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PNAS 102 (21): 7481-7486

Copyright © 2005 by the National Academy of Sciences.


The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)

Abdullah Ozer, Leeju C. Wu, and Richard K. Bruick *

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038

Communicated by Steven L. McKnight, University of Texas Southwestern Medical Center, Dallas, TX, April 1, 2005

Received for publication January 31, 2005.

Abstract: The hypoxia inducible factor (HIF) plays an important role in the progression of a number of pathophysiological processes including tumorigenesis. In addition to several well characterized oxygen-dependent modes of regulation, the function of the HIF transcription factor can also be influenced through the action of other regulatory pathways. Misregulation of these factors resulting in inappropriate HIF expression or activity can contribute to the progression of human cancers through the induction of genes promoting angiogenesis, glycolysis, cell survival, and metastasis, among other processes. The candidate tumor suppressor protein inhibitor of growth family member 4 (ING4) has recently been implicated as a repressor of angiogenesis and tumor growth through association with NF-{kappa}B. Here we demonstrate that suppression of ING4 further induces HIF transcriptional activity as well. ING4 directly associates with the HIF prolyl hydroxylase, an Fe(II)-dependent oxygenase previously shown to mediate HIF stability as a function of oxygen availability. However, rather than affecting HIF's stability, ING4 mediates HIF's activity. These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex.

Key Words: prolyl hydroxylase • inhibitor of growth

Abbreviations: HIF, hypoxia inducible factor; VHL, von Hippel–Lindau tumor suppressor gene; HPH, HIF prolyl hydroxylase; FIH-1, factor inhibiting HIF-1; ING, inhibitor of growth family member; PHD, plant homeodomain; siRNA, short interfering RNA.

* To whom correspondence should be addressed. E-mail: bruick{at}

© 2005 by The National Academy of Sciences of the USA

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S. Culurgioni, I. G. Munoz, A. Moreno, A. Palacios, M. Villate, I. Palmero, G. Montoya, and F. J. Blanco (2012)
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A. Saha, A. Bamidele, M. Murakami, and E. S. Robertson (2011)
J. Virol. 85, 2079-2088
   Abstract »    Full Text »    PDF »
Cell Cycle Regulator ING4 Is a Suppressor of Melanoma Angiogenesis That Is Regulated by the Metastasis Suppressor BRMS1.
J. Li and G. Li (2010)
Cancer Res. 70, 10445-10453
   Abstract »    Full Text »    PDF »
Functional impact of cancer-associated mutations in the tumor suppressor protein ING4.
A. Moreno, A. Palacios, J. L. Orgaz, B. Jimenez, F. J. Blanco, and I. Palmero (2010)
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S. Kim, A. L. Welm, and J. M. Bishop (2010)
Cancer Res. 70, 5155-5162
   Abstract »    Full Text »    PDF »
Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells.
R. H. Wenger and D. Hoogewijs (2010)
Am J Physiol Renal Physiol 298, F1287-F1296
   Abstract »    Full Text »    PDF »
Hypoxic Repression of Endothelial Nitric-oxide Synthase Transcription Is Coupled with Eviction of Promoter Histones.
J. E. Fish, M. S. Yan, C. C. Matouk, R. St. Bernard, J. J. D. Ho, A. Gavryushova, D. Srivastava, and P. A. Marsden (2010)
J. Biol. Chem. 285, 810-826
   Abstract »    Full Text »    PDF »
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J. A. Garcia (2009)
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Z. Shao, Y. Zhang, and J. A. Powell-Coffman (2009)
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Decreased Expression of Inhibitor of Growth 4 Correlated with Poor Prognosis of Hepatocellular Carcinoma.
F. Fang, L.-B. Luo, Y.-M. Tao, F. Wu, and L.-Y. Yang (2009)
Cancer Epidemiol. Biomarkers Prev. 18, 409-416
   Abstract »    Full Text »    PDF »
Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response.
O. Aprelikova, S. Pandolfi, S. Tackett, M. Ferreira, K. Salnikow, Y. Ward, J. I. Risinger, J. C. Barrett, and J. Niederhuber (2009)
Cancer Res. 69, 616-624
   Abstract »    Full Text »    PDF »
The ING4 Tumor Suppressor Attenuates NF-{kappa}B Activity at the Promoters of Target Genes.
S. Nozell, T. Laver, D. Moseley, L. Nowoslawski, M. DeVos, G. P. Atkinson, K. Harrison, L. B. Nabors, and E. N. Benveniste (2008)
Mol. Cell. Biol. 28, 6632-6645
   Abstract »    Full Text »    PDF »
Role of ING4 in human melanoma cell migration, invasion and patient survival.
J. Li, M. Martinka, and G. Li (2008)
Carcinogenesis 29, 1373-1379
   Abstract »    Full Text »    PDF »
The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 {alpha} (HIF-1{alpha}) activity: involvement in myeloma-induced angiogenesis.
S. Colla, S. Tagliaferri, F. Morandi, P. Lunghi, G. Donofrio, D. Martorana, C. Mancini, M. Lazzaretti, L. Mazzera, L. Ravanetti, et al. (2007)
Blood 110, 4464-4475
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Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation.
X. Zhang, D.-H. Lin, Y. Jin, K.-S. Wang, Y. Zhang, E. Babilonia, Z. Wang, Z. Wang, G. Giebisch, Z.-G. Han, et al. (2007)
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   Abstract »    Full Text »    PDF »
The Peptidyl Prolyl cis/trans Isomerase FKBP38 Determines Hypoxia-Inducible Transcription Factor Prolyl-4-Hydroxylase PHD2 Protein Stability.
S. Barth, J. Nesper, P. A. Hasgall, R. Wirthner, K. J. Nytko, F. Edlich, D. M. Katschinski, D. P. Stiehl, R. H. Wenger, and G. Camenisch (2007)
Mol. Cell. Biol. 27, 3758-3768
   Abstract »    Full Text »    PDF »
EGLN3 Prolyl Hydroxylase Regulates Skeletal Muscle Differentiation and Myogenin Protein Stability.
J. Fu, K. Menzies, R. S. Freeman, and M. B. Taubman (2007)
J. Biol. Chem. 282, 12410-12418
   Abstract »    Full Text »    PDF »
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J.-C. Shen, M. Unoki, D. Ythier, A. Duperray, L. Varticovski, K. Kumamoto, R. Pedeux, and C. C. Harris (2007)
Cancer Res. 67, 2552-2558
   Abstract »    Full Text »    PDF »
Prolyl Hydroxylase Domain 2 Protein Suppresses Hypoxia-Induced Endothelial Cell Proliferation.
K. Takeda and G.-H. Fong (2007)
Hypertension 49, 178-184
   Abstract »    Full Text »    PDF »
Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor {alpha} Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2.
K. Takeda, V. C. Ho, H. Takeda, L.-J. Duan, A. Nagy, and G.-H. Fong (2006)
Mol. Cell. Biol. 26, 8336-8346
   Abstract »    Full Text »    PDF »
Novel Splice Variants of ING4 and Their Possible Roles in the Regulation of Cell Growth and Motility.
M. Unoki, J. C. Shen, Z.-M. Zheng, and C. C. Harris (2006)
J. Biol. Chem. 281, 34677-34686
   Abstract »    Full Text »    PDF »
The Caenorhabditis elegans rhy-1 Gene Inhibits HIF-1 Hypoxia-Inducible Factor Activity in a Negative Feedback Loop That Does Not Include vhl-1.
C. Shen, Z. Shao, and J. A. Powell-Coffman (2006)
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   Abstract »    Full Text »    PDF »
Posttranslational hydroxylation of ankyrin repeats in I{kappa}B proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH).
M. E. Cockman, D. E. Lancaster, I. P. Stolze, K. S. Hewitson, M. A. McDonough, M. L. Coleman, C. H. Coles, X. Yu, R. T. Hay, S. C. Ley, et al. (2006)
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   Abstract »    Full Text »    PDF »
Regulating cellular oxygen sensing by hydroxylation.
J. Fandrey, T. A. Gorr, and M. Gassmann (2006)
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   Abstract »    Full Text »    PDF »
The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases.
T. Acker, J. Fandrey, and H. Acker (2006)
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   Abstract »    Full Text »    PDF »
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).
M. A. McDonough, V. Li, E. Flashman, R. Chowdhury, C. Mohr, B. M. R. Lienard, J. Zondlo, N. J. Oldham, I. J. Clifton, J. Lewis, et al. (2006)
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   Abstract »    Full Text »    PDF »
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T. Jokilehto, K. Rantanen, M. Luukkaa, P. Heikkinen, R. Grenman, H. Minn, P. Kronqvist, and P. M. Jaakkola (2006)
Clin. Cancer Res. 12, 1080-1087
   Abstract »    Full Text »    PDF »
Suppression of Hypoxia-inducible Factor 1{alpha} (HIF-1{alpha}) Transcriptional Activity by the HIF Prolyl Hydroxylase EGLN1.
K. K. W. To and L. E. Huang (2005)
J. Biol. Chem. 280, 38102-38107
   Abstract »    Full Text »    PDF »
Integration of Oxygen Signaling at the Consensus HRE.
R. H. Wenger, D. P. Stiehl, and G. Camenisch (2005)
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   Abstract »    Full Text »    PDF »

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