2006 Fiscal Year Final Research Report Summary
Thrombopoietin (TPO) regulates HIF-la levels through generation of mitochondrial reactive oxygen species
| Project/Area Number |
17591005
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | University of Yamanashi |
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Principal Investigator |
KIRITO Keita University of Yamanashi, University of Yamanashi Hospital, Associate Proffessor, 医学部附属病院・助教授, 助教授 (90306150)
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| Co-Investigator(Kenkyū-buntansha) |
KOMATSUU Norio University of Yamanashi, University of Yamanashi Hospital, Proffessor, 医学部附属病院, 教授 (50186798)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Thrombopoietin / HIF-1 / reactive oxygen species / mitochondria / glucose / hematopoietic stem cells / P13-kinase / PI3キナーゼ |
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| Research Abstract |
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.
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