HIF activation by pH-dependent nucleolar sequestration of VHL

Karim Mekhail, Lakshman Gunaratnam, Marie Eve Bonicalzi, Stephen Lee

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Hypoxia and acidosis occur in a wide variety of physiological and pathological settings that include muscle stress, tumour development and ischaemic disorders. A central element in the adaptive response to cellular hypoxia is HIF (hypoxia-inducible factor), a transcription factor that activates an array of genes implicated in oxygen homeostasis, tumour vascularization and ischaemic preconditioning1. HIF is activated by hypoxia, but undergoes degradation by the VHL (von Hippel-Lindau) tumour suppressor protein in the presence of oxygen2,3. Here, we demonstrate that hypoxia induction or normoxic acidosis can neutralize the function of VHL by triggering its nucleolar sequestration, a regulatory mechanism of protein function that is observed rarely4-7. VHL is confined to nucleoli until neutral pH conditions are re-instated. Nucleolar sequestration of VHL enables HIF to evade destruction in the presence of oxygen and activate its target genes. Our findings suggest that an increase in hydrogen ions elicits a transient and reversible loss of VHL function by promoting its nucleolar sequestration.

Original languageEnglish (US)
Pages (from-to)642-647
Number of pages6
JournalNature Cell Biology
Volume6
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

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Acidosis
Von Hippel-Lindau Tumor Suppressor Protein
Oxygen
Cell Hypoxia
Genes
Hypoxia
Protons
Neoplasms
Homeostasis
Transcription Factors
Muscles
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

HIF activation by pH-dependent nucleolar sequestration of VHL. / Mekhail, Karim; Gunaratnam, Lakshman; Bonicalzi, Marie Eve; Lee, Stephen.

In: Nature Cell Biology, Vol. 6, No. 7, 07.2004, p. 642-647.

Research output: Contribution to journalArticle

Mekhail, K, Gunaratnam, L, Bonicalzi, ME & Lee, S 2004, 'HIF activation by pH-dependent nucleolar sequestration of VHL', Nature Cell Biology, vol. 6, no. 7, pp. 642-647. https://doi.org/10.1038/ncb1144
Mekhail, Karim ; Gunaratnam, Lakshman ; Bonicalzi, Marie Eve ; Lee, Stephen. / HIF activation by pH-dependent nucleolar sequestration of VHL. In: Nature Cell Biology. 2004 ; Vol. 6, No. 7. pp. 642-647.
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