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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:
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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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Regulation of alveolar epithelial function by hypoxia.
G. Zhou, L. A. Dada, and J. I. Sznajder (2008)
Eur. Respir. J.
31, 1107-1113
|Abstract »|Full Text »|PDF »
Premenstrual Regulation of the Pro-Angiogenic Factor CYR61 in Human Endometrium.
I. Gashaw, S. Stiller, C. Boing, R. Kimmig, and E. Winterhager (2008)
Endocrinology
149, 2261-2269
|Abstract »|Full Text »|PDF »
Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein.
G. Zhou, L. A. Dada, N. S. Chandel, K. Iwai, E. Lecuona, A. Ciechanover, and J. I. Sznajder (2008)
FASEB J
22, 1335-1342
|Abstract »|Full Text »|PDF »
Prolyl Hydroxylase PHD3 Activates Oxygen-dependent Protein Aggregation.
K. Rantanen, J. Pursiheimo, H. Hogel, V. Himanen, E. Metzen, and P. M. Jaakkola (2008)
Mol. Biol. Cell
19, 2231-2240
|Abstract »|Full Text »|PDF »
Notch signaling mediates hypoxia-induced tumor cell migration and invasion.
C. Sahlgren, M. V. Gustafsson, S. Jin, L. Poellinger, and U. Lendahl (2008)
PNAS
105, 6392-6397
|Abstract »|Full Text »|PDF »
HIF-1{alpha} Signaling Upstream of NKX2.5 Is Required for Cardiac Development in Xenopus.
K. Nagao, Y. Taniyama, T. Kietzmann, T. Doi, I. Komuro, and R. Morishita (2008)
J. Biol. Chem.
283, 11841-11849
|Abstract »|Full Text »|PDF »
The von Hippel-Lindau Tumor Suppressor Protein and Egl-9-Type Proline Hydroxylases Regulate the Large Subunit of RNA Polymerase II in Response to Oxidative Stress.
O. Mikhaylova, M. L. Ignacak, T. J. Barankiewicz, S. V. Harbaugh, Y. Yi, P. H. Maxwell, M. Schneider, K. Van Geyte, P. Carmeliet, M. P. Revelo, et al. (2008)
Mol. Cell. Biol.
28, 2701-2717
|Abstract »|Full Text »|PDF »
Evidence for sustained renal hypoxia and transient hypoxia adaptation in experimental rhabdomyolysis-induced acute kidney injury.
C. Rosenberger, M. Goldfarb, A. Shina, S. Bachmann, U. Frei, K.-U. Eckardt, T. Schrader, S. Rosen, and S. N. Heyman (2008)
Nephrol. Dial. Transplant.
23, 1135-1143
|Abstract »|Full Text »|PDF »
Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells.
S.-N. Jung, W. K. Yang, J. Kim, H. S. Kim, E. J. Kim, H. Yun, H. Park, S. S. Kim, W. Choe, I. Kang, et al. (2008)
Carcinogenesis
29, 713-721
|Abstract »|Full Text »|PDF »
PHDs overactivation during chronic hypoxia "desensitizes" HIF{alpha} and protects cells from necrosis.
A. Ginouves, K. Ilc, N. Macias, J. Pouyssegur, and E. Berra (2008)
PNAS
105, 4745-4750
|Abstract »|Full Text »|PDF »
Y. C. Shin, C.-H. Joo, M. U. Gack, H.-R. Lee, and J. U. Jung (2008)
Cancer Res.
68, 1751-1759
|Abstract »|Full Text »|PDF »
Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins.
K. Takeda, H. L. Aguila, N. S. Parikh, X. Li, K. Lamothe, L.-J. Duan, H. Takeda, F. S. Lee, and G.-H. Fong (2008)
Blood
111, 3229-3235
|Abstract »|Full Text »|PDF »
Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1.
D. H. Shin, Y.-S. Chun, D. S. Lee, L. E. Huang, and J.-W. Park (2008)
Blood
111, 3131-3136
|Abstract »|Full Text »|PDF »
Biophytum sensitivum (L.) DC Inhibits Tumor Cell Invasion and Metastasis Through a Mechanism Involving Regulation of MMPs, Prolyl Hydroxylase, Lysyl Oxidase, nm23, ERK-1, ERK-2, STAT-1, and Proinflammatory Cytokine Gene Expression in Metastatic Lung Tissue.
C. Guruvayoorappan and G. Kuttan (2008)
Integr Cancer Ther
7, 42-50
|Abstract »|PDF »
The HIF/VHL Pathway: From Oxygen Sensing to Innate Immunity.
S. R. Walmsley, N. N. McGovern, M. K. B. Whyte, and E. R. Chilvers (2008)
Am. J. Respir. Cell Mol. Biol.
38, 251-255
|Abstract »|Full Text »|PDF »
B. M. Emerling, F. Weinberg, J.-L. Liu, T. W. Mak, and N. S. Chandel (2008)
PNAS
105, 2622-2627
|Abstract »|Full Text »|PDF »
Kinetic Rationale for Selectivity toward N- and C-terminal Oxygen-dependent Degradation Domain Substrates Mediated by a Loop Region of Hypoxia-Inducible Factor Prolyl Hydroxylases.
E. Flashman, E. A. L. Bagg, R. Chowdhury, J. Mecinovic, C. Loenarz, M. A. McDonough, K. S. Hewitson, and C. J. Schofield (2008)
J. Biol. Chem.
283, 3808-3815
|Abstract »|Full Text »|PDF »
Regulation of Angiogenic Factors by HDM2 in Renal Cell Carcinoma.
Activation of the hypoxia-inducible factor-1{alpha} pathway accelerates bone regeneration.
C. Wan, S. R. Gilbert, Y. Wang, X. Cao, X. Shen, G. Ramaswamy, K. A. Jacobsen, Z. S. Alaql, A. W. Eberhardt, L. C. Gerstenfeld, et al. (2008)
PNAS
105, 686-691
|Abstract »|Full Text »|PDF »
Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
