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HIF Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
Mircea Ivan,1Keiichi Kondo,1Haifeng Yang,1William Kim,1Jennifer Valiando,1Michael Ohh,1Adrian Salic,3John M. Asara,4William S. Lane,4William G. Kaelin Jr.12*
HIF (hypoxia-inducible factor) is a transcription factor
that plays a pivotal role in cellular adaptation to changes in oxygenavailability. In the presence of oxygen, HIF is targeted for
destructionby an E3 ubiquitin ligase containing the von Hippel-Lindau
tumorsuppressor protein (pVHL). We found that human pVHL binds
to ashort HIF-derived peptide when a conserved proline residue atthe
core of this peptide is hydroxylated. Because proline hydroxylationrequires molecular oxygen and Fe2+, this protein
modification may play a key role in mammalian oxygensensing.
1 Dana-Farber Cancer Institute and Brigham and
Women's Hospital,
2 Howard Hughes Medical
Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
3 Department of Cell Biology, Harvard Medical
School, Boston, MA 02115, USA.
4 Microchemistry and
Proteomics Analysis Facility, Harvard University, Cambridge, MA 02138, USA.
*
To whom correspondence should be addressed. E-mail:
william_kaelin{at}dfci.harvard.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
RESEARCH ARTICLES
Panu Jaakkola, David R. Mole, Ya-Min Tian, Michael I. Wilson, Janine Gielbert, Simon J. Gaskell, Alexander von Kriegsheim, Holger F. Hebestreit, Mridul Mukherji, Christopher J. Schofield, Patrick H. Maxwell, Christopher W. Pugh, and Peter J. Ratcliffe (20 April 2001) Science292 (5516), 468.
[DOI: 10.1126/science.1059796] |Abstract »|Full Text »|PDF »
PERSPECTIVES
Hao Zhu and H. Franklin Bunn (20 April 2001) Science292 (5516), 449.
[DOI: 10.1126/science.1060849] |Summary »|Full Text »
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Mechanism of CRL4Cdt2, a PCNA-dependent E3 ubiquitin ligase.
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2{alpha} gain-of-function mutation.
F. Formenti, P. A. Beer, Q. P. P. Croft, K. L. Dorrington, D. P. Gale, T. R. J. Lappin, G. S. Lucas, E. R. Maher, P. H. Maxwell, M. F. McMullin, et al. (2011)
FASEB J
25, 2001-2011
|Abstract »|Full Text »|PDF »
Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
T. D. Barrett, H. L. Palomino, T. I. Brondstetter, K. C. Kanelakis, X. Wu, P. V. Haug, W. Yan, A. Young, H. Hua, J. C. Hart, et al. (2011)
Mol. Pharmacol.
79, 910-920
|Abstract »|Full Text »|PDF »
Differential Hypoxic Regulation of Hypoxia-Inducible Factors 1{alpha} and 2{alpha}.
Molecular Evolution of the Metazoan PHD-HIF Oxygen-Sensing System.
K. T. Rytkonen, T. A. Williams, G. M. Renshaw, C. R. Primmer, and M. Nikinmaa (2011)
Mol. Biol. Evol.
28, 1913-1926
|Abstract »|Full Text »|PDF »
Vitamin C is dispensable for oxygen sensing in vivo.
K. J. Nytko, N. Maeda, P. Schlafli, P. Spielmann, R. H. Wenger, and D. P. Stiehl (2011)
Blood
117, 5485-5493
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Src activates HIF-1{alpha} not through direct phosphorylation of HIF-1{alpha}-specific prolyl-4 hydroxylase 2 but through activation of the NADPH oxidase/Rac pathway.
H.-Y. Lee, T. Lee, N. Lee, E. G. Yang, C. Lee, J. Lee, E.-Y. Moon, J. Ha, and H. Park (2011)
Carcinogenesis
32, 703-712
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Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Antiproliferative Activity of TGF{beta}.
A. K.-v. Ameln, A. Muschter, S. Mamlouk, J. Kalucka, I. Prade, K. Franke, M. Rezaei, D. M. Poitz, G. Breier, and B. Wielockx (2011)
Cancer Res.
71, 3306-3316
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Normoxic Expression of Hypoxia-Inducible Factor 1 in Rat Leydig Cells In Vivo and In Vitro.
M. A. Palladino, P. R. Pirlamarla, J. McNamara, C. M. Sottas, N. Korah, M. P. Hardy, D. B. Hales, and L. Hermo (2011) 32, 307-323
|Abstract »|Full Text »|PDF »
Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner.
R. Chen, E. M. Dioum, R. T. Hogg, R. D. Gerard, and J. A. Garcia (2011)
J. Biol. Chem.
286, 13869-13878
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Differential Sensitivity of Hypoxia Inducible Factor Hydroxylation Sites to Hypoxia and Hydroxylase Inhibitors.
Y.-M. Tian, K. K. Yeoh, M. K. Lee, T. Eriksson, B. M. Kessler, H. B. Kramer, M. J. Edelmann, C. Willam, C. W. Pugh, C. J. Schofield, et al. (2011)
J. Biol. Chem.
286, 13041-13051
|Abstract »|Full Text »|PDF »
Mitotic spindle misorientation in cancer - out of alignment and into the fire.
Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
