Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation
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- 17 September 2001
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 20 (18), 5197-5206
- https://doi.org/10.1093/emboj/20.18.5197
Abstract
Oxygen‐dependent proteolytic destruction of hypoxia‐inducible factor‐α (HIF‐α) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel–Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF‐1α that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF‐α oxygen‐dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non‐redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL–HIF‐α interactions, but reinforces the role of prolyl hydroxylation as an oxygen‐dependent destruction signal.Keywords
This publication has 36 references indexed in Scilit:
- Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau proteinNature, 2000
- Mammalian Oxygen Sensing, Signalling and Gene RegulationJournal of Experimental Biology, 2000
- Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutationsProceedings of the National Academy of Sciences of the United States of America, 2000
- Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1αGenes & Development, 2000
- p42/p44 Mitogen-activated Protein Kinases Phosphorylate Hypoxia-inducible Factor 1α (HIF-1α) and Enhance the Transcriptional Activity of HIF-1Journal of Biological Chemistry, 1999
- Structure of the VHL-ElonginC-ElonginB Complex: Implications for VHL Tumor Suppressor FunctionScience, 1999
- Combinatorial control in ubiquitin-dependent proteolysis: don't Skp the F-box hypothesisTrends in Genetics, 1998
- Selection and Analysis of a Mutant Cell Line Defective in the Hypoxia-inducible Factor-1 α-Subunit (HIF-1α)Online Journal of Public Health Informatics, 1998
- Prolyl 4-hydroxylases and their protein disulfide isomerase subunitMatrix Biology, 1998
- Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α: MODULATION OF TRANSCRIPTIONAL ACTIVITY BY OXYGEN TENSIONOnline Journal of Public Health Informatics, 1997