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Molecular and Cellular Biology, May 2002, p. 2984-2992, Vol. 22, No. 9
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.9.2984-2992.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1{alpha} Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

Nianli Sang, Jie Fang, Vickram Srinivas, Irene Leshchinsky, and Jaime Caro*

Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5099

Received 6 December 2001/ Returned for modification 24 January 2002/ Accepted 4 February 2002

Hypoxia-inducible factor 1 complex (HIF-1) plays a pivotal role in oxygen homeostasis and adaptation to hypoxia. Its function is controlled by both the protein stability and the transactivation activity of its alpha subunit, HIF-1{alpha}. Hydroxylation of at least two prolyl residues in the oxygen-dependent degradation domain of HIF-1{alpha} regulates its interaction with the von Hippel-Lindau protein (VHL) that targets HIF-1{alpha} for ubiquitination and proteasomal degradation. Several prolyl hydroxylases have been found to specifically hydroxylate HIF-1{alpha}. In this report, we investigated possible roles of VHL and hydroxylases in the regulation of the transactivation activity of the C-terminal activating domain (CAD) of HIF-1{alpha}. We demonstrate that regulation of the transactivation activity of HIF-1{alpha} CAD also involves hydroxylase activity but does not require functional VHL. In addition, stimulation of the CAD activity by a hydoxylase inhibitor, hypoxia, and desferrioxamine was severely blocked by the adenoviral oncoprotein E1A but not by an E1A mutant defective in targeting p300/CBP. We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1{alpha} CAD and p300/CBP in vivo. Taken together, our data provide evidence that hypoxia-regulated stabilization and transcriptional stimulation of HIF-1{alpha} function are regulated through partially overlapping but distinguishable pathways.

* Corresponding author. Mailing address: Cardeza Foundation for Hematologic Research, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut St., Curtis Bldg., Rm. 810, Philadelphia, PA 19107-5099. Phone: (215) 955-7775. Fax: (215) 923-3836. E-mail: jaime.caro{at}mail.tju.edu.

Molecular and Cellular Biology, May 2002, p. 2984-2992, Vol. 22, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.9.2984-2992.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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