Nature Cell Biology6, 642 - 647 (2004)
Published online: 6 June 2004; | doi:10.1038/ncb1144
HIF activation by pH-dependent nucleolar sequestration of VHL
Karim Mekhail, Lakshman Gunaratnam, Marie-Eve Bonicalzi
& Stephen Lee
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Correspondence should be addressed to Stephen Lee slee@uottawa.ca
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,
5,
6,
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.
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