒细胞的形态学变化。细胞的发育和分化通常由含有锌指结构域的转录因子决定。我们已经分离出一种新形式的髓样锌指蛋白（MZF）。