Oxygen sensing by H+: Implications for HIF and hypoxic cell memory

Karim Mekhail, Mireille Khacho, Lakshman Gunaratnam, Stephen Lee

Research output: Contribution to journalReview articlepeer-review

25 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1025-1027
Number of pages3
JournalCell Cycle
Issue number8
StatePublished - Aug 2004
Externally publishedYes


  • Acidosis
  • Cancer
  • Cardiac arrest
  • HIF
  • Hypoxia
  • Nucleolus
  • Stroke
  • VHL
  • pH

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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