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Thrombopoietin (TPO) regulates HIF-la levels through generation of mitochondrial reactive oxygen species

血小板生成素 (TPO) 通过产生线粒体活性氧来调节 HIF-1α 水平

基本信息

批准号：
17591005
负责人：
KIRITO Keita
金额：
$ 2.24万
依托单位：
University of Yamanashi
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591005/
关键词：
Thrombopoietin HIF-1 reactive oxygen species mitochondria glucose hematopoietic stem cells P13-kinase PI3キナーゼ Hematopoietic stem cell ROS glucose mitochondria flavonoid 活性酸素ポリフェノール

项目摘要

Hypoxia inducible factor (HIF)-1 is a master transcriptional regulator mediating the cellular adaptation to hypoxia. In addition, HIF-1 is also vital for the development of hematopoietic stem cells (HSCs). In a previous study we found that thrombopoietin (TPO), an important and non-redundant cytokine for HSC maintenance and expansion, induces HIF-1 α expression in primitive hematopoietic cells by enhancing the stability of HIF-1 α under normoxic conditions. However, the molecular mechanism of these effects are not yet fully understood. Recently, it was reported that mitochondrial reactive oxygen species (ROS) play a crucial role in hypoxia-induced stabilization of HIF-1 α. Thus, we speculated that ROS might also be involved in TPO-induced HIF-1 α expression. Both ROS scavengers and inhibitors of mitochondrial electron transport completely blocked HIF-1 α induction by TPO in UT-7/TPO cells and in primary immature mouse bone marrow cells. These results indicate that TPO induces HIF-1 a expression in a manner very similar to that of hypoxia, and helps to explain the favorable effects of the hormone on genes vital for HSC development.

缺氧诱导因子（Hypoxia inducible factor，HIF）-1是调节细胞缺氧适应的主要转录调节因子。此外，HIF-1对造血干细胞（HSC）的发育也至关重要。在以前的研究中，我们发现血小板生成素（TPO），一个重要的和非冗余的细胞因子，造血干细胞的维持和扩增，诱导HIF-1 α在原始造血细胞中的表达，通过增强HIF-1 α在常氧条件下的稳定性。然而，这些影响的分子机制尚未完全了解。近年来研究发现，线粒体活性氧（reactive oxygen species，ROS）在低氧诱导的HIF-1 α稳定过程中发挥重要作用。因此，我们推测活性氧也可能参与TPO诱导的缺氧诱导因子-1 α表达。ROS清除剂和线粒体电子传递抑制剂均能完全阻断TPO对UT-7/TPO细胞和原代未成熟小鼠骨髓细胞中HIF-1 α的诱导作用。这些结果表明，TPO诱导HIF-1 α表达的方式非常相似的缺氧，并有助于解释的有利影响的激素对基因至关重要的HSC的发展。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RUNX1 suppression induces megakaryocytic differentiation of UT- 7/GM cells

RUNX1抑制诱导UT-7/GM细胞巨核细胞分化

DOI：
发表时间：
2006
期刊：
Biochem Biophys Res Commun 345
影响因子：
0
作者：
Nagai R;Matsuura E;Hoshika Y;Nakata E;Nagura H;Watanabe A;Komatsu N;Okada Y;Doi T.
通讯作者：
Doi T.

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus-negative leukemia cell lines