Thrombopoietin (TPO) regulates HIF-1alpha levels through generation of mitochondrial reactive oxygen species.
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-1alpha expression in HSCs by enhancing the stability of HIF-1alpha 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-1alpha induction by TPO in UT-7/TPO cells and in primary immature mouse bone marrow cells. We also found that TPO-induced HIF-1alpha induction was tightly coupled with glucose metabolism. Inhibition of glucose transporter or glycolytic enzyme blocked HIF-1alpha elevation of TPO. These results indicate that TPO induces HIF-1alpha expression in a manner very similar to that of hypoxia.
Yoshida
Kozue
K
Department of Hematology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.|Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
Kirito
Keita
K
Department of Hematology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. kirito@yamanashi.ac.jp.
Yongzhen
Hu
H
Department of Hematology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Ozawa
Keiya
K
Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
Kaushansky
Kenneth
K
Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, USA.
Komatsu
Norio
N
Department of Hematology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. komatsun@yamanashi.ac.jp.
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013926:Thrombopoietin / Q000378:metabolism / Q000494:pharmacology*
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D013926:Thrombopoietin