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).

发现在正常的人造血祖细胞（CD34^+细胞）中激活不同的MAP激酶亚型级联反应（MEK-ERK，MKK3/6-P38和MKK4/7-JNK）。 TNFα，IFNα和IFNγ）以细胞因子特异性方式。同样，这些细胞因子以细胞因子特异性的方式被这些细胞因子酪氨酸磷酸化的不同STAT分子（STAT3，STAT5A，STAT5B和Stat1）也被酪氨酸磷酸化。 SCF，IL-6/SIL-6R和G-CSF丝氨酸磷酸化的STAT3通过使用ERK和/或H7敏感激酶的激活，根据所使用的刺激； I. e。，ERK参与SCF和G-CSF介导的磷酸化，H7敏感激酶参与IL-6/SIL-6R和G-CSF介导的磷酸化。 STAT3的丝氨酸磷酸化也受PI-3激酶调节。 ERK主要参与CD34^+细胞的增殖，而STAT3主要参与细胞存活。 ERK和STAT3的协调激活对CD34^+细胞的增殖和存活产生了协同作用。通过用细胞因子刺激激活的MAK激酶亚型及其在细胞功能中的作用在分化为成熟中性粒细胞的过程中会改变，并依赖于细胞分化的阶段。在成熟的嗜中性粒细胞中，MEK-ERK和/或MKK3/6-P38，而不是MKK4/7-JNK，通过用各种细胞因子（GM-CSF，GM-CSF，TNFα和IL-1β）刺激以细胞因子特异性方式激活。两种途径均参与细胞因子诱导的中性粒细胞功能的激活，例如超氧化物释放，粘附和粘附分子的上调（CD11b和CD15）。