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PNAS 98 (17): 9630-9635

Copyright © 2001 by the National Academy of Sciences.


HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation

Fang Yu*, Sarah B. White*, Quan Zhao, and Frank S. Lee{dagger}

Department of Pathology and Laboratory Medicine, University of Pennsylvania Cancer Center, University of Pennsylvania School of Medicine, 605 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104

Accepted for publication July 5, 2001.

Received for publication May 3, 2001.

Abstract: Hypoxia-inducible factor-1α (HIF-1α)1 is a global transcriptional regulator of the hypoxic response. Under normoxic conditions, HIF-1α 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-1α. Under hypoxic conditions, HIF-1α is stabilized. We have previously shown that VHL binds in a hypoxia-sensitive manner to a 27-aa segment of HIF-1α, and that this regulation depends on a posttranslational modification of HIF-1α. Through a combination of in vivo coimmunoprecipitation assays using VHL and a panel of point mutants of HIF-1α 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-1α. The data furthermore show that this proline hydroxylation is the primary regulator of VHL binding.

* F.Y. and S.B.W. contributed equally to this work.

{dagger} To whom reprint requests should be addressed. E-mail: franklee{at}

Communicated by Thomas Maniatis, Harvard University, Cambridge, MA

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BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1{alpha}.
X. Pi, G. Garin, L. Xie, Q. Zheng, H. Wei, J.-i. Abe, C. Yan, and B. C. Berk (2005)
Circ. Res. 96, 1145-1151
   Abstract »    Full Text »    PDF »
Decreased Growth of Vhl-/- Fibrosarcomas Is Associated with Elevated Levels of Cyclin Kinase Inhibitors p21 and p27.
F. A. Mack, J. H. Patel, M. P. Biju, V. H. Haase, and M. C. Simon (2005)
Mol. Cell. Biol. 25, 4565-4578
   Abstract »    Full Text »    PDF »
Oligomycin inhibits HIF-1{alpha} expression in hypoxic tumor cells.
Y. Gong and F. H. Agani (2005)
Am J Physiol Cell Physiol 288, C1023-C1029
   Abstract »    Full Text »    PDF »
Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1.
L. Xie, R. S. Johnson, and R. S. Freeman (2005)
J. Cell Biol. 168, 911-920
   Abstract »    Full Text »    PDF »
Role of CBP in regulating HIF-1-mediated activation of transcription.
J. L. Ruas, L. Poellinger, and T. Pereira (2005)
J. Cell Sci. 118, 301-311
   Abstract »    Full Text »    PDF »
Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.
D. J. Manalo, A. Rowan, T. Lavoie, L. Natarajan, B. D. Kelly, S. Q. Ye, J. G. N. Garcia, and G. L. Semenza (2005)
Blood 105, 659-669
   Abstract »    Full Text »    PDF »
The von Hippel-Lindau Tumor Suppressor Protein: Roles in Cancer and Oxygen Sensing.
W.G. KAELIN JR. (2005)
Cold Spring Harb Symp Quant Biol 70, 159-166
   Abstract »    PDF »
Many Amino Acid Substitutions in a Hypoxia-inducible Transcription Factor (HIF)-1{alpha}-like Peptide Cause Only Minor Changes in Its Hydroxylation by the HIF Prolyl 4-Hydroxylases: SUBSTITUTION OF 3,4-DEHYDROPROLINE OR AZETIDINE-2-CARBOXYLIC ACID FOR THE PROLINE LEADS TO A HIGH RATE OF UNCOUPLED 2-OXOGLUTARATE DECARBOXYLATION.
D. Li, M. Hirsila, P. Koivunen, M. C. Brenner, L. Xu, C. Yang, K. I. Kivirikko, and J. Myllyharju (2004)
J. Biol. Chem. 279, 55051-55059
   Abstract »    Full Text »    PDF »
Role of VHL Gene Mutation in Human Cancer.
W. Y. Kim and W. G. Kaelin (2004)
J. Clin. Oncol. 22, 4991-5004
   Abstract »    Full Text »    PDF »
Genetic Analysis of the Role of the Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-inducible Factor (HIF) in Regulating HIF Transcriptional Target Genes.
I. P. Stolze, Y.-M. Tian, R. J. Appelhoff, H. Turley, C. C. Wykoff, J. M. Gleadle, and P. J. Ratcliffe (2004)
J. Biol. Chem. 279, 42719-42725
   Abstract »    Full Text »    PDF »
Identification of Elongin C and Skp1 Sequences That Determine Cullin Selection.
Q. Yan, T. Kamura, Y. Cai, J. Jin, M. Ivan, A. Mushegian, R. C. Conaway, and J. W. Conaway (2004)
J. Biol. Chem. 279, 43019-43026
   Abstract »    Full Text »    PDF »
Hypoxic reduction in cellular glutathione levels requires mitochondrial reactive oxygen species.
K. D. Mansfield, M. C. Simon, and B. Keith (2004)
J Appl Physiol 97, 1358-1366
   Abstract »    Full Text »    PDF »
The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer.
W. G. Kaelin Jr. (2004)
Clin. Cancer Res. 10, 6290S-6295S
   Abstract »    Full Text »    PDF »
Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor.
R. J. Appelhoff, Y.-M. Tian, R. R. Raval, H. Turley, A. L. Harris, C. W. Pugh, P. J. Ratcliffe, and J. M. Gleadle (2004)
J. Biol. Chem. 279, 38458-38465
   Abstract »    Full Text »    PDF »
Hydroxylation of HIF-1: Oxygen Sensing at the Molecular Level.
G. L. Semenza (2004)
Physiology 19, 176-182
   Abstract »    Full Text »    PDF »
Epstein-Barr Virus Latent Membrane Protein 1 Induces Synthesis of Hypoxia-Inducible Factor 1{alpha}.
N. Wakisaka, S. Kondo, T. Yoshizaki, S. Murono, M. Furukawa, and J. S. Pagano (2004)
Mol. Cell. Biol. 24, 5223-5234
   Abstract »    Full Text »    PDF »
Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis.
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon (2004)
Cancer Res. 64, 3500-3507
   Abstract »    Full Text »    PDF »
VEGFA is necessary for chondrocyte survival during bone development.
E. Zelzer, R. Mamluk, N. Ferrara, R. S. Johnson, E. Schipani, and B. R. Olsen (2004)
Development 131, 2161-2171
   Abstract »    Full Text »    PDF »

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