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

• 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

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 (HIF)-1 是介导细胞适应缺氧的主要转录调节因子。此外，在之前的研究中，我们发现血小板生成素 (TPO) 对造血干细胞 (HSC) 的发育也至关重要。 ）是HSC维持和扩增的重要且非冗余的细胞因子，通过增强HIF-1α在原始造血细胞中的稳定性来诱导HIF-1α表达。然而，这些作用的分子机制尚未完全了解，最近有报道称线粒体活性氧 (ROS) 在缺氧诱导的 HIF-1 α 稳定中发挥着至关重要的作用。 ROS 也可能参与 TPO 诱导的 HIF-1 α 表达，在 UT-7/TPO 细胞和原代未成熟小鼠中，ROS 清除剂和线粒体电子传递抑制剂完全阻断 TPO 诱导的 HIF-1 α。这些结果表明，TPO 以与缺氧非常相似的方式诱导 HIF-1a 表达，并有助于解释该激素对 HSC 发育至关重要的基因的有利影响。

项目成果

Suppression of RUNX1 by siRNA in megakaryocytic UT-7/GM cells

巨核细胞 UT-7/GM 细胞中 siRNA 对 RUNX1 的抑制

• 发表时间: 2006
• 期刊: Nucleic Acids Symp Ser (Oxf) 50
• 作者: Okada;Y et al.
• 通讯作者: Y et al.

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

• DOI: 10.1038/sj.leu.2404593
• 发表时间: 2007-05-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Furukawa, Y.;Vu, H. A.;Kano, Y.
• 通讯作者: Kano, Y.

Thrombopoietin initiates demethylation-based transcription of GP6 during megakaryocyte differentiation

• DOI: 10.1182/blood-2004-08-3109
• 发表时间: 2005-05-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Kanaji, S;Kanaji, T;Kunicki, TJ
• 通讯作者: Kunicki, TJ

Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells

• DOI: 10.4161/cc.4.12.2197
• 发表时间: 2005-12-01
• 期刊: CELL CYCLE
• 影响因子: 4.3
• 作者: Kirito, K;Kaushansky, K
• 通讯作者: Kaushansky, K

Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines

• DOI: 10.1016/j.bcp.2005.02.021
• 发表时间: 2005-06-01
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Miyoshi, T;Nagai, T;Ozawa, K
• 通讯作者: Ozawa, K