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HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A 2001 Aug 14;98(17):9630-5

Date

08/16/2001

Pubmed ID

11504942

Pubmed Central ID

PMC55503

DOI

10.1073/pnas.181341498

Scopus ID

2-s2.0-0035859692 (requires institutional sign-in at Scopus site)   685 Citations

Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a global transcriptional regulator of the hypoxic response. Under normoxic conditions, HIF-1alpha is recognized by the von Hippel-Lindau tumor-suppressor protein (VHL), a component of an E3 ubiquitin ligase complex. This interaction thereby promotes the rapid degradation of HIF-1alpha. Under hypoxic conditions, HIF-1alpha is stabilized. We have previously shown that VHL binds in a hypoxia-sensitive manner to a 27-aa segment of HIF-1alpha, and that this regulation depends on a posttranslational modification of HIF-1alpha. Through a combination of in vivo coimmunoprecipitation assays using VHL and a panel of point mutants of HIF-1alpha in this region, as well as MS and in vitro binding assays, we now provide evidence that this modification, which occurs under normoxic conditions, is hydroxylation of Pro-564 of HIF-1alpha. The data furthermore show that this proline hydroxylation is the primary regulator of VHL binding.

Author List

Yu F, White SB, Zhao Q, Lee FS

Author

Sarah B. White MD, MS, FSIR, FCIRSE Associate Dean, Vice Chair, Professor in the Radiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
COS Cells
Cell Hypoxia
Cobalt
DNA-Binding Proteins
HeLa Cells
Humans
Hydroxylation
Hydroxyproline
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Ligases
Macromolecular Substances
Molecular Sequence Data
Nuclear Proteins
Peptide Fragments
Point Mutation
Proline
Protein Binding
Protein Processing, Post-Translational
Proteins
Recombinant Fusion Proteins
Transcription Factors
Transfection
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein