HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
- 14 August 2001
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 98 (17), 9630-9635
- https://doi.org/10.1073/pnas.181341498
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.Keywords
This publication has 22 references indexed in Scilit:
- The von Hippel–Lindau Tumor Suppressor GeneExperimental Cell Research, 2001
- Mechanism of regulation of the hypoxia-inducible factor-1alpha by the von Hippel-Lindau tumor suppressor proteinThe EMBO Journal, 2000
- Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor ProteinJournal of Biological Chemistry, 2000
- Bacterial protein toxins targeting Rho GTPasesFEMS Microbiology Letters, 2000
- Hypoxic Induction of Prolyl 4-Hydroxylase α(I) in Cultured CellsJournal of Biological Chemistry, 2000
- Regulation of Mammalian O2Homeostasis by Hypoxia-Inducible Factor 1Annual Review of Cell and Developmental Biology, 1999
- Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathwayProceedings of the National Academy of Sciences of the United States of America, 1998
- Effect of Protein Kinase and Phosphatase Inhibitors on Expression of Hypoxia Inducible Factor 1Biochemical and Biophysical Research Communications, 1995
- Regulation of the Erythropoietin Gene: Evidence That the Oxygen Sensor Is a Heme ProteinScience, 1988
- Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferaseGene, 1988