权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Roles of MAP kinases and STAT3 in proliferation and differentiation of normal human hematopoietic progenitor cells

MAP激酶和STAT3在正常人造血祖细胞增殖和分化中的作用

基本信息

批准号：
11470213
负责人：
KITAGAWA Seiichi
金额：
$ 4.8万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470213/
关键词：
hematopoietic progenitor cells neutrophils MAP kinase STAT3 CD34 SCF IL-6 G-CSF ERK p38 アポトーシス

项目摘要

Distinct MAP kinase subtype cascades (MEK-ERK, MKK3/6-p38 and MKK4/7-JNK) were found to be activated in normal human hematopoietic progenitor cells (CD34^+ cells) stimulated by various cytokines (SCF, G-CSF, TPO, GM-CSF, IL-6/sIL-6R, IL-3, IL-1β, TNFα, IFNα and IFNγ) in a cytokine-specific manner. Likewise, distinct STAT molecules (STAT3, STAT5a, STAT5b and STAT1) were also tyrosine-phosphorylated by these cytokines in a cytokine-specific manner. SCF, IL-6/sIL-6R and G-CSF serine-phosphorylated STAT3 through activation of ERK and/or H7-sensitive kinase according to the stimuli used ; I. e., ERK was involved in SCF- and G-CSF-mediated phosphorylation, and H7-sensitive kinase was involved in IL-6/sIL-6R- and G-CSF-mediated phosphorylation. Serine-phosphorylation of STAT3 was also regulated by PI-3 kinase. ERK was primarily involved in proliferation of CD34^+ cells, whereas STAT3 was primarily involved in cell survival. Coordinated activation of ERK and STAT3 resulted in the synergistic effect on proliferation and survival of CD34^+ cells. MAK kinase subtypes activated by stimulation with cytokines and their roles in cell functions were altered during differentiation into mature neutrophils and were dependent on the stages of differentiation of cells. In mature neutrophils, MEK-ERK and/or MKK3/6-p38, but not MKK4/7-JNK, were activated by stimulation with various cytokines (G-CSF, GM-CSF, TNFα and IL-1β) in a cytokine-specific manner. Both pathways were involved in cytokine-induced activation of neutrophil functions such as superoxide release, adherence and up-regulation of adhesion molecules (CD11b and CD15).

不同的MAP激酶亚型级联（MEK-ERK、MKK 3/6-p38和MKK 4/7-JNK）在正常人造血祖细胞（CD 34 ^+细胞）中被多种细胞因子（SCF、G-CSF、TPO、GM-CSF、IL-6/sIL-6 R、IL-3、IL-1β、TNFα、IFNα和IFNγ）以精氨酸特异性方式激活。同样地，不同的STAT分子（STAT 3、STAT 5a、STAT 5 b和STAT 1）也被这些细胞因子以精氨酸特异性方式酪氨酸磷酸化。SCF、IL-6/sIL-6 R和G-CSF丝氨酸磷酸化的STAT 3通过根据所使用的刺激激活ERK和/或H7敏感性激酶; I.例如，ERK参与SCF和G-CSF介导的磷酸化，H7敏感激酶参与IL-6/sIL-6 R和G-CSF介导的磷酸化。STAT 3的丝氨酸磷酸化也受到PI-3激酶的调节。ERK主要参与CD 34 ^+细胞的增殖，而STAT 3主要参与细胞的存活。ERK和STAT 3的协同激活对CD 34 ^+细胞的增殖和存活产生协同效应。MAK激酶亚型激活的刺激与细胞因子和它们的作用在细胞功能中的变化在分化成成熟的中性粒细胞，并依赖于细胞的分化阶段。在成熟的中性粒细胞中，MEK-ERK和/或MKK 3/6-p38，但不是MKK 4/7-JNK，通过各种细胞因子（G-CSF、GM-CSF、TNFα和IL-1β）以精氨酸特异性方式刺激而被激活。这两种途径都参与了尼古丁诱导的中性粒细胞功能激活，如超氧化物释放，粘附和上调粘附分子（CD 11b和CD 15）。