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Article

Hypoxia-Associated Factor, a Novel E3-Ubiquitin Ligase, Binds and Ubiquitinates Hypoxia-Inducible Factor 1α, Leading to Its Oxygen-Independent Degradation

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Pages 7081-7095 | Received 14 May 2008, Accepted 24 Sep 2008, Published online: 27 Mar 2023
 

Abstract

The hypoxia-inducible factor 1α (HIF-1α) is the master regulator of the cellular response to hypoxia. A key regulator of HIF-1α is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal degradation of HIF-1α in normoxia. Here, we describe a new regulator of HIF-1α, the hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase that binds HIF-1α leading to its proteasome-dependent degradation irrespective of cellular oxygen tension. HAF, a protein expressed in proliferating cells, binds and ubiquitinates HIF-1α in vitro, and both binding and E3 ligase activity are mediated by HAF amino acids 654 to 800. Furthermore, HAF overexpression decreases HIF-1α levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdown increases HIF-1α levels in normoxia, hypoxia, and under epidermal growth factor stimulation. In contrast, HIF-2α is not regulated by HAF. In vivo, tumor xenografts from cells overexpressing HAF show decreased levels of HIF-1α accompanied by decreased tumor growth and angiogenesis. Therefore, HAF is the key mediator of a new HIF-1α-specific degradation pathway that degrades HIF-1α through a new, oxygen-independent mechanism.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank C. Franklin, R. Williams, and A. Campos for technical assistance and B. Lamothe and T. Spivak-Kroizman for helpful discussions.

This work was supported in part by National Institute of Health grants CA109552, CA098929, CA95060, and CA52995 (G.P.) and Institutional Start-Up Funds (B.G.D.).

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