The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions.
The hypoxia-inducible factor (HIF) transcriptional system enables cell adaptation to limited O(2) availability, transducing this signal into patho-physiological responses such as angiogenesis, erythropoiesis, vasomotor control, and altered energy metabolism, as well as cell survival decisions. However, other factors beyond hypoxia are known to activate this pleiotropic transcription factor. The aim of this study was to characterize HIF in human hematopoietic stem cells (HSCs) and evidence is provided that granulocyte colony stimulating factor-mobilized CD34+- and CD133+-HSCs express a stabilized cytoplasmic form of HIF-1alpha under normoxic conditions. It is shown that HIF-1alpha stabilization correlates with down-regulation of the tumour suppressor von Hippel-Lindau protein (pVHL) and is positively controlled by NADPH-oxidase-dependent production of reactive oxygen species, indicating a specific O(2)-independent post-transcriptional control of HIF in mobilized HSCs. This novel finding is discussed in the context of the proposed role of HIF as a mediator of progenitor cell recruitment to injured ischemic tissues and/or in the control of the maintenance of the undifferentiated state.
Piccoli
Claudia
C
Department of Biomedical Science, University of Foggia, Foggia, Italy.
D'Aprile
Annamaria
A
Ripoli
Maria
M
Scrima
Rosella
R
Boffoli
Domenico
D
Tabilio
Antonio
A
Capitanio
Nazzareno
N
D018952:Antigens, CD34 / Q000378:metabolism; D001775:Blood Circulation; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D018952:Antigens, CD34; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human