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Molecular and Cellular Biology, December 2008, p. 7081-7095, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00773-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hypoxia-Associated Factor, a Novel E3-Ubiquitin Ligase, Binds and Ubiquitinates Hypoxia-Inducible Factor 1{alpha}, Leading to Its Oxygen-Independent Degradation {triangledown} ,{dagger}

Mei Yee Koh,* Bryant G. Darnay, and Garth Powis

Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas 77030

Received 14 May 2008/ Returned for modification 29 June 2008/ Accepted 24 September 2008

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

* Corresponding author. Mailing address: Department of Experimental Therapeutics, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 563-1890. Fax: (713) 792-1204. E-mail: mykoh{at}mdanderson.org

{triangledown} Published ahead of print on 6 October 2008.

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

Molecular and Cellular Biology, December 2008, p. 7081-7095, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00773-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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