Oxygen sensing by H+: implications for HIF and hypoxic cell memory.
Hypoxia and acidosis are common features of several physiological and pathological situations, including cancer and stroke. The HIF (hypoxia-inducible factor) transcription factor plays a seminal role in orchestrating cellular responses to alterations in oxygen availability. HIF is degraded in normal oxygen tension by the VHL (von Hippel-Lindau) tumor suppressor protein but stabilized by hypoxia to activate an array of genes implicated in oxygen homeostasis including vascular endothelial growth factor. Cells respond to a comparatively mild decline in oxygen tension by converting to an anaerobic state of respiration and secreting lactic acid. We recently reported that a decrease in environmental pH triggers sequestration of VHL into the nucleolus neutralizing its ability to degrade HIF. This implies that cells have evolved a parallel mechanism of HIF activation that responds to changes in oxygen levels by sensing extracellular [H+]. Here we discuss the implications of this new VHL regulatory mechanism on oxygen homeostasis and hypoxic cell memory.
Mekhail
Karim
K
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Khacho
Mireille
M
Gunaratnam
Lakshman
L
Lee
Stephen
S
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D006859:Hydrogen / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D006859:Hydrogen; D010100:Oxygen