期刊
INTERNATIONAL JOURNAL OF HEMATOLOGY
卷 88, 期 1, 页码 43-51出版社
SPRINGER TOKYO
DOI: 10.1007/s12185-008-0091-6
关键词
hematopoietic stem cells; TPO; HIF-1; mitochondria; ROS
类别
资金
- NCI NIH HHS [R01 CA31615] Funding Source: Medline
- NIDDK NIH HHS [R01DK49855] Funding Source: Medline
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 alpha expression in HSCs by enhancing the stability of HIF-1 alpha under normoxic conditions. However, the molecular mechanisms of these effects are not yet fully understood. In this study, we explored the mechanisms and found that TPO-induced mitochondrial reactive oxygen species (ROS) played a crucial role in stabilization of HIF-1. Both ROS scavengers and inhibitors of mitochondrial electron transport completely blocked HIF-1 alpha induction by TPO in UT-7/TPO cells and in primary immature mouse bone marrow cells. We also found that TPO-induced HIF-1 alpha induction was tightly coupled with glucose metabolism. Inhibition of glucose transporter or glycolytic enzyme blocked HIF-1 alpha elevation of TPO. These results indicate that TPO induces HIF-1 alpha expression in a manner very similar to that of hypoxia.
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