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Medline ® Abstract for Reference 13

of 'Molecular biology and pathogenesis of von Hippel-Lindau disease'

Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation.
Koh MY, Darnay BG, Powis G
Mol Cell Biol. 2008 Dec;28(23):7081-95. Epub 2008 Oct 6.
The hypoxia-inducible factor 1alpha (HIF-1alpha) is the master regulator of the cellular response to hypoxia. A key regulator of HIF-1alpha is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal degradation of HIF-1alpha in normoxia. Here, we describe a new regulator of HIF-1alpha, the hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase that binds HIF-1alpha leading to its proteasome-dependent degradation irrespective of cellular oxygen tension. HAF, a protein expressed in proliferating cells, binds and ubiquitinates HIF-1alpha in vitro, and both binding and E3 ligase activity are mediated by HAF amino acids 654 to 800. Furthermore, HAF overexpression decreases HIF-1alpha levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdown increases HIF-1alpha levels in normoxia, hypoxia, and under epidermal growth factor stimulation. In contrast, HIF-2alpha is not regulated by HAF. In vivo, tumor xenografts from cells overexpressing HAF show decreased levels of HIF-1alpha accompanied by decreased tumor growth and angiogenesis. Therefore, HAF is the key mediator of a new HIF-1alpha-specific degradation pathway that degrades HIF-1alpha through a new, oxygen-independent mechanism.
Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas 77030, USA. mykoh@mdanderson.org