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HIF activation by pH-dependent nucleolar sequestration of VHL

Nature Cell Biology volume 6, pages 642–647 (2004)Cite this article

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 rarely4,5,6,7. 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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Figure 1: VHL localizes to sub-nuclear foci under physiological acidosis.
Figure 3: Acidosis prolongs HIF stabilization after re-oxygenation.
Figure 2: VHL redistributes to the nucleolus during acidosis.
Figure 4: Nucleolar sequestration of VHL prevents the degradation of HIF.
Figure 5: Normoxic acidosis triggers nucleolar sequestration of VHL to activate HIF.

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Acknowledgements

We thank C. Lavigne for technical expertise. This work was supported by a grant from the Canadian Institutes of Health Research (CIHR). K.M. is supported by the Natural Science and Engineering Research Council of Canada (NSERC). S.L. is a Harold E. Johns investigator of the National Cancer Institute of Canada (NCIC).

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, K1H 8M5, Ontario, Canada

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

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Correspondence to Stephen Lee.

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Mekhail, K., Gunaratnam, L., Bonicalzi, ME. et al. HIF activation by pH-dependent nucleolar sequestration of VHL. Nat Cell Biol 6, 642–647 (2004). https://doi.org/10.1038/ncb1144

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