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.

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 hydroxylase 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.
Mesh Terms:
Adenovirus E1A Proteins, Anoxia, Aspartate Carbamoyltransferase, Blotting, Western, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cell Line, DNA-Binding Proteins, Deferoxamine, Dihydroorotase, Hela Cells, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Ligases, Mixed Function Oxygenases, Multienzyme Complexes, Nuclear Proteins, Protein Binding, Protein Isoforms, Trans-Activators, Transcription Factors, Transcriptional Activation, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Mol. Cell. Biol.
Date: May. 01, 2002
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