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Science 292 (5516): 464-468

Copyright © 2001 by the American Association for the Advancement of Science

HIFalpha Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing

Mircea Ivan,1 Keiichi Kondo,1 Haifeng Yang,1 William Kim,1 Jennifer Valiando,1 Michael Ohh,1 Adrian Salic,3 John M. Asara,4 William S. Lane,4 William G. Kaelin Jr.12*

HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe2+, this protein modification may play a key role in mammalian oxygen sensing.

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}

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I. Paatero, A. Jokilammi, P. T. Heikkinen, K. Iljin, O.-P. Kallioniemi, F. E. Jones, P. M. Jaakkola, and K. Elenius (2012)
J. Biol. Chem. 287, 9659-9671
   Abstract »    Full Text »    PDF »
Structural and Molecular Characterization of Iron-sensing Hemerythrin-like Domain within F-box and Leucine-rich Repeat Protein 5 (FBXL5).
J. W. Thompson, A. A. Salahudeen, S. Chollangi, J. C. Ruiz, C. A. Brautigam, T. M. Makris, J. D. Lipscomb, D. R. Tomchick, and R. K. Bruick (2012)
J. Biol. Chem. 287, 7357-7365
   Abstract »    Full Text »    PDF »
The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.
S. S. Han, M. Yeager, L. E. Moore, M.-H. Wei, R. Pfeiffer, O. Toure, M. P. Purdue, M. Johansson, G. Scelo, C. C. Chung, et al. (2012)
Hum. Mol. Genet. 21, 1190-1200
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Four-and-a-Half LIM Domain Proteins Inhibit Transactivation by Hypoxia-inducible Factor 1.
M. E. Hubbi, D. M. Gilkes, J. H. Baek, and G. L. Semenza (2012)
J. Biol. Chem. 287, 6139-6149
   Abstract »    Full Text »    PDF »
Myc Posttranscriptionally Induces HIF1 Protein and Target Gene Expression in Normal and Cancer Cells.
M. R. Doe, J. M. Ascano, M. Kaur, and M. D. Cole (2012)
Cancer Res. 72, 949-957
   Abstract »    Full Text »    PDF »
Increased Angiogenesis Protects against Adipose Hypoxia and Fibrosis in Metabolic Disease-resistant 11{beta}-Hydroxysteroid Dehydrogenase Type 1 (HSD1)-deficient Mice.
Z. Michailidou, S. Turban, E. Miller, X. Zou, J. Schrader, P. J. Ratcliffe, P. W. F. Hadoke, B. R. Walker, J. P. Iredale, N. M. Morton, et al. (2012)
J. Biol. Chem. 287, 4188-4197
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GSK-3{beta} regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1{alpha}.
D. Flugel, A. Gorlach, and T. Kietzmann (2012)
Blood 119, 1292-1301
   Abstract »    Full Text »    PDF »
Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1{alpha} and inhibits stromal cell-derived factor-1 in human endometrial stromal cells.
T. Tsuzuki, H. Okada, H. Cho, S. Tsuji, A. Nishigaki, K. Yasuda, and H. Kanzaki (2012)
Hum. Reprod. 27, 523-530
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Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses.
E. A. White, M. E. Sowa, M. J. A. Tan, S. Jeudy, S. D. Hayes, S. Santha, K. Munger, J. W. Harper, and P. M. Howley (2012)
PNAS 109, E260-E267
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Digoxin inhibits development of hypoxic pulmonary hypertension in mice.
E. M. Abud, J. Maylor, C. Undem, A. Punjabi, A. L. Zaiman, A. C. Myers, J. T. Sylvester, G. L. Semenza, and L. A. Shimoda (2012)
PNAS 109, 1239-1244
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Hypoxic Pulmonary Vasoconstriction.
J. T. Sylvester, L. A. Shimoda, P. I. Aaronson, and J. P. T. Ward (2012)
Physiol Rev 92, 367-520
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Apnea stimulates the adaptive response to oxidative stress in elephant seal pups.
J. P. Vazquez-Medina, T. Zenteno-Savin, M. S. Tift, H. J. Forman, D. E. Crocker, and R. M. Ortiz (2011)
J. Exp. Biol. 214, 4193-4200
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Loss of epidermal hypoxia-inducible factor-1{alpha} accelerates epidermal aging and affects re-epithelialization in human and mouse.
H. R. Rezvani, N. Ali, M. Serrano-Sanchez, P. Dubus, C. Varon, C. Ged, C. Pain, M. Cario-Andre, J. Seneschal, A. Taieb, et al. (2011)
J. Cell Sci. 124, 4172-4183
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