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Physiologic role of signal transaction pathways in primary cultured human erythroid progenitor cells.

原代培养的人红系祖细胞中信号处理途径的生理作用。

基本信息

批准号：
12670970
负责人：
SAWADA Kenichi
金额：
$ 2.5万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670970/
关键词：
Fas SCF EPO apoptosis ZNF317 TPO FKHRL1 Src GPA c-kit

项目摘要

Development of erythrocytes is a comlex process governed by multiple cytokines. Colony assay revealed the physiologic importance of each of the cytokines. However, biochemical studies of highly purified human colony forming unit-erythroid (CFU-E) generated in vitro from CD34+ cells have only recently begun. Studies from our groups and others suggested that signal transduction in the primary erythroid cells may differ considerably from that in cell lines or the primary cells from other species. We have developed a method to generate purified erythroid progenitors, which are expanded from CD34+ cells in human peripheral blood in a sufficient number to allow for examination of early signaling by EPO or apoptosis. Using these cells, we have found that SCF protected purified human glycophorin A-positive (GPA^+)/c-kit^+ cells from apoptosis, and suggeswted that mediated Src kinase activation is involved in Akt activation and cell survival. Further, we have suggested that SCF prevents Fas-med … More iated apoptosis of erythroid progenitor cells in a manner dependent on the activity of Src-family tyrosine kinases. We also identified active Lyn in erythroid cells. These data suggest the presence of a novel Src-family/AKT dependent function of SCF in the development of erythrocytes. At the same time, we identified a novel Kruppel associated box (KRAB) zinc finger gene, ZNF317. ZNF317 encoded a protein comprised of thirteen Kruppel-like zinc fingers and a KRAB domain. RT-PCR analysis revealed four alternatively splicing products (ZNF317-1 through ZNF317-4). The ZNF317 gene has seven exons and is located in human chromosome 19p13. ZNF317-1 and ZNF317-2 transcripts were ubiquitously expressed, whereas ZNF317-3 and ZNF317-4 transcripts were detected only in lymphocytes, spleen and lung. The expression of ZNF317 mRNA significantly decreased during erythroid maturation. In lymphocytes, ZNF317 expression was reduced in response to mitogenic stimulation. We propose that ZNF317 may play an important role in erythroid maturation and lymphoid proliferation. Less

红细胞的发育是一个受多种细胞因子调控的复杂过程。集落测定揭示了每种细胞因子的生理重要性。然而，从CD 34+细胞体外产生的高度纯化的人红系集落形成单位（CFU-E）的生物化学研究最近才开始。本课题组和其他研究小组的研究表明，原代红系细胞中的信号转导可能与其他物种的细胞系或原代细胞中的信号转导有很大不同。我们已经开发了一种产生纯化的红系祖细胞的方法，所述红系祖细胞从人外周血中的CD 34+细胞扩增，其数量足以允许检查EPO或细胞凋亡的早期信号传导。使用这些细胞，我们发现SCF保护纯化的人血型糖蛋白A阳性（GPA^+）/c-kit^+细胞免于凋亡，并证实介导的Src激酶激活参与Akt激活和细胞存活。此外，我们认为SCF可以阻止Fas-med ...更多信息以依赖于Src家族酪氨酸激酶活性的方式诱导红系祖细胞凋亡。我们还鉴定了红系细胞中的活性林恩。这些数据表明SCF在红细胞发育中存在新的Src家族/AKT依赖性功能。同时，我们还发现了一个新的Kruppel相关盒（KRAB）锌指基因ZNF 317。ZNF 317编码的蛋白质由13个Kruppel样锌指和一个KRAB结构域组成。RT-PCR分析显示了4个选择性剪接产物（ZNF 317 -1至ZNF 317 -4）。ZNF 317基因有7个外显子，位于人类染色体19 p13。ZNF 317 -1和ZNF 317 -2的转录本广泛表达，而ZNF 317 -3和ZNF 317 -4的转录本仅在淋巴细胞、脾和肺中检测到。ZNF 317 mRNA的表达在红系成熟过程中显著降低。在淋巴细胞中，ZNF 317的表达减少有丝分裂刺激。我们认为ZNF 317可能在红系成熟和淋巴细胞增殖中起重要作用。少